Inactivation of Platelet-derived Growth Factor Receptor by the Tumor Suppressor PTEN Provides a Novel Mechanism of Action of the Phosphatase

Name: Inactivation of Platelet-derived Growth Factor Receptor by the Tumor Suppressor PTEN Provides a Novel Mechanism of Action of the Phosphatase
Uploaded: 2004-04-01

Lenin Mahimainathan; Goutam Ghosh Choudhury

Basic Information

ID: W2085641812
Title: Inactivation of Platelet-derived Growth Factor Receptor by the Tumor Suppressor PTEN Provides a Novel Mechanism of Action of the Phosphatase
Abstract: PTEN, mutated in a variety of human cancers, is a dual specificity protein phosphatase and also possesses D3-phosphoinositide phosphatase activity on phosphatidylinositol 3,4,5-tris-phosphate (PIP3), a product of phosphatidylinositol 3-kinase. This PIP3 phosphatase activity of PTEN contributes to its tumor suppressor function by inhibition of Akt kinase, a direct target of PIP3. We have recently shown that Akt regulates PDGF-induced DNA synthesis in mesangial cells. In this study, we demonstrate that expression of PTEN in mesangial cells inhibits PDGF-induced Akt activation leading to reduction in PDGF-induced DNA synthesis. As a potential mechanism, we show that PTEN inhibits PDGF-induced protein tyrosine phosphorylation with concomitant dephosphorylation and inactivation of tyrosine phosphorylated and activated PDGF receptor. Recombinant as well as immunopurified PTEN dephosphorylates autophosphorylated PDGF receptor in vitro. Expression of phosphatase deficient mutant of PTEN does not dephosphorylate PDGF-induced tyrosine phosphorylated PDGF receptor. Rather its expression increases tyrosine phosphorylation of PDGF receptor. Furthermore, expression of PTEN attenuated PDGF-induced signal transduction including phosphatidylinositol 3-kinase and Erk1/2 MAPK activities. Our data provide the first evidence that PTEN is physically associated with platelet-derived growth factor (PDGF) receptor and that PDGF causes its dissociation from the receptor. Finally, we show that both the C2 and tail domains of PTEN contribute to binding to the PDGF receptor. These data demonstrate a novel aspect of PTEN function where it acts as an effector for the PDGF receptor function and negatively regulates PDGF receptor activation. PTEN, mutated in a variety of human cancers, is a dual specificity protein phosphatase and also possesses D3-phosphoinositide phosphatase activity on phosphatidylinositol 3,4,5-tris-phosphate (PIP3), a product of phosphatidylinositol 3-kinase. This PIP3 phosphatase activity of PTEN contributes to its tumor suppressor function by inhibition of Akt kinase, a direct target of PIP3. We have recently shown that Akt regulates PDGF-induced DNA synthesis in mesangial cells. In this study, we demonstrate that expression of PTEN in mesangial cells inhibits PDGF-induced Akt activation leading to reduction in PDGF-induced DNA synthesis. As a potential mechanism, we show that PTEN inhibits PDGF-induced protein tyrosine phosphorylation with concomitant dephosphorylation and inactivation of tyrosine phosphorylated and activated PDGF receptor. Recombinant as well as immunopurified PTEN dephosphorylates autophosphorylated PDGF receptor in vitro. Expression of phosphatase deficient mutant of PTEN does not dephosphorylate PDGF-induced tyrosine phosphorylated PDGF receptor. Rather its expression increases tyrosine phosphorylation of PDGF receptor. Furthermore, expression of PTEN attenuated PDGF-induced signal transduction including phosphatidylinositol 3-kinase and Erk1/2 MAPK activities. Our data provide the first evidence that PTEN is physically associated with platelet-derived growth factor (PDGF) receptor and that PDGF causes its dissociation from the receptor. Finally, we show that both the C2 and tail domains of PTEN contribute to binding to the PDGF receptor. These data demonstrate a novel aspect of PTEN function where it acts as an effector for the PDGF receptor function and negatively regulates PDGF receptor activation. The tumor suppressor protein, PTEN (phosphatase and tensin homolog deleted on chromosome ten) is frequently inactivated in advanced cancer including endometrial carcinoma, sporadic glioblastoma, melanoma, meningioma, and breast, prostate, renal, and small cell lung cancer (1Li J. Yen C. Liaw D. Podsypanina K. Bose S. Wang S.I. Puc J. Miliaesis C. Rodgers L. McCombie R. Bigner S.H. Giovanella B.C. Ittmann M. Tycko B. Hibshoosh H. Wigler M.H. Parsons R. Science. 1997; 275: 1943-1947Crossref PubMed Scopus (4235) Google Scholar, 2Cantley L.C. Neel B.G. Proc. Natl. Acad. Sci. U. S. A. 1998; 96: 4240-4245Crossref Scopus (1740) Google Scholar, 3Besson A. Robbins S.M. Yong V.W. Eur. J. Biochem. 1999; 263: 605-611Crossref PubMed Scopus (132) Google Scholar). Germ line mutations are often recognized in familial cancer predisposition syndromes, such as Cowden disease, Lhermitte-Duclos disease, and Bannayan-Zonana syndrome (2Cantley L.C. Neel B.G. Proc. Natl. Acad. Sci. U. S. A. 1998; 96: 4240-4245Crossref Scopus (1740) Google Scholar, 3Besson A. Robbins S.M. Yong V.W. Eur. J. Biochem. 1999; 263: 605-611Crossref PubMed Scopus (132) Google Scholar). Disruption of the mouse PTEN gene demonstrates strong correlation between loss of PTEN function and tumorigenesis (4Di Cristofano A. Pesce B. Cordon-Cardo C. Pandofi P.P. Nat. Genet. 1998; 19: 348-355Crossref PubMed Scopus (1288) Google Scholar, 5Suzuki A. de la Pompa J.L. Stambolic V. Elia A.J. Sasaki T. del Braco Barrantes I. Ho A. Wakeham A. Itie A. Khoo W. Fukumoto M. Mak T.W. Curr. Biol. 1998; 8: 1169-1178Abstract Full Text Full Text PDF PubMed Scopus (695) Google Scholar, 6Podsypanina K. Elleson L.H. Nemes A. Gu J. Tamura M. Yamada K.M. Cordon-Cardo C. Catoretti G. Fisher P.E. Parsons R. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 1563-1568Crossref PubMed Scopus (828) Google Scholar, 7Stambolic V. Tsao M.S. Macpherson D. Suzuki A. Chapman W.B. Mak T.W. Cancer Res. 2000; 60: 3605-3611PubMed Google Scholar). Homozygous mutation of the PTEN locus is embryonically lethal in mice in all genetic backgrounds (4Di Cristofano A. Pesce B. Cordon-Cardo C. Pandofi P.P. Nat. Genet. 1998; 19: 348-355Crossref PubMed Scopus (1288) Google Scholar, 5Suzuki A. de la Pompa J.L. Stambolic V. Elia A.J. Sasaki T. del Braco Barrantes I. Ho A. Wakeham A. Itie A. Khoo W. Fukumoto M. Mak T.W. Curr. Biol. 1998; 8: 1169-1178Abstract Full Text Full Text PDF PubMed Scopus (695) Google Scholar, 6Podsypanina K. Elleson L.H. Nemes A. Gu J. Tamura M. Yamada K.M. Cordon-Cardo C. Catoretti G. Fisher P.E. Parsons R. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 1563-1568Crossref PubMed Scopus (828) Google Scholar, 7Stambolic V. Tsao M.S. Macpherson D. Suzuki A. Chapman W.B. Mak T.W. Cancer Res. 2000; 60: 3605-3611PubMed Google Scholar, 8Stambolic V. Suzuki A. de la Pompa J.L. Brothers G.M. Mirtsos C. Sasaki T. Ruland J. Penninger J.M. Siderovski D.P. Mak T.W. Cell. 1998; 95: 29-38Abstract Full Text Full Text PDF PubMed Scopus (2088) Google Scholar). PTEN heterozygous mice are viable but susceptible to different types of cancer; atypical endometrial hyperplasia occurs in females with 100% penetrance (6Podsypanina K. Elleson L.H. Nemes A. Gu J. Tamura M. Yamada K.M. Cordon-Cardo C. Catoretti G. Fisher P.E. Parsons R. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 1563-1568Crossref PubMed Scopus (828) Google Scholar, 7Stambolic V. Tsao M.S. Macpherson D. Suzuki A. Chapman W.B. Mak T.W. Cancer Res. 2000; 60: 3605-3611PubMed Google Scholar).Structurally, PTEN resembles the dual specificity phosphatases, which dephosphorylate serine, threonine, and tyrosine residues in protein (1Li J. Yen C. Liaw D. Podsypanina K. Bose S. Wang S.I. Puc J. Miliaesis C. Rodgers L. McCombie R. Bigner S.H. Giovanella B.C. Ittmann M. Tycko B. Hibshoosh H. Wigler M.H. Parsons R. Science. 1997; 275: 1943-1947Crossref PubMed Scopus (4235) Google Scholar). However, extensive studies revealed that PTEN is a poor phosphatase for proteins (9Myers M.P. Stolarov J.P. Eng C. Li J. Wang S.I. Wigler M.H. Parsons R. Tonks N.K. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 9052-9057Crossref PubMed Scopus (726) Google Scholar, 10Li L.W. Ernsting B.R. Wishart M.J. Lohse D.L. Dixon J.E. J. Biol. Chem. 1997; 272: 29403-29406Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar, 11Li D.M. Sun H. Cancer Res. 1997; 57: 2124-2129PubMed Google Scholar). Crystal structure of PTEN showed that the active site pocket in the phosphatase domain is very deep and wide unlike the catalytic sites of tyrosine and dual specificity phosphatases that indispensably recognize protein substrates (12Lee J.O. Yang H. Georgescu M.M. Di Cristofano A. Maehama T. Shi Y. Dixon J.E. Pandolfi P. Pavletich N.P. Cell. 1999; 99: 323-334Abstract Full Text Full Text PDF PubMed Scopus (863) Google Scholar). Another feature of the PTEN catalytic pocket is that it is highly basic, indicating that it may accommodate highly acidic substrates. This observation led to the discovery of phosphatidylinositol 3,4,5-trisphosphate (PIP3), 1The abbreviations used are: PIP3, phosphatidylinositol 3,4,5-trisphosphate; PI, phosphatidylinositol; PDGF, platelet-derived growth factor; PDGFR, PDGF receptor β; MAPK, mitogen-activated protein kinase; Ad, adenovirus; GFP, green fluorescent protein; GST, glutathione S-transferase. 1The abbreviations used are: PIP3, phosphatidylinositol 3,4,5-trisphosphate; PI, phosphatidylinositol; PDGF, platelet-derived growth factor; PDGFR, PDGF receptor β; MAPK, mitogen-activated protein kinase; Ad, adenovirus; GFP, green fluorescent protein; GST, glutathione S-transferase. the product of PI 3-kinase, as the primary physiologic substrate of PTEN (13Maehema T. Dixon J.E. J. Biol. Chem. 1998; 273: 13375-13378Abstract Full Text Full Text PDF PubMed Scopus (2571) Google Scholar, 14Myers M.P. Pass I. Batty I.H. van der Kaay J. Stolarov J.P. Hemming B.A. Wigler M.H. Downes C.P. Tonks N.K. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 13513-13518Crossref PubMed Scopus (995) Google Scholar). This observation is also supported by the presence of an increased level of PIP3 in the embryonic fibroblasts isolated from PTEN null mice (7Stambolic V. Tsao M.S. Macpherson D. Suzuki A. Chapman W.B. Mak T.W. Cancer Res. 2000; 60: 3605-3611PubMed Google Scholar, 8Stambolic V. Suzuki A. de la Pompa J.L. Brothers G.M. Mirtsos C. Sasaki T. Ruland J. Penninger J.M. Siderovski D.P. Mak T.W. Cell. 1998; 95: 29-38Abstract Full Text Full Text PDF PubMed Scopus (2088) Google Scholar). Restoration of wild type PTEN in mutated tumor cells has established that the lipid phosphatase activity of the protein is sufficient to repress the tumor cell growth (14Myers M.P. Pass I. Batty I.H. van der Kaay J. Stolarov J.P. Hemming B.A. Wigler M.H. Downes C.P. Tonks N.K. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 13513-13518Crossref PubMed Scopus (995) Google Scholar). This ability of PTEN to antagonize PI 3-kinase signaling by down-regulating its immediate target, Akt serine threonine kinase, is consistent in different cells, although the downstream consequences of this lipid phosphatase activity vary widely and include cell cycle arrest and apoptosis (15Li J. Simpson L. Takahashi M. Miliaresis C. Myers M.P. Tonks N.K. Parsons R. Cancer Res. 1998; 58: 5667-5672PubMed Google Scholar, 16Furmari F.B. Huang J.J. Cavence W.K. Cancer Res. 1998; 58: 5002-5008PubMed Google Scholar, 17Cheney I.W. Neuteboom S.T. Vailliancourt M.T. Ramachandra M. Bookstein R. 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Danen E.H. Takino T. Miyamot S. Yamada K.M. J. Biol. Chem. 1999; 274: 20693-20703Abstract Full Text Full Text PDF PubMed Scopus (323) Google Scholar).Platelet-derived growth factor (PDGF) plays an important role in many proliferative disorders. It stimulates proliferation of a variety of cells, including fibroblast, smooth muscle, glial, and glomerular mesangial cells (21Abboud H.E. Annu. Rev. Physiol. 1995; 57: 297-309Crossref PubMed Scopus (104) Google Scholar, 22Heldin C.H. Westermark B. Physiol. Rev. 1999; 79: 1283-1316Crossref PubMed Scopus (1945) Google Scholar, 23Rosenkranz S. Kazlauskas A. Growth Factors. 1999; 16: 201-216Crossref PubMed Scopus (181) Google Scholar, 24Betsholtz C. Karlsson L. Lindahl P. BioEssays. 2001; 23: 494-507Crossref PubMed Scopus (289) Google Scholar). Four different polypeptide subunits (A, B, C, and D) have been identified, which can give rise to five different isoforms of PDGF (24Betsholtz C. Karlsson L. Lindahl P. BioEssays. 2001; 23: 494-507Crossref PubMed Scopus (289) Google Scholar). Most extensively studied PDGF is formed by dimerization of the B-chain to form BB homodimer or AB heterodimer. Although these dimers bind both PDGF receptors, the affinity for PDGF receptor β (PDGFR) is higher (23Rosenkranz S. Kazlauskas A. Growth Factors. 1999; 16: 201-216Crossref PubMed Scopus (181) Google Scholar, 24Betsholtz C. Karlsson L. Lindahl P. BioEssays. 2001; 23: 494-507Crossref PubMed Scopus (289) Google Scholar, 25Abboud H.E. Bhandari B. Ghosh Choudhury G. Bonventre J. Schlondorf D. Molecular Nephrology: Kidney Function in Health and Disease. Marcel Dekker Inc., New York1995: 573-590Google Scholar). Mice with a targeted homozygous mutation of PDGF B-chain or PDGFR exhibit a common phenotype of lacking glomerular mesangial cells (26Leveen P. Pekny M. Gebre-Medhin S. Swolin B. Larsson E. Betsholtz C. Genes Dev. 1994; 8: 1875-1887Crossref PubMed Scopus (861) Google Scholar, 27Soriano P. Genes Dev. 1994; 8: 1888-1896Crossref PubMed Scopus (791) Google Scholar). Indeed, PDGF is required for the proliferation, survival, and development of mesangial cells (25Abboud H.E. Bhandari B. Ghosh Choudhury G. Bonventre J. Schlondorf D. Molecular Nephrology: Kidney Function in Health and Disease. Marcel Dekker Inc., New York1995: 573-590Google Scholar, 26Leveen P. Pekny M. Gebre-Medhin S. Swolin B. Larsson E. Betsholtz C. Genes Dev. 1994; 8: 1875-1887Crossref PubMed Scopus (861) Google Scholar, 27Soriano P. Genes Dev. 1994; 8: 1888-1896Crossref PubMed Scopus (791) Google Scholar). Expression of both PDGF B-chain and PDGFR is increased in mesangioproliferative glomerulonephritis in which proliferation of mesangial cells is the major pathologic feature (28Jefferson J.A. Johnson R.J. J. Nephrol. 1999; 12: 297-309PubMed Google Scholar). Introduction of antibody against PDGF B-chain ameliorates this disease (29Johnson R.J. Raines E.W. Floege J. Yoshimura A. Pritzl P. Alpers C. Ross R. J. Exp. Med. 1992; 175: 1413-1416Crossref PubMed Scopus (350) Google Scholar). These results suggest that PDGFR signal transduction plays a key role in the development and survival of these cells during embryogenesis as well as contributes to their proliferation in glomerular disease.Binding of PDGF to its cognate receptor induces a conformational change relieving an inhibitory effect of the juxtamembrane domain on the intrinsic tyrosine kinase activity (22Heldin C.H. Westermark B. Physiol. Rev. 1999; 79: 1283-1316Crossref PubMed Scopus (1945) Google Scholar, 25Abboud H.E. Bhandari B. Ghosh Choudhury G. Bonventre J. Schlondorf D. Molecular Nephrology: Kidney Function in Health and Disease. Marcel Dekker Inc., New York1995: 573-590Google Scholar, 30Blume-Jensen P. Hunter T. Nature. 2001; 411: 355-365Crossref PubMed Scopus (3099) Google Scholar). Activated PDGFR then undergoes autophosphorylation to create binding sites for signaling proteins containing Src homology 2 domains (22Heldin C.H. Westermark B. Physiol. Rev. 1999; 79: 1283-1316Crossref PubMed Scopus (1945) Google Scholar, 23Rosenkranz S. Kazlauskas A. Growth Factors. 1999; 16: 201-216Crossref PubMed Scopus (181) Google Scholar). One of the Src homology 2 domain-containing proteins, PI 3-kinase, physically binds to the specific phosphotyrosines of the PDGFR, resulting in its activation to produce PIP3. This D3-phosphoinositide then binds to the pleckstrin homology domain of Akt (also known as PKB) serine threonine kinase to induce translocation to the plasma membrane, where it is phosphorylated and activated by PDK1 and PDK2 kinases (31Frake T.F. Kaplan D.R. Cantley L.C. Toker A. Science. 1997; 275: 665-668Crossref PubMed Scopus (1293) Google Scholar, 32Toker A. Newton A.C. Cell. 2000; 103: 185-188Abstract Full Text Full Text PDF PubMed Scopus (366) Google Scholar). We and others have shown that PI 3-kinase/Akt signal transduction is necessary for PDGF-induced proliferation of various cells including mesangial cells (33Valius M. Kazlauskas A. Cell. 1993; 73: 321-334Abstract Full Text PDF PubMed Scopus (569) Google Scholar, 34Franke T.F. Yang L-I. Chan T.O. Datta K. Kazlauskas A. Morrison D.K. Kaplan D.R. Tsichlis P.N. Cell. 1995; 81: 727-736Abstract Full Text PDF PubMed Scopus (1820) Google Scholar, 35Ghosh Choudhury G. Karamitsos C. Hernandez J. Gentilini A. Bardgette J. Abboud H.E. Am. J. Physiol. 1997; 273: F931-F938Crossref PubMed Google Scholar, 36Ghosh Choudhury G. J. Biol. Chem. 2001; 276: 35636-35643Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar).The lipid phosphatase activity of PTEN has been extensively studied in the context of attenuating the tumor cell growth and apoptosis (37Medema R.H. Kops G.J.P.L. Bos J.L. Burgering B.M.T. Nature. 2000; 404: 782-7787Crossref PubMed Scopus (1216) Google Scholar, 38Gottschalk A.R. Basila D. Wong M. Dean N.M. Brandts C.H. Stokoe D. Haas-Kogan D.A. Cancer Res. 2001; 61: 2105-2111PubMed Google Scholar, 39Weng L-P. Smith W.M. Dahia P.L.M. Ziebold U. Gil E. Lees J.A. Eng C. Cancer Res. 1999; 59: 5808-5814PubMed Google Scholar, 40Davies M.A. Koul D. Dhesi H. Berman R. McDonnell T.J. McConkey D. Yung W.K. Steck P.A. Cancer Res. 1999; 59: 2551-2556PubMed Google Scholar, 41Huang J. Kontos C.D. Arterioscler. Thromb. Vasc. Biol. 2002; 22: 741-751Crossref Scopus (98) Google Scholar). However, its role in normal cell function is largely unknown. PTEN dephosphorylates highly negatively charged artificial substrate in vitro (9Myers M.P. Stolarov J.P. Eng C. Li J. Wang S.I. Wigler M.H. Parsons R. Tonks N.K. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 9052-9057Crossref PubMed Scopus (726) Google Scholar). Upon binding, to PDGF, PDGFR is autophosphorylated in at least 16 tyrosine residues, thus becoming a negatively charged protein. We hypothesized that tyrosine-phosphorylated PDGFR may be a substrate for PTEN and that PTEN may regulate PDGF-induced biological activity by inhibiting the receptor phosphorylation at the membrane. We report here that expression of PTEN in mesangial cells significantly abolished PDGF-induced Akt activation, resulting in inhibition of PDGF-induced DNA synthesis without inducing apoptosis. This action of PTEN was due to inhibition of PDGF-induced tyrosine phosphorylation of proteins. PTEN blocked tyrosine phosphorylation of PDGFR in vivo, resulting in inhibition of its tyrosine kinase activity. PTEN also dephosphorylated PDGFR in vitro. Furthermore, PTEN expression attenuated the PDGFR-mediated PI 3-kinase and MAPK activities. Finally, we provide evidence that PTEN is associated with PDGFR, and the addition of PDGF causes dissociation of this phosphatase from the receptor. We conclude that PTEN is a PDGFR phosphatase and may act to negatively regulate the receptor tyrosine kinase activity.MATERIALS AND METHODSPlasmids and Antibodies—Adenovirus vectors encoding PTEN (Ad PTEN) and phosphatase-dead PTEN C/S (Ad PTEN C/S) were provided by Dr. Ramon Parsons (Department of Pathology and Medicine, Columbia University, New York) and Dr. Christopher D. Kontos (Department of Medicine, Duke University Medical Center, Durham, NC), respectively. pGEX2T-PTEN expressing wild type PTEN and pSGL HA PTEN were kind gifts from Dr. William R. Sellers (Dana-Farber Cancer Institute, Boston, MA). Human PDGFR was subcloned into pGem for making [35S]methionine-labeled receptor protein using TNT transcription coupled translation system (Promega). The coding sequences for catalytic plus C2 domains (amino acids 1–353), C2 plus tail domains (amino acids 177–403) and tail domain (amino acids 354–403) were amplified from wild type PTEN template (pSGL HA PTEN) by PCR and cloned in frame with glutathione S-tranferase in pGSTag bacterial expression vector (42Ron D. Dressler H. BioTechniques. 1992; 13: 866-869PubMed Google Scholar). The sequence identity of the DNA fragments was confirmed by sequencing both strands. The recombinant proteins were purified by GSH-Sepharose. Cat-C2 (catalytic plus C2 domains) and tail domains were cloned into a 3× FLAG CMV7 expression vector. This vector and FLAG antibody were purchased from Sigma. PTEN, p27kip1, Erk1/2 MAPK, epidermal growth factor receptor, PDGFR, and PTP1B antibodies were obtained from Santa Cruz Biotechnology, Inc. (Santa Cruz, CA). Anti-phosphotyrosine antibody 4G10 and Akt antibody were purchased from UBI Inc. Phospho-Akt (Ser473) and phospho-Erk1/2 antibodies were obtained from Cell Signaling. The Annexin V binding assay kit for detection of apoptosis was purchased from Oncogene Science. The LipofectAMINE Plus transfection reagent was obtained from Invitrogen.Cell Culture and Adenovirus Infection—Harlan Sprague-Dawley rat glomerular mesangial cells were cultured in RPMI 1640 medium with 17% fetal bovine serum as described (43Ghosh Choudhury G. Kim Y-S. Simon M. Wozney J. Harris S. Ghosh-Choudhury N. Abboud H.E. J. Biol. Chem. 1999; 274: 10897-10902Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar). NIH 3T3, 293, and HepG2 cells were grown in DMEM with high glucose supplemented with 10% fetal bovine serum. C6 glioma cells were grown in F10 medium with l-glutamine-containing 10% fetal bovine serum. All cells were kept at 37 °C in a humidified atmosphere of 5% CO2. Mesangial cells were made quiescent by serum deprivation for 48 h, whereas the NIH 3T3 and C6 cells were serum-deprived for 24 h. Cells were infected in PBS with Ad PTEN or Ad PTEN C/S at a multiplicity of infection of 50 for 1 h at room temperature followed by the addition of serum-free medium. Experiments were carried out at 24 h postinfection (36Ghosh Choudhury G. J. Biol. Chem. 2001; 276: 35636-35643Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar, 44Ghosh-Choudhury N. Abboud S.L. Nishimura R. Celeste A. Mahimainathan L. Ghosh Choudhury G. J. Biol. Chem. 2002; 277: 33363-33368Abstract Full Text Full Text PDF Scopus (261) Google Scholar).Transfection—HepG2 and mesangial cells were transfected with indicated plasmid constructs using LipofectAMINE Plus reagent as described (36Ghosh Choudhury G. J. Biol. Chem. 2001; 276: 35636-35643Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar, 43Ghosh Choudhury G. Kim Y-S. Simon M. Wozney J. Harris S. Ghosh-Choudhury N. Abboud H.E. J. Biol. Chem. 1999; 274: 10897-10902Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar, 44Ghosh-Choudhury N. Abboud S.L. Nishimura R. Celeste A. Mahimainathan L. Ghosh Choudhury G. J. Biol. Chem. 2002; 277: 33363-33368Abstract Full Text Full Text PDF Scopus (261) Google Scholar).Immunoprecipitation and Immunoblotting—Cells were lysed in radioimmune precipitation buffer (20 mm Tris-HCl, pH 7.5, 150 mm NaCl, 5 mm EDTA, 1 mm Na3VO4, 1 mm phenylmethylsulfonyl fluoride, 0.05% aprotinin, and 1% Nonidet P-40) at 4 °C for 45 min. Lysates were cleared of cell debris by centrifugation, and protein was estimated as described before (43Ghosh Choudhury G. Kim Y-S. Simon M. Wozney J. Harris S. Ghosh-Choudhury N. Abboud H.E. J. Biol. Chem. 1999; 274: 10897-10902Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar, 44Ghosh-Choudhury N. Abboud S.L. Nishimura R. Celeste A. Mahimainathan L. Ghosh Choudhury G. J. Biol. Chem. 2002; 277: 33363-33368Abstract Full Text Full Text PDF Scopus (261) Google Scholar). Equal amounts of cell lysates were immunoblotted or immunoprecipitated with specific antibodies (36Ghosh Choudhury G. J. Biol. Chem. 2001; 276: 35636-35643Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar, 43Ghosh Choudhury G. Kim Y-S. Simon M. Wozney J. Harris S. Ghosh-Choudhury N. Abboud H.E. J. Biol. Chem. 1999; 274: 10897-10902Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar, 44Ghosh-Choudhury N. Abboud S.L. Nishimura R. Celeste A. Mahimainathan L. Ghosh Choudhury G. J. Biol. Chem. 2002; 277: 33363-33368Abstract Full Text Full Text PDF Scopus (261) Google Scholar). For PDGFR immunecomplex kinase assay, the immunoprecipitates were incubated with 20 μCi of [γ-32P]ATP at 30 °C for 15 min, and the phosphorylated receptor was analyzed by 7.5% SDS-gel electrophoresis followed by alkali treatment as described (43Ghosh Choudhury G. Kim Y-S. Simon M. Wozney J. Harris S. Ghosh-Choudhury N. Abboud H.E. J. Biol. Chem. 1999; 274: 10897-10902Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar, 45Ghosh Choudhury G. Ghosh-Choudhury N. Abboud H.E. J. Clin. Invest. 1998; 101: 2751-2760Crossref PubMed Google Scholar). The PI 3-kinase assay was performed in PDGFR immunoprecipitates using PI as substrate in the presence of [γ-32P]ATP essentially as described (44Ghosh-Choudhury N. Abboud S.L. Nishimura R. Celeste A. Mahimainathan L. Ghosh Choudhury G. J. Biol. Chem. 2002; 277: 33363-33368Abstract Full Text Full Text PDF Scopus (261) Google Scholar, 46Ghosh Choudhury G. Wang L-M. Pierce J. Harvey S.A. Sakaguchi A.Y. J. Biol. Chem. 1991; 266: 8068-8072Abstract Full Text PDF PubMed Google Scholar).DNA Synthesis—[3H]Thymidine incorporation into trichloroacetic acid insoluble material was determined as a measure of DNA synthesis as described before (36Ghosh Choudhury G. J. Biol. Chem. 2001; 276: 35636-35643Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar, 43Ghosh Choudhury G. Kim Y-S. Simon M. Wozney J. Harris S. Ghosh-Choudhury N. Abboud H.E. J. Biol. Chem. 1999; 274: 10897-10902Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar).Annexin V Binding and Hoechst Staining for Examining Apoptotic Cells—Mesangial cells were cultured in 6-well plates and infected with Ad GFP or Ad PTEN for 24 h. Apoptosis was measured using an apoptosis detection kit, which utilizes Annexin V-FITC and propidium iodide fluorescence, as described by the vendor. The cells were analyzed by flow cytometry with the excitation wavelength at 488 nm. The FITC signal was detected at 518 nm. The propidium iodide fluorescence was measured at 620 nm. For Hoechst staining, cells in chamber slides were infected with a multiplicity of infection of 50 Ad PTEN or Ad GFP for 48 h. The cells were then fixed with 4% paraformaldehyde and stained with Hoechst 33258 essentially as described (47Ghosh Choudhury G. Zhang J-H. Ghosh-Choudhury N. Abboud H.E. Biochem. Biophys. Res. Commun. 2001; 286: 1183-1190Crossref PubMed Scopus (7) Google Scholar).Protein-Protein Interaction—Protein association was analyzed by incubating [35S]methionine-labeled PTEN with PDGFR immunoprecipitates. After incubation, the beads were washed three times with radioimmune precipitation buffer, twice with 0.5 m LiCl plus 0.1 m Tris-HCl, pH 7.5, and once with PBS before analyzing by SDS-gel electrophoresis and autoradiography. In some experiments, [35S]methionine-labeled PDGFR was incubated with full-length PTEN or domains of PTEN fused to GST immobilized on GSH-Sepharose beads. After incubation, the beads were washed as described above and analyzed by gel electrophoresis and autoradiography.Immunofluorescence Microscopy—Confluent cells in chamber slides were serum starved for 48 h, washed with PBS, fixed, and double-stained with rabbit anti-PDGFR and Cy3-conjugated donkey anti-rabbit antibodies and with anti-PTEN monoclonal antibody and FITC-tagged donkey anti-mouse secondary antibodies. PDGFR and PTEN were visualized with a confocal laser microscopy system (Olympus Fluoview 500). The confocal images were analyzed by FluoView software to determine the colocalization of PDGFR and PTEN.PTEN Lipid Phosphatase Assay—Radiolabeled PI 3-32P was prepared using a PI 3-kinase assay of PDGFR immunoprecipitates from PDGF-stimulated mesangial cells. Equal amounts of radioactive PI 3-32P were incubated with PTEN immunoprecipitates. The reaction products were extracted with chloroform/methanol/12 n HCl (50:100:1) followed by methanol/1 n HCl (1:1). The organic layer was separated by TLC as described (44Ghosh-Choudhury N. Abboud S.L. Nishimura R. Celeste A. Mahimainathan L. Ghosh Choudhury G. J. Biol. Chem. 2002; 277: 33363-33368Abstract Full Text Full Text PDF Scopus (261) Google Scholar, 46Ghosh Choudhury G. Wang L-M. Pierce J. Harvey S.A. Sakaguchi A.Y. J. Biol. Chem. 1991; 266: 8068-8072Abstract Full Text PDF PubMed Google Scholar).RESULTSPTEN Inhibits PDGF-induced DNA Synthesis in the Absence of Apoptosis—Depending on the cell type, PTEN induces either cell cycle arrest or apoptosis of tumor cells by directly down-regulating the level of PIP3, resulting in inhibition of the Akt kinase activity (37Medema R.H. Kops G.J.P.L. Bos J.L. Burgering B.M.T. Nature. 2000; 404: 782-7787Crossref PubMed Scopus (1216) Google Scholar, 38Gottschalk A.R. Basila D. Wong M. Dean N.M. Brandts C.H. Stokoe D. Haas-Kogan D.A. Cancer Res. 2001; 61: 2105-2111PubMed Google Scholar, 39Weng L-P. Smith W.M. Dahia P.L.M. Ziebold U. Gil E. Lees J.A. Eng C. Cancer Res. 1999; 59: 5808-5814PubMed Google Scholar, 40Davies M.A. Koul D. Dhesi H. Berman R. McDonnell T.J. McConkey D. Yung W.K. Steck P.A. Cancer Res. 1999; 59: 2551-2556PubMed Google Scholar). However, its role in normal cells is poorly understood. W
Publication Year: 2004
Publication Date: 2004-04-01
Language: en
Type: article
Indexed In: ['crossref', 'pubmed']

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'https://openalex.org/W4313376294', 'https://openalex.org/W2183062661', 'https://openalex.org/W2134529646', 'https://openalex.org/W2064460444', 'https://openalex.org/W2063872168', 'https://openalex.org/W2046914298', 'https://openalex.org/W2033837164', 'https://openalex.org/W2027995286', 'https://openalex.org/W1580168755'], 'abstract_inverted_index': {'PTEN,': [0, 234, 3051], 'mutated': [1, 235, 1457], 'in': [2, 61, 73, 83, 122, 236, 295, 307, 317, 356, 484, 587, 777, 779, 951, 1023, 1158, 1387, 1456, 1533, 1635, 1680, 1684, 1780, 1972, 2065, 2119, 2122, 2189, 2206, 2262, 2351, 2543, 2654, 2668, 2708, 2754, 2763, 2792, 2795, 2806, 2985, 2990, 3129, 3179, 3195, 3211, 3244, 3425, 3712, 3719, 3858, 3928, 4069, 4243, 4271, 4363], 'a': [3, 9, 24, 46, 88, 211, 237, 243, 258, 280, 322, 445, 1075, 1687, 1788, 1985, 1995, 2186, 2216, 2716, 2727, 2847, 3036, 3212, 3254, 3788, 3934, 4109, 4141], 'variety': [4, 238, 1789], 'of': [5, 26, 33, 43, 49, 71, 105, 125, 129, 145, 150, 199, 214, 239, 260, 267, 277, 283, 305, 339, 359, 363, 379, 384, 433, 448, 637, 647, 770, 945, 1150, 1171, 1217, 1242, 1308, 1316, 1381, 1385, 1452, 1467, 1515, 1540, 1608, 1689, 1695, 1787, 1790, 1877, 1902, 1989, 1998, 2047, 2111, 2125, 2145, 2194, 2209, 2223, 2332, 2347, 2366, 2443, 2537, 2546, 2752, 2765, 2774, 2780, 2784, 2790, 2797, 2832, 2836, 2884, 2898, 3008, 3102, 3215, 3256, 3258, 3270, 3462, 3535, 3635, 3722, 3790, 3936, 3938, 4042, 4129, 4145, 4154, 4246, 4260, 4268, 4273], 'human': [6, 240], 'cancers,': [7, 241], 'is': [8, 171, 242, 405, 481, 774, 1074, 1162, 1222, 1225, 1375, 1470, 1531, 1610, 1898, 1926, 2039, 2117, 2128, 2384, 2438, 2658, 2706, 2825, 2846, 4366], 'dual': [10, 244, 1013, 1174], 'specificity': [11, 245, 1014, 1175], 'protein': [12, 97, 246, 331, 1024, 1180, 1265, 1295, 1469, 1619, 1633, 1678, 2939, 3468], 'phosphatase': [13, 18, 31, 126, 247, 252, 265, 360, 1077, 1160, 1465, 1543, 1615, 1620, 2535, 2838, 2849], 'and': [14, 103, 108, 159, 180, 196, 228, 248, 337, 342, 393, 414, 430, 462, 474, 494, 498, 598, 650, 1020, 1165, 1173, 1547, 1552, 1676, 1797, 1864, 1974, 2045, 2067, 2115, 2192, 2264, 2386, 2390, 2429, 2552, 2731, 2816, 2829, 2850, 2863, 2870, 2886, 2892, 2912, 2965, 2983, 3030, 3044, 3060, 3076, 3086, 3119, 3174, 3233, 3328, 3421, 3449, 3467, 3643, 3848, 3861, 3884, 3956, 4019, 4028, 4060, 4065, 4082, 4087, 4092, 4097, 4104, 4131], 'also': [15, 249, 1376, 1630, 2803], 'possesses': [16, 250], 'D3-phosphoinositide': [17, 251, 2358], 'activity': [19, 32, 253, 266, 1466, 1544, 1607, 1621, 2232, 2536, 2738, 4277], 'on': [20, 254, 478, 1632, 2227, 4048, 4248], 'phosphatidylinositol': [21, 27, 157, 255, 261, 391, 1243, 1251, 1281], '3,4,5-tris-phosphate': [22, 256], '(PIP3),': [23, 257, 1245], 'product': [25, 259, 1307], '3-kinase.': [28, 262], 'This': [29, 263, 1236, 1373, 1513, 2357, 2772, 3042], 'PIP3': [30, 264, 1386], 'PTEN': [34, 72, 94, 117, 130, 151, 170, 200, 215, 268, 306, 328, 351, 364, 385, 404, 434, 449, 472, 640, 648, 772, 935, 1010, 1073, 1151, 1219, 1317, 1393, 1455, 1516, 1609, 1628, 1670, 1692, 2538, 2661, 2730, 2733, 2753, 2775, 2786, 2802, 2809, 2824, 2845, 2867, 2872, 2875, 2911, 2915, 2976, 3248, 3251, 3868, 3941, 3992, 4039, 4043, 4105, 4161, 4252], 'contributes': [35, 269, 2202], 'to': [36, 81, 202, 204, 270, 315, 436, 438, 942, 1239, 1472, 1517, 1873, 1905, 2203, 2211, 2291, 2343, 2354, 2361, 2375, 2378, 2703, 2778, 2853, 4045, 4125], 'its': [37, 140, 184, 271, 374, 418, 1524, 1613, 1617, 2212, 2352, 2652, 2798, 4361], 'tumor': [38, 272, 469, 1458, 1475, 1605, 2549, 4261], 'suppressor': [39, 273, 470, 1606], 'function': [40, 216, 227, 274, 450, 461, 649, 2657], 'by': [41, 275, 1378, 1522, 1612, 1900, 2388, 2739, 2879, 2981, 3014, 3023, 3223, 3267, 3465, 3649, 3654, 3890, 3897, 3989, 4025, 4062, 4122, 4174, 4184, 4263], 'inhibition': [42, 276, 2764, 2779, 2796, 4272], 'Akt': [44, 56, 78, 278, 290, 312, 1527, 2367, 2760, 3077, 4275], 'kinase,': [45, 279, 1530], 'direct': [47, 281], 'target': [48, 282], 'PIP3.': [50, 284, 2356], 'We': [51, 285, 2428, 2720, 2747, 2842], 'have': [52, 286, 1866, 2431], 'recently': [53, 287], 'shown': [54, 288, 2432], 'that': [55, 69, 93, 169, 181, 192, 289, 303, 327, 403, 415, 426, 1072, 1153, 1177, 1223, 1229, 1462, 1627, 2181, 2433, 2722, 2732, 2750, 2823, 2844], 'regulates': [57, 230, 291, 464], 'PDGF-induced': [58, 77, 84, 96, 134, 153, 292, 311, 318, 330, 368, 387, 2441, 2736, 2759, 2766, 2781, 4240], 'DNA': [59, 85, 293, 319, 2767, 3010, 3791, 4241], 'synthesis': [60, 294, 2768, 3792], 'mesangial': [62, 74, 296, 308, 1799, 2001, 2048, 2126, 2447, 2755, 3125, 3329, 4150], 'cells.': [63, 297, 4151], 'In': [64, 298, 1668, 4030], 'this': [65, 299, 1541, 2151, 2837], 'study,': [66, 300], 'we': [67, 91, 190, 301, 325, 424, 2820], 'demonstrate': [68, 210, 302, 444], 'expression': [70, 141, 149, 304, 375, 383, 2751, 2810, 2993, 3040], 'cells': [75, 309, 1459, 1800, 2002, 2049, 2127, 2196, 2445, 2448, 2756, 3126, 3176, 3192, 3205, 3219, 3235, 3330, 3855, 3894, 3927, 3949, 4068, 4262, 4365], 'inhibits': [76, 95, 310, 329], 'activation': [79, 313, 2353], 'leading': [80, 314], 'reduction': [82, 316], 'synthesis.': [86, 320], 'As': [87, 321], 'potential': [89, 323], 'mechanism,': [90, 324], 'show': [92, 191, 326, 425], 'tyrosine': [98, 106, 135, 143, 332, 340, 369, 377, 1021, 1172, 2230, 2712, 2782, 2788, 2799, 2858], 'phosphorylation': [99, 144, 333, 378, 2743, 2783, 2789], 'with': [100, 174, 334, 408, 953, 1984, 2827, 2987, 3133, 3181, 3185, 3198, 3246, 3333, 3542, 3632, 3863, 3900, 3933, 3953, 3958, 3993, 4004, 4009, 4021, 4037, 4079, 4084, 4093, 4108, 4160, 4168], 'concomitant': [101, 335], 'dephosphorylation': [102, 336], 'inactivation': [104, 338], 'phosphorylated': [107, 136, 341, 370, 1624, 2385, 3645], 'activated': [109, 343, 2387], 'PDGF': [110, 120, 137, 146, 182, 206, 225, 231, 344, 354, 371, 380, 416, 440, 459, 465, 1260, 1290, 1878, 1897, 1917, 1922, 1990, 2038, 2113, 2148, 2210, 2833], 'receptor.': [111, 138, 147, 188, 207, 345, 372, 381, 422, 441, 2841], 'Recombinant': [112, 346], 'as': [113, 115, 220, 347, 349, 454, 593, 1311, 1686, 2199, 2201, 2370, 3138, 3341, 3471, 3657, 3717, 3725, 3787, 3793, 3888, 3962, 4057, 4186], 'well': [114, 348, 2200], 'immunopurified': [116, 350], 'dephosphorylates': [118, 352, 1693, 2662], 'autophosphorylated': [119, 353, 2707], 'receptor': [121, 179, 226, 232, 355, 413, 460, 466, 1261, 1291, 1923, 2214, 2742, 2857, 2938, 3646], 'vitro.': [123, 357, 1681, 2807], 'Expression': [124, 358, 2110], 'deficient': [127, 361], 'mutant': [128, 362], 'does': [131, 365], 'not': [132, 366], 'dephosphorylate': [133, 367, 1017, 1672], 'Rather': [139, 373], 'increases': [142, 376], 'Furthermore,': [148, 382, 2808], 'attenuated': [152, 386, 2811], 'signal': [154, 388, 2183, 2436, 3909], 'transduction': [155, 389, 2184, 2437], 'including': [156, 390, 487, 1792, 2446], '3-kinase': [158, 392, 1520, 2815, 3708, 4143], 'Erk1/2': [160, 394, 3053], 'MAPK': [161, 395, 2817], 'activities.': [162, 396, 2818], 'Our': [163, 397], 'data': [164, 209, 398, 443], 'provide': [165, 399, 2821], 'the': [166, 187, 194, 205, 224, 400, 421, 428, 439, 458, 638, 771, 1012, 1154, 1159, 1168, 1218, 1240, 1306, 1312, 1379, 1388, 1463, 1468, 1474, 1537, 1903, 1919, 2042, 2129, 2190, 2224, 2228, 2333, 2344, 2348, 2362, 2379, 2544, 2548, 2741, 2745, 2812, 2830, 2840, 2856, 3009, 3230, 3268, 3628, 3644, 3720, 3891, 3901, 3998, 4053, 4127, 4244, 4249, 4266, 4274], 'first': [167, 401], 'evidence': [168, 402, 2822], 'physically': [172, 406, 2341], 'associated': [173, 407, 2826], 'platelet-derived': [175, 409, 1256, 1286], 'growth': [176, 410, 1257, 1287, 1477, 1773, 2551, 3056], 'factor': [177, 411, 1774, 3057], '(PDGF)': [178, 412, 1775], 'causes': [183, 417, 2834], 'dissociation': [185, 419, 2835], 'from': [186, 420, 1392, 2839, 2919, 2973, 3049, 3065, 3081, 3091, 3106, 3116, 4148], 'Finally,': [189, 423, 2819], 'both': [193, 427, 1694, 1916, 2112, 3016], 'C2': [195, 429, 2953, 2958, 3028], 'tail': [197, 431, 2960, 2966, 3031], 'domains': [198, 432, 2302, 2954, 2961, 3032, 4041], 'contribute': [201, 435], 'binding': [203, 437, 2293, 3097], 'These': [208, 442, 2178], 'novel': [212, 446], 'aspect': [213, 447], 'where': [217, 451, 2382], 'it': [218, 452, 1224, 1230, 2383], 'acts': [219, 453], 'an': [221, 455, 1382, 1777, 2220, 3876], 'effector': [222, 456], 'for': [223, 457, 1078, 1921, 2041, 2295, 2440, 2729, 2935, 2950, 3100, 3226, 3238, 3260, 3456, 3640, 3851, 3869, 3945, 4075], 'negatively': [229, 463, 2664, 2717, 2854], 'activation.': [233, 467], 'The': [468, 2947, 3005, 3018, 3094, 3109, 3706, 3893, 3907, 3915, 3948, 4117, 4163, 4179], 'protein,': [471], '(phosphatase': [473], 'tensin': [475], 'homolog': [476], 'deleted': [477], 'chromosome': [479], 'ten)': [480], 'frequently': [482], 'inactivated': [483], 'advanced': [485], 'cancer': [486, 502, 589], 'endometrial': [488, 948], 'carcinoma,': [489], 'sporadic': [490], 'glioblastoma,': [491], 'melanoma,': [492], 'meningioma,': [493], 'breast,': [495], 'prostate,': [496], 'renal,': [497], 'small': [499], 'cell': [500, 1476, 1549, 2550, 2656, 3463, 3536, 4250, 4255], 'lung': [501], '(1Li': [503, 1025], 'J.': [504, 516, 571, 626, 721, 852, 914, 963, 1026, 1038, 1087, 1121, 1322, 1347, 1430, 1487, 1555, 1644, 1702, 1721, 1734, 1748, 1757, 1965, 2058, 2137, 2158, 2167, 2255, 2499, 2503, 2507, 2518, 2637, 2677, 3148, 3155, 3284, 3313, 3346, 3370, 3377, 3406, 3482, 3489, 3518, 3548, 3572, 3579, 3608, 3667, 3674, 3697, 3740, 3761, 3766, 3799, 3823, 3830, 4201, 4222, 4227], 'Yen': [505, 1027], 'C.': [506, 518, 658, 727, 789, 858, 910, 969, 1028, 1040, 1085, 1426, 1561, 1642, 1843, 1880, 1943, 2014, 2087, 2164, 2497, 2605, 2675, 4329], 'Liaw': [507, 1029], 'D.': [508, 754, 885, 996, 1030, 1401, 1967, 2060, 2257, 2574, 2582, 2616, 2624, 2895, 2996, 4298, 4306, 4340, 4348], 'Podsypanina': [509, 1031], 'K.': [510, 715, 846, 957, 1032, 1704, 1731, 2472], 'Bose': [511, 1033], 'S.': [512, 555, 610, 739, 870, 981, 1034, 1101, 1363, 1503, 1658, 1754, 1829, 1929, 2008, 2081, 2318, 2691, 3150, 3372, 3484, 3574, 3669, 3825], 'Wang': [513, 1035, 1088, 1645, 2678, 3758, 4219], 'S.I.': [514, 1036, 1089, 1646, 2679], 'Puc': [515, 1037], 'Miliaesis': [517, 1039], 'Rodgers': [519, 1041], 'L.': [520, 1042, 1557, 1845, 1882, 1945, 3309, 3402, 3514, 3604, 3736, 4197], 'McCombie': [521, 1043], 'R.': [522, 536, 733, 864, 975, 1044, 1058, 1093, 1567, 1597, 1650, 1708, 1725, 2166, 2620, 2683, 2922, 3305, 3398, 3510, 3600, 3732, 4193, 4344], 'Bigner': [523, 1045], 'S.H.': [524, 1046], 'Giovanella': [525, 1047], 'B.C.': [526, 1048], 'Ittmann': [527, 1049], 'M.': [528, 696, 723, 827, 854, 965, 1050, 1559, 1595, 1700, 1723, 1746, 2006, 2079, 2450, 2576, 3146, 3368, 3480, 3570, 3665, 3821, 4300], 'Tycko': [529, 1051], 'B.': [530, 656, 787, 1052, 1817, 1960, 2010, 2053, 2083, 2236, 2250, 2306], 'Hibshoosh': [531, 1053], 'H.': [532, 1054, 1140, 1185, 2618, 2998, 4342], 'Wigler': [533, 1055, 1090, 1352, 1492, 1647, 2680], 'M.H.': [534, 1056, 1091, 1353, 1493, 1648, 2681], 'Parsons': [535, 732, 863, 974, 1057, 1092, 1566, 1649, 1707, 2682, 2882], 'Science.': [537, 1059, 1711, 2401, 3108], '1997;': [538, 1060, 1103, 1124, 1143, 1660, 2402, 2509, 2693], '275:': [539, 1061, 2403], '1943-1947Crossref': [540, 1062], 'PubMed': [541, 576, 631, 666, 709, 744, 797, 840, 875, 930, 986, 1063, 1106, 1132, 1210, 1333, 1368, 1446, 1508, 1663, 1715, 1740, 1768, 1809, 1823, 1837, 1852, 1889, 1937, 1952, 2020, 2032, 2093, 2105, 2173, 2242, 2281, 2312, 2326, 2405, 2423, 2460, 2488, 2512, 2529, 2566, 2696, 3166, 3295, 3357, 3388, 3500, 3559, 3590, 3685, 3703, 3775, 3810, 3841, 3980, 4236, 4290], 'Scopus': [542, 560, 577, 615, 632, 667, 710, 745, 798, 841, 876, 931, 987, 1064, 1107, 1133, 1211, 1334, 1369, 1447, 1509, 1664, 1716, 1741, 1769, 1810, 1824, 1838, 1853, 1890, 1938, 1953, 2021, 2033, 2094, 2106, 2174, 2243, 2282, 2313, 2327, 2406, 2424, 2461, 2489, 2530, 2567, 2647, 2697, 3167, 3296, 3324, 3358, 3389, 3417, 3501, 3529, 3560, 3591, 3619, 3686, 3751, 3811, 3842, 3981, 4212, 4291], '(4235)': [543, 1065], 'Google': [544, 562, 579, 617, 634, 669, 712, 747, 766, 800, 843, 878, 897, 933, 989, 1008, 1066, 1109, 1135, 1146, 1213, 1336, 1371, 1413, 1449, 1511, 1573, 1586, 1603, 1666, 1718, 1743, 1771, 1812, 1826, 1840, 1855, 1892, 1940, 1955, 2023, 2035, 2096, 2108, 2142, 2176, 2245, 2284, 2315, 2329, 2408, 2426, 2463, 2491, 2513, 2532, 2569, 2590, 2611, 2634, 2649, 2699, 3003, 3169, 3298, 3326, 3360, 3391, 3419, 3503, 3531, 3562, 3593, 3621, 3688, 3704, 3753, 3776, 3813, 3844, 3983, 4214, 4237, 4293, 4314, 4335, 4358], 'Scholar,': [545, 563, 618, 670, 713, 748, 801, 844, 879, 898, 990, 1110, 1136, 1337, 1414, 1574, 1587, 1719, 1744, 1813, 1827, 1841, 1941, 1956, 2024, 2075, 2097, 2246, 2272, 2316, 2409, 2464, 2492, 2514, 2570, 2591, 2612, 2635, 3299, 3361, 3392, 3504, 3563, 3594, 3689, 3754, 3814, 4215, 4294, 4315, 4336], '2Cantley': [546], 'L.C.': [547, 602, 2398], 'Neel': [548, 603], 'B.G.': [549, 604], 'Proc.': [550, 605, 734, 865, 976, 1096, 1358, 1498, 1653, 2686], 'Natl.': [551, 606, 735, 866, 977, 1097, 1359, 1499, 1654, 2687], 'Acad.': [552, 607, 736, 867, 978, 1098, 1360, 1500, 1655, 2688], 'Sci.': [553, 608, 737, 868, 979, 1099, 1361, 1501, 1656, 2689], 'U.': [554, 609, 738, 869, 980, 1100, 1362, 1502, 1657, 2599, 2690, 4323], 'A.': [556, 565, 611, 620, 654, 672, 688, 690, 692, 719, 740, 756, 785, 803, 819, 821, 823, 850, 871, 887, 902, 961, 982, 998, 1102, 1190, 1364, 1403, 1418, 1504, 1659, 1831, 1931, 2160, 2320, 2400, 2411, 2452, 2474, 2501, 2692, 3307, 3400, 3512, 3602, 3734, 4195], '1998;': [557, 612, 663, 701, 794, 832, 922, 1325, 1365, 1438, 1505, 1570, 1583, 1712, 3700], '96:': [558, 613, 742, 873, 984], '4240-4245Crossref': [559, 614], '(1740)': [561, 616], '3Besson': [564, 619], 'Robbins': [566, 621], 'S.M.': [567, 622], 'Yong': [568, 623], 'V.W.': [569, 624], 'Eur.': [570, 625], 'Biochem.': [572, 627, 3973], '1999;': [573, 628, 741, 872, 983, 1202, 1600, 1737, 1760, 1820, 1834, 1934, 2139, 2239, 2309, 2323, 2608, 2631, 3158, 3380, 3492, 3582, 3677, 3833, 4332, 4355], '263:': [574, 629], '605-611Crossref': [575, 630], '(132)': [578, 633], 'Scholar).': [580, 635, 767, 934, 1067, 1147, 1214, 1372, 1450, 1512, 1667, 1856, 1893, 1982, 2036, 2109, 2143, 2177, 2285, 2330, 2427, 2650, 2700, 3004, 3170, 3532, 3622, 3705, 4359], 'Germ': [581], 'line': [582], 'mutations': [583], 'are': [584, 938], 'often': [585], 'recognized': [586], 'familial': [588], 'predisposition': [590], 'syndromes,': [591], 'such': [592], 'Cowden': [594], 'disease,': [595, 597], 'Lhermitte-Duclos': [596], 'Bannayan-Zonana': [599], 'syndrome': [600], '(2Cantley': [601], 'Disruption': [636], 'mouse': [639], 'gene': [641], 'demonstrates': [642], 'strong': [643], 'correlation': [644], 'between': [645], 'loss': [646], 'tumorigenesis': [651], '(4Di': [652, 783], 'Cristofano': [653, 784, 1189], 'Pesce': [655, 786], 'Cordon-Cardo': [657, 726, 788, 857, 968], 'Pandofi': [659, 790], 'P.P.': [660, 791], 'Nat.': [661, 792], 'Genet.': [662, 793], '19:': [664, 795], '348-355Crossref': [665, 796], '(1288)': [668, 799], '5Suzuki': [671, 802], 'de': [673, 804, 903, 1419], 'la': [674, 805, 904, 1420], 'Pompa': [675, 806, 905, 1421], 'J.L.': [676, 807, 906, 1422, 2559, 4283], 'Stambolic': [677, 808], 'V.': [678, 750, 809, 881, 900, 992, 1397, 1416], 'Elia': [679, 810], 'A.J.': [680, 811], 'Sasaki': [681, 812, 911, 1427], 'T.': [682, 813, 912, 1192, 1319, 1428, 1729, 1752, 2276], 'del': [683, 814], 'Braco': [684, 815], 'Barrantes': [685, 816], 'I.': [686, 817, 1341, 1481], 'Ho': [687, 818], 'Wakeham': [689, 820], 'Itie': [691, 822], 'Khoo': [693, 824], 'W.': [694, 825], 'Fukumoto': [695, 826], 'Mak': [697, 759, 828, 890, 919, 1001, 1406, 1435], 'T.W.': [698, 760, 829, 891, 920, 1002, 1407, 1436], 'Curr.': [699, 830], 'Biol.': [700, 831, 1122, 1323, 1736, 1758, 2519, 2643, 3156, 3285, 3314, 3347, 3378, 3407, 3490, 3519, 3549, 3580, 3609, 3675, 3741, 3767, 3800, 3831, 4202, 4228], '8:': [702, 833, 2018, 2030, 2091, 2103], '1169-1178Abstract': [703, 834], 'Full': [704, 706, 835, 837, 925, 927, 1127, 1129, 1205, 1207, 1328, 1330, 1441, 1443, 1763, 1765, 2418, 2420, 2457, 2485, 2524, 2526, 3161, 3163, 3290, 3292, 3319, 3321, 3352, 3354, 3383, 3385, 3412, 3414, 3495, 3497, 3524, 3526, 3554, 3556, 3585, 3587, 3614, 3616, 3680, 3682, 3746, 3748, 3772, 3805, 3807, 3836, 3838, 4207, 4209, 4233], 'Text': [705, 707, 836, 838, 926, 928, 1128, 1130, 1206, 1208, 1329, 1331, 1442, 1444, 1764, 1766, 2419, 2421, 2458, 2486, 2525, 2527, 3162, 3164, 3291, 3293, 3320, 3322, 3353, 3355, 3384, 3386, 3413, 3415, 3496, 3498, 3525, 3527, 3555, 3557, 3586, 3588, 3615, 3617, 3681, 3683, 3747, 3749, 3773, 3806, 3808, 3837, 3839, 4208, 4210, 4234], 'PDF': [708, 839, 929, 1131, 1209, 1332, 1445, 1767, 2422, 2459, 2487, 2528, 3165, 3294, 3323, 3356, 3387, 3416, 3499, 3528, 3558, 3589, 3618, 3684, 3750, 3774, 3809, 3840, 4211, 4235], '(695)': [711, 842], '6Podsypanina': [714, 845], 'Elleson': [716, 847, 958], 'L.H.': [717, 848, 959], 'Nemes': [718, 849, 960], 'Gu': [720, 851, 962, 1701, 1747], 'Tamura': [722, 853, 964, 1722], 'Yamada': [724, 855, 966, 1709, 1732, 1755], 'K.M.': [725, 856, 967, 1710, 1733, 1756], 'Catoretti': [728, 859, 970], 'G.': [729, 860, 971, 1963, 2056, 2253, 2495, 2517, 3142, 3283, 3312, 3345, 3364, 3405, 3476, 3517, 3547, 3566, 3607, 3661, 3692, 3739, 3757, 3798, 3817, 3966, 4200, 4218], 'Fisher': [730, 861, 972], 'P.E.': [731, 862, 973], '1563-1568Crossref': [743, 874, 985], '(828)': [746, 877, 988], '7Stambolic': [749, 880, 991], 'Tsao': [751, 882, 993, 1398], 'M.S.': [752, 883, 994, 1399], 'Macpherson': [753, 884, 995, 1400], 'Suzuki': [755, 886, 901, 997, 1402, 1417], 'Chapman': [757, 888, 999, 1404], 'W.B.': [758, 889, 1000, 1405], 'Cancer': [761, 892, 1003, 1141, 1408, 1568, 1581, 1598, 2585, 2606, 2629, 2925, 4309, 4330, 4353], 'Res.': [762, 893, 1004, 1142, 1409, 1569, 1582, 1599, 2586, 2607, 2630, 3975, 4310, 4331, 4354], '2000;': [763, 894, 1005, 1410, 2415, 2563, 4287], '60:': [764, 895, 1006, 1411], '3605-3611PubMed': [765, 896, 1007, 1412], 'Homozygous': [768], 'mutation': [769, 1988], 'locus': [773], 'embryonically': [775], 'lethal': [776], 'mice': [778, 937, 1395], 'all': [780], 'genetic': [781], 'backgrounds': [782], '8Stambolic': [899, 1415], 'Brothers': [907, 1423], 'G.M.': [908, 1424], 'Mirtsos': [909, 1425], 'Ruland': [913, 1429], 'Penninger': [915, 1431], 'J.M.': [916, 1432], 'Siderovski': [917, 1433], 'D.P.': [918, 1434], 'Cell.': [921, 1201, 1437, 2414, 2453, 2481], '95:': [923, 1366, 1439, 1506], '29-38Abstract': [924, 1440], '(2088)': [932, 1448], 'heterozygous': [936], 'viable': [939], 'but': [940], 'susceptible': [941], 'different': [943, 1534, 1858, 1875], 'types': [944], 'cancer;': [946], 'atypical': [947], 'hyperplasia': [949], 'occurs': [950], 'females': [952], '100%': [954], 'penetrance': [955], '(6Podsypanina': [956], 'Scholar).Structurally,': [1009], 'resembles': [1011], 'phosphatases,': [1015], 'which': [1016, 1869, 2123, 3880], 'serine,': [1018], 'threonine,': [1019], 'residues': [1022], 'However,': [1068, 2651, 4360], 'extensive': [1069], 'studies': [1070], 'revealed': [1071], 'poor': [1076], 'proteins': [1079, 1625, 1698, 2297, 3020], '(9Myers': [1080, 1637, 2670], 'M.P.': [1081, 1339, 1479, 1563, 1638, 2671], 'Stolarov': [1082, 1348, 1488, 1639, 2672], 'J.P.': [1083, 1349, 1489, 1640, 2673], 'Eng': [1084, 1641, 2604, 2674, 4328], 'Li': [1086, 1643, 2676], 'Tonks': [1094, 1356, 1496, 1564, 1651, 2684], 'N.K.': [1095, 1357, 1497, 1565, 1652, 2685], '94:': [1104, 1661, 2694], '9052-9057Crossref': [1105, 1662, 2695], '(726)': [1108, 1665, 2698], '10Li': [1111], 'L.W.': [1112], 'Ernsting': [1113], 'B.R.': [1114], 'Wishart': [1115], 'M.J.': [1116], 'Lohse': [1117], 'D.L.': [1118], 'Dixon': [1119, 1195, 1320], 'J.E.': [1120, 1196, 1321], 'Chem.': [1123, 1324, 1759, 2520, 3157, 3286, 3315, 3348, 3379, 3408, 3491, 3520, 3550, 3581, 3610, 3676, 3742, 3768, 3801, 3832, 4203, 4229], '272:': [1125], '29403-29406Abstract': [1126], '(141)': [1134], '11Li': [1137], 'D.M.': [1138], 'Sun': [1139], '57:': [1144, 1807], '2124-2129PubMed': [1145], 'Crystal': [1148], 'structure': [1149], 'showed': [1152], 'active': [1155], 'site': [1156], 'pocket': [1157, 1221], 'domain': [1161, 2226, 2365, 2967], 'very': [1163], 'deep': [1164], 'wide': [1166], 'unlike': [1167], 'catalytic': [1169, 1220, 2951], 'sites': [1170, 2294], 'phosphatases': [1176], 'indispensably': [1178], 'recognize': [1179], 'substrates': [1181, 1634], '(12Lee': [1182], 'J.O.': [1183], 'Yang': [1184, 2467], 'Georgescu': [1186], 'M.M.': [1187], 'Di': [1188], 'Maehama': [1191], 'Shi': [1193], 'Y.': [1194], 'Pandolfi': [1197], 'P.': [1198, 1847, 1884, 1947, 2004, 2026, 2077, 2099, 2162, 2274], 'Pavletich': [1199], 'N.P.': [1200], '99:': [1203], '323-334Abstract': [1204], '(863)': [1212], 'Another': [1215], 'feature': [1216, 2132], 'highly': [1226, 1233, 2663], 'basic,': [1227], 'indicating': [1228], 'may': [1231, 1629, 2725, 2734, 2851], 'accommodate': [1232], 'acidic': [1234], 'substrates.': [1235], 'observation': [1237, 1374], 'led': [1238], 'discovery': [1241], '3,4,5-trisphosphate': [1244], '1The': [1246, 1276], 'abbreviations': [1247, 1277], 'used': [1248, 1278], 'are:': [1249, 1279], 'PIP3,': [1250, 1280, 4269], '3,4,5-trisphosphate;': [1252, 1282], 'PI,': [1253, 1283], 'phosphatidylinositol;': [1254, 1284], 'PDGF,': [1255, 1285, 2704], 'factor;': [1258, 1288], 'PDGFR,': [1259, 1289, 2349, 2828, 3059], 'β;': [1262, 1292], 'MAPK,': [1263, 1293, 3054], 'mitogen-activated': [1264, 1294], 'kinase;': [1266, 1296], 'Ad,': [1267, 1297], 'adenovirus;': [1268, 1298], 'GFP,': [1269, 1299], 'green': [1270, 1300], 'fluorescent': [1271, 1301], 'protein;': [1272, 1302], 'GST,': [1273, 1303], 'glutathione': [1274, 1304, 2988], 'S-transferase.': [1275, 1305], 'PI': [1309, 1519, 2339, 2434, 2814, 3707, 3716, 4136, 4142, 4156], '3-kinase,': [1310, 2340], 'primary': [1313], 'physiologic': [1314], 'substrate': [1315, 2667, 2728, 3718], '(13Maehema': [1318], '273:': [1326, 2510], '13375-13378Abstract': [1327], '(2571)': [1335], '14Myers': [1338], 'Pass': [1340, 1480], 'Batty': [1342, 1482], 'I.H.': [1343, 1483], 'van': [1344, 1484], 'der': [1345, 1485], 'Kaay': [1346, 1486], 'Hemming': [1350, 1490], 'B.A.': [1351, 1491], 'Downes': [1354, 1494], 'C.P.': [1355, 1495], '13513-13518Crossref': [1367, 1507], '(995)': [1370, 1510], 'supported': [1377], 'presence': [1380, 3721], 'increased': [1383, 2118], 'level': [1384, 4267], 'embryonic': [1389], 'fibroblasts': [1390], 'isolated': [1391], 'null': [1394], '(7Stambolic': [1396], 'Restoration': [1451], 'wild': [1453, 2909, 2974], 'type': [1454, 2910, 2975], 'has': [1460, 2539], 'established': [1461], 'lipid': [1464, 1542, 1614, 2534], 'sufficient': [1471], 'repress': [1473], '(14Myers': [1478], 'ability': [1514], 'antagonize': [1518], 'signaling': [1521, 1697, 2296], 'down-regulating': [1523, 4265], 'immediate': [1525], 'target,': [1526], 'serine': [1528, 2372], 'threonine': [1529, 2373], 'consistent': [1532], 'cells,': [1535, 1685, 1791], 'although': [1536], 'downstream': [1538], 'consequences': [1539], 'vary': [1545], 'widely': [1546], 'include': [1548], 'cycle': [1550, 4256], 'arrest': [1551, 4257], 'apoptosis': [1553, 2553, 3103, 3877, 4259], '(15Li': [1554], 'Simpson': [1556], 'Takahashi': [1558], 'Miliaresis': [1560], 'Myers': [1562], '58:': [1571, 1584], '5667-5672PubMed': [1572], '16Furmari': [1575], 'F.B.': [1576], 'Huang': [1577], 'J.J.': [1578], 'Cavence': [1579], 'W.K.': [1580, 2626, 4350], '5002-5008PubMed': [1585], '17Cheney': [1588], 'I.W.': [1589], 'Neuteboom': [1590], 'S.T.': [1591], 'Vailliancourt': [1592], 'M.T.': [1593], 'Ramachandra': [1594], 'Bookstein': [1596], '59:': [1601, 2609, 2632, 4333, 4356], '2318-2323PubMed': [1602], 'Scholar).Whereas': [1604], 'elicited': [1611], 'activity,': [1616], 'detectable': [1618], 'toward': [1622], 'multiply': [1623], 'suggested': [1626], 'act': [1631, 2852], 'vivo': [1636], 'fact,': [1669], 'can': [1671, 1870], 'focal': [1673], 'adhesion': [1674], 'kinase': [1675, 2231, 2374, 2800, 2859, 3626, 4276], 'adaptor': [1677], 'Shc': [1679], 'When': [1682], 'overexpressed': [1683], 'result': [1688], 'integrin': [1690], 'ligation,': [1691], 'these': [1696, 1913, 2195], '(18Tamura': [1699], 'Matsumuto': [1703], 'Aota': [1705], 'S-I.': [1706], '280:': [1713], '1614-1617Crossref': [1714], '(1073)': [1717], '19Gu': [1720], 'Pankov': [1724], 'Danen': [1726, 1749], 'E.H.J.': [1727], 'Takino': [1728, 1751], 'Matsumoto': [1730], 'Cell': [1735, 3092], '146:': [1738], '389-403Crossref': [1739], '(373)': [1742], '20Tamura': [1745], 'E.H.': [1750], 'Miyamot': [1753], '274:': [1761, 3159, 3381, 3493, 3583, 3678, 3834], '20693-20703Abstract': [1762], '(323)': [1770], 'Scholar).Platelet-derived': [1772], 'plays': [1776, 2185], 'important': [1778], 'role': [1779, 2188, 2653, 4362], 'many': [1781], 'proliferative': [1782], 'disorders.': [1783], 'It': [1784], 'stimulates': [1785], 'proliferation': [1786, 2124, 2205, 2442], 'fibroblast,': [1793], 'smooth': [1794], 'muscle,': [1795], 'glial,': [1796], 'glomerular': [1798, 2000, 2207, 3124], '(21Abboud': [1801], 'H.E.': [1802, 1958, 2051, 2248, 2505, 3154, 3376, 3488, 3578, 3673, 3696, 3829, 3972], 'Annu.': [1803], 'Rev.': [1804, 1819, 2238, 2308], 'Physiol.': [1805, 1818, 2237, 2307, 2508], '1995;': [1806, 2482], '297-309Crossref': [1808], '(104)': [1811], '22Heldin': [1814], 'C.H.': [1815, 2234, 2304, 2580, 4304], 'Westermark': [1816, 2235, 2305], '79:': [1821, 2240, 2310], '1283-1316Crossref': [1822, 2241, 2311], '(1945)': [1825, 2244, 2314], '23Rosenkranz': [1828, 2317], 'Kazlauskas': [1830, 1930, 2319, 2451, 2473], 'Growth': [1832, 1932, 2321], 'Factors.': [1833, 1933, 2322], '16:': [1835, 1935, 2324], '201-216Crossref': [1836, 1936, 2325], '(181)': [1839, 1939, 2328], '24Betsholtz': [1842, 1942], 'Karlsson': [1844, 1881, 1944], 'Lindahl': [1846, 1883, 1946], 'BioEssays.': [1848, 1885, 1948], '2001;': [1849, 1886, 1949, 2278, 2521, 2587, 3287, 3349, 3551, 3802, 3977, 4311], '23:': [1850, 1887, 1950], '494-507Crossref': [1851, 1888, 1951], '(289)': [1854, 1891, 1954], 'Four': [1857], 'polypeptide': [1859], 'subunits': [1860], '(A,': [1861], 'B,': [1862], 'C,': [1863], 'D)': [1865], 'been': [1867, 2540], 'identified,': [1868], 'give': [1871], 'rise': [1872], 'five': [1874], 'isoforms': [1876], '(24Betsholtz': [1879], 'Most': [1894], 'extensively': [1895, 2541], 'studied': [1896, 2542], 'formed': [1899], 'dimerization': [1901], 'B-chain': [1904, 1991, 2114, 2149], 'form': [1906], 'BB': [1907], 'homodimer': [1908], 'or': [1909, 1992, 3249, 3540, 3866, 3942, 4040, 4258], 'AB': [1910], 'heterodimer.': [1911], 'Although': [1912], 'dimers': [1914], 'bind': [1915], 'receptors,': [1918], 'affinity': [1920], 'β': [1924], '(PDGFR)': [1925], 'higher': [1927], '(23Rosenkranz': [1928], '25Abboud': [1957, 2247], 'Bhandari': [1959, 2052, 2249], 'Ghosh': [1961, 2054, 2251, 3310, 3403, 3515, 3605, 3737, 4198], 'Choudhury': [1962, 2055, 2252, 2494, 2516, 3141, 3282, 3311, 3344, 3363, 3404, 3475, 3516, 3546, 3565, 3606, 3660, 3691, 3738, 3756, 3797, 3816, 3965, 4199, 4217], 'Bonventre': [1964, 2057, 2254], 'Schlondorf': [1966, 2059, 2256], 'Molecular': [1968, 2061, 2258], 'Nephrology:': [1969, 2062, 2259], 'Kidney': [1970, 2063, 2260], 'Function': [1971, 2064, 2261], 'Health': [1973, 2066, 2263], 'Disease.': [1975, 2068, 2265], 'Marcel': [1976, 2069, 2266], 'Dekker': [1977, 2070, 2267], 'Inc.,': [1978, 2071, 2268], 'New': [1979, 2072, 2269, 2890], 'York1995:': [1980, 2073, 2270], '573-590Google': [1981, 2074, 2271], 'Mice': [1983], 'targeted': [1986], 'homozygous': [1987], 'PDGFR': [1993, 2116, 2182, 2287, 2705, 2724, 2791, 2805, 2848, 2930, 3624, 3713, 3994, 4034, 4103, 4130, 4146], 'exhibit': [1994], 'common': [1996], 'phenotype': [1997], 'lacking': [1999], '(26Leveen': [2003], 'Pekny': [2005, 2078], 'Gebre-Medhin': [2007, 2080], 'Swolin': [2009, 2082], 'Larsson': [2011, 2084], 'E.': [2012, 2085, 2601, 4325], 'Betsholtz': [2013, 2086], 'Genes': [2015, 2027, 2088, 2100], 'Dev.': [2016, 2028, 2089, 2101], '1994;': [2017, 2029, 2090, 2102], '1875-1887Crossref': [2019, 2092], '(861)': [2022, 2095], '27Soriano': [2025, 2098], '1888-1896Crossref': [2031, 2104], '(791)': [2034, 2107], 'Indeed,': [2037], 'required': [2040], 'proliferation,': [2043], 'survival,': [2044], 'development': [2046, 2191], '(25Abboud': [2050], '26Leveen': [2076], 'mesangioproliferative': [2120], 'glomerulonephritis': [2121], 'major': [2130], 'pathologic': [2131], '(28Jefferson': [2133], 'J.A.': [2134, 2603, 4327], 'Johnson': [2135], 'R.J.': [2136, 2154], 'Nephrol.': [2138], '12:': [2140], '297-309PubMed': [2141], 'Introduction': [2144], 'antibody': [2146, 3046, 3074, 3078, 4096], 'against': [2147], 'ameliorates': [2150], 'disease': [2152], '(29Johnson': [2153], 'Raines': [2155], 'E.W.': [2156], 'Floege': [2157], 'Yoshimura': [2159], 'Pritzl': [2161], 'Alpers': [2163], 'Ross': [2165], 'Exp.': [2168], 'Med.': [2169], '1992;': [2170, 3000], '175:': [2171], '1413-1416Crossref': [2172], '(350)': [2175], 'results': [2179], 'suggest': [2180], 'key': [2187], 'survival': [2193], 'during': [2197], 'embryogenesis': [2198], 'their': [2204], 'disease.Binding': [2208], 'cognate': [2213], 'induces': [2215, 4253], 'conformational': [2217], 'change': [2218], 'relieving': [2219], 'inhibitory': [2221], 'effect': [2222], 'juxtamembrane': [2225], 'intrinsic': [2229], '(22Heldin': [2233, 2303], '30Blume-Jensen': [2273], 'Hunter': [2275], 'Nature.': [2277, 2562, 4286], '411:': [2279], '355-365Crossref': [2280], '(3099)': [2283], 'Activated': [2286], 'then': [2288, 2359, 3951], 'undergoes': [2289], 'autophosphorylation': [2290], 'create': [2292], 'containing': [2298], 'Src': [2299, 2334], 'homology': [2300, 2335, 2364], '2': [2301, 2336], 'One': [2331], 'domain-containing': [2337], 'proteins,': [2338], 'binds': [2342, 2360], 'specific': [2345, 3543], 'phosphotyrosines': [2346], 'resulting': [2350, 2762, 2794, 4270], 'produce': [2355], 'pleckstrin': [2363], '(also': [2368], 'known': [2369], 'PKB)': [2371], 'induce': [2376], 'translocation': [2377], 'plasma': [2380], 'membrane,': [2381], 'PDK1': [2389], 'PDK2': [2391], 'kinases': [2392], '(31Frake': [2393], 'T.F.': [2394, 2466], 'Kaplan': [2395, 2477], 'D.R.': [2396, 2478], 'Cantley': [2397], 'Toker': [2399], '665-668Crossref': [2404], '(1293)': [2407], '32Toker': [2410], 'Newton': [2412], 'A.C.': [2413], '103:': [2416], '185-188Abstract': [2417], '(366)': [2425], 'others': [2430], '3-kinase/Akt': [2435], 'necessary': [2439], 'various': [2444], '(33Valius': [2449], '1993;': [2454], '73:': [2455], '321-334Abstract': [2456], '(569)': [2462], '34Franke': [2465], 'L-I.': [2468], 'Chan': [2469], 'T.O.': [2470], 'Datta': [2471], 'Morrison': [2475], 'D.K.': [2476], 'Tsichlis': [2479], 'P.N.': [2480], '81:': [2483], '727-736Abstract': [2484], '(1820)': [2490], '35Ghosh': [2493], 'Karamitsos': [2496], 'Hernandez': [2498], 'Gentilini': [2500], 'Bardgette': [2502], 'Abboud': [2504, 3153, 3302, 3375, 3395, 3487, 3507, 3577, 3597, 3672, 3695, 3729, 3828, 3971, 4190], 'Am.': [2506], 'F931-F938Crossref': [2511], '36Ghosh': [2515], '276:': [2522, 3288, 3350, 3552, 3803], '35636-35643Abstract': [2523, 3289, 3351, 3553, 3804], '(81)': [2531, 3297, 3359, 3561, 3812], 'Scholar).The': [2533], 'context': [2545], 'attenuating': [2547], '(37Medema': [2554, 4278], 'R.H.': [2555, 4279], 'Kops': [2556, 4280], 'G.J.P.L.': [2557, 4281], 'Bos': [2558, 4282], 'Burgering': [2560, 4284], 'B.M.T.': [2561, 4285], '404:': [2564, 4288], '782-7787Crossref': [2565, 4289], '(1216)': [2568, 4292], '38Gottschalk': [2571, 4295], 'A.R.': [2572, 4296], 'Basila': [2573, 4297], 'Wong': [2575, 4299], 'Dean': [2577, 4301], 'N.M.': [2578, 4302], 'Brandts': [2579, 4303], 'Stokoe': [2581, 4305], 'Haas-Kogan': [2583, 4307], 'D.A.': [2584, 4308], '61:': [2588, 4312], '2105-2111PubMed': [2589, 4313], '39Weng': [2592, 4316], 'L-P.': [2593, 4317], 'Smith': [2594, 4318], 'W.M.': [2595, 4319], 'Dahia': [2596, 4320], 'P.L.M.': [2597, 4321], 'Ziebold': [2598, 4322], 'Gil': [2600, 4324], 'Lees': [2602, 4326], '5808-5814PubMed': [2610, 4334], '40Davies': [2613, 4337], 'M.A.': [2614, 4338], 'Koul': [2615, 4339], 'Dhesi': [2617, 4341], 'Berman': [2619, 4343], 'McDonnell': [2621, 4345], 'T.J.': [2622, 4346], 'McConkey': [2623, 4347], 'Yung': [2625, 4349], 'Steck': [2627, 4351], 'P.A.': [2628, 4352], '2551-2556PubMed': [2633, 4357], '41Huang': [2636], 'Kontos': [2638, 2896], 'C.D.': [2639], 'Arterioscler.': [2640], 'Thromb.': [2641], 'Vasc.': [2642], '2002;': [2644, 3316, 3409, 3521, 3611, 3743, 4204], '22:': [2645], '741-751Crossref': [2646], '(98)': [2648], 'normal': [2655, 4364], 'largely': [2659], 'unknown.': [2660], 'charged': [2665, 2718], 'artificial': [2666], 'vitro': [2669], 'Upon': [2701], 'binding,': [2702], 'at': [2709, 2744, 3208, 3253, 3263, 3277, 3453, 3637, 3904, 3912, 3921], 'least': [2710], '16': [2711], 'residues,': [2713], 'thus': [2714], 'becoming': [2715], 'protein.': [2719], 'hypothesized': [2721], 'tyrosine-phosphorylated': [2723], 'be': [2726], 'regulate': [2735, 2855], 'biological': [2737], 'inhibiting': [2740], 'membrane.': [2746], 'report': [2748], 'here': [2749], 'significantly': [2757], 'abolished': [2758], 'activation,': [2761], 'without': [2769], 'inducing': [2770], 'apoptosis.': [2771], 'action': [2773], 'was': [2776, 2931, 3012, 3104, 3114, 3469, 3647, 3710, 3785, 3873, 3910, 3919, 3987, 4035, 4138, 4182], 'due': [2777], 'proteins.': [2785], 'blocked': [2787], 'vivo,': [2793], 'activity.': [2801], 'dephosphorylated': [2804], 'PDGFR-mediated': [2813], 'addition': [2831, 3269], 'conclude': [2843], 'activity.MATERIALS': [2860], 'AND': [2861], 'METHODSPlasmids': [2862], 'Antibodies—Adenovirus': [2864], 'vectors': [2865], 'encoding': [2866], '(Ad': [2868, 2874], 'PTEN)': [2869, 2980], 'phosphatase-dead': [2871], 'C/S': [2873, 3252], 'C/S)': [2876], 'were': [2877, 2916, 2971, 3021, 3033, 3047, 3063, 3079, 3089, 3127, 3177, 3193, 3206, 3220, 3236, 3242, 3274, 3331, 3423, 3460, 3538, 3630, 3856, 3895, 3931, 3950, 4000, 4055, 4072, 4106, 4120, 4158, 4166], 'provided': [2878], 'Dr.': [2880, 2893, 2920], 'Ramon': [2881], '(Department': [2883, 2897], 'Pathology': [2885], 'Medicine,': [2887, 2899], 'Columbia': [2888], 'University,': [2889], 'York)': [2891], 'Christopher': [2894], 'Duke': [2900], 'University': [2901], 'Medical': [2902], 'Center,': [2903], 'Durham,': [2904], 'NC),': [2905], 'respectively.': [2906], 'pGEX2T-PTEN': [2907], 'expressing': [2908], 'pSGL': [2913], 'HA': [2914, 2979], 'kind': [2917], 'gifts': [2918], 'William': [2921], 'Sellers': [2923], '(Dana-Farber': [2924], 'Institute,': [2926], 'Boston,': [2927], 'MA).': [2928], 'Human': [2929], 'subcloned': [2932], 'into': [2933, 3035, 3780], 'pGem': [2934], 'making': [2936], '[35S]methionine-labeled': [2937, 3991, 4033], 'using': [2940, 3337, 3715, 3875, 4140], 'TNT': [2941], 'transcription': [2942], 'coupled': [2943], 'translation': [2944], 'system': [2945, 4113], '(Promega).': [2946], 'coding': [2948], 'sequences': [2949], 'plus': [2952, 2959, 3027, 4013], '(amino': [2955, 2962, 2968], 'acids': [2956, 2963, 2969], '1–353),': [2957], '177–403)': [2964], '354–403)': [2970], 'amplified': [2972], 'template': [2977], '(pSGL': [2978], 'PCR': [2982], 'cloned': [2984, 3034], 'frame': [2986], 'S-tranferase': [2989], 'pGSTag': [2991], 'bacterial': [2992], 'vector': [2994, 3043], '(42Ron': [2995], 'Dressler': [2997], 'BioTechniques.': [2999], '13:': [3001], '866-869PubMed': [3002], 'sequence': [3006], 'identity': [3007], 'fragments': [3011], 'confirmed': [3013], 'sequencing': [3015], 'strands.': [3017], 'recombinant': [3019], 'purified': [3022], 'GSH-Sepharose.': [3024], 'Cat-C2': [3025], '(catalytic': [3026], 'domains)': [3029], '3×': [3037], 'FLAG': [3038, 3045], 'CMV7': [3039], 'vector.': [3041], 'purchased': [3048, 3080, 3105], 'Sigma.': [3050], 'p27kip1,': [3052], 'epidermal': [3055], 'receptor,': [3058], 'PTP1B': [3061], 'antibodies': [3062, 3088, 3544, 4091], 'obtained': [3064, 3090, 3115], 'Santa': [3066], 'Cruz': [3067], 'Biotechnology,': [3068], 'Inc.': [3069, 3083], '(Santa': [3070], 'Cruz,': [3071], 'CA).': [3072], 'Anti-phosphotyrosine': [3073], '4G10': [3075], 'UBI': [3082], 'Phospho-Akt': [3084], '(Ser473)': [3085], 'phospho-Erk1/2': [3087], 'Signaling.': [3093], 'Annexin': [3095, 3882], 'V': [3096, 3846], 'assay': [3098, 3709, 4144], 'kit': [3099], 'detection': [3101, 3878], 'Oncogene': [3107], 'LipofectAMINE': [3110, 3338], 'Plus': [3111, 3339], 'transfection': [3112], 'reagent': [3113, 3340], 'Invitrogen.Cell': [3117], 'Culture': [3118], 'Adenovirus': [3120], 'Infection—Harlan': [3121], 'Sprague-Dawley': [3122], 'rat': [3123], 'cultured': [3128, 3857], 'RPMI': [3130], '1640': [3131], 'medium': [3132, 3197], '17%': [3134], 'fetal': [3135, 3187, 3201], 'bovine': [3136, 3188, 3202], 'serum': [3137, 3224, 4073], 'described': [3139, 3342, 3472, 3658, 3726, 3794, 3889, 3963, 4058, 4187], '(43Ghosh': [3140, 3474, 3659], 'Kim': [3143, 3365, 3477, 3567, 3662, 3818], 'Y-S.': [3144, 3366, 3478, 3568, 3663, 3819], 'Simon': [3145, 3367, 3479, 3569, 3664, 3820], 'Wozney': [3147, 3369, 3481, 3571, 3666, 3822], 'Harris': [3149, 3371, 3483, 3573, 3668, 3824], 'Ghosh-Choudhury': [3151, 3373, 3485, 3575, 3670, 3693, 3826, 3969], 'N.': [3152, 3301, 3374, 3394, 3486, 3506, 3576, 3596, 3671, 3694, 3728, 3827, 3970, 4189], '10897-10902Abstract': [3160, 3382, 3494, 3584, 3679, 3835], '(54)': [3168, 3390, 3502, 3592, 3687, 3843], 'NIH': [3171, 3231], '3T3,': [3172], '293,': [3173], 'HepG2': [3175], 'grown': [3178, 3194], 'DMEM': [3180], 'high': [3182], 'glucose': [3183], 'supplemented': [3184], '10%': [3186, 3200], 'serum.': [3189, 3203], 'C6': [3190, 3234], 'glioma': [3191], 'F10': [3196], 'l-glutamine-containing': [3199], 'All': [3204], 'kept': [3207], '37': [3209], '°C': [3210, 3455, 3639], 'humidified': [3213], 'atmosphere': [3214], '5%': [3216], 'CO2.': [3217], 'Mesangial': [3218], 'made': [3221], 'quiescent': [3222], 'deprivation': [3225], '48': [3227, 3946, 4076], 'h,': [3228, 4077], 'whereas': [3229], '3T3': [3232], 'serum-deprived': [3237], '24': [3239, 3278, 3870], 'h.': [3240, 3871, 3947], 'Cells': [3241], 'infected': [3243, 3862, 3932], 'PBS': [3245, 4022], 'Ad': [3247, 3250, 3864, 3867, 3940, 3943], 'multiplicity': [3255, 3935], 'infection': [3257, 3937], '50': [3259, 3939], '1': [3261, 3440, 3443], 'h': [3262, 3279], 'room': [3264], 'temperature': [3265], 'followed': [3266, 3653, 4173], 'serum-free': [3271], 'medium.': [3272], 'Experiments': [3273], 'carried': [3275], 'out': [3276], 'postinfection': [3280], '(36Ghosh': [3281, 3343, 3545, 3796], '44Ghosh-Choudhury': [3300, 3393, 3505, 3595], 'S.L.': [3303, 3396, 3508, 3598, 3730, 4191], 'Nishimura': [3304, 3397, 3509, 3599, 3731, 4192], 'Celeste': [3306, 3399, 3511, 3601, 3733, 4194], 'Mahimainathan': [3308, 3401, 3513, 3603, 3735, 4196], '277:': [3317, 3410, 3522, 3612, 3744, 4205], '33363-33368Abstract': [3318, 3411, 3523, 3613, 3745, 4206], '(261)': [3325, 3418, 3530, 3620, 3752, 4213], 'Scholar).Transfection—HepG2': [3327], 'transfected': [3332], 'indicated': [3334], 'plasmid': [3335], 'constructs': [3336], '43Ghosh': [3362, 3564, 3815], 'Scholar).Immunoprecipitation': [3420], 'Immunoblotting—Cells': [3422], 'lysed': [3424], 'radioimmune': [3426, 4005], 'precipitation': [3427, 4006], 'buffer': [3428], '(20': [3429], 'mm': [3430, 3435, 3438, 3441, 3444], 'Tris-HCl,': [3431, 4016], 'pH': [3432, 4017], '7.5,': [3433, 4018], '150': [3434], 'NaCl,': [3436], '5': [3437], 'EDTA,': [3439], 'Na3VO4,': [3442], 'phenylmethylsulfonyl': [3445], 'fluoride,': [3446], '0.05%': [3447], 'aprotinin,': [3448], '1%': [3450], 'Nonidet': [3451], 'P-40)': [3452], '4': [3454], '45': [3457], 'min.': [3458], 'Lysates': [3459], 'cleared': [3461], 'debris': [3464], 'centrifugation,': [3466], 'estimated': [3470], 'before': [3473, 3795, 4023], 'Equal': [3533, 4152], 'amounts': [3534, 4153], 'lysates': [3537], 'immunoblotted': [3539], 'immunoprecipitated': [3541], 'For': [3623, 3924], 'immunecomplex': [3625], 'assay,': [3627], 'immunoprecipitates': [3629, 3714, 4147], 'incubated': [3631, 4036, 4159], '20': [3633], 'μCi': [3634], '[γ-32P]ATP': [3636, 3723], '30': [3638], '15': [3641], 'min,': [3642], 'analyzed': [3648, 3896, 3988, 4061, 4121], '7.5%': [3650], 'SDS-gel': [3651, 4026], 'electrophoresis': [3652, 4027, 4064], 'alkali': [3655], 'treatment': [3656], '45Ghosh': [3690], 'Clin.': [3698], 'Invest.': [3699], '101:': [3701], '2751-2760Crossref': [3702], 'performed': [3711], 'essentially': [3724, 3961], '(44Ghosh-Choudhury': [3727, 4188], '46Ghosh': [3755, 4216], 'L-M.': [3759, 4220], 'Pierce': [3760, 4221], 'Harvey': [3762, 4223], 'S.A.': [3763, 4224], 'Sakaguchi': [3764, 4225], 'A.Y.': [3765, 4226], '1991;': [3769, 4230], '266:': [3770, 4231], '8068-8072Abstract': [3771, 4232], 'Scholar).DNA': [3777], 'Synthesis—[3H]Thymidine': [3778], 'incorporation': [3779], 'trichloroacetic': [3781], 'acid': [3782], 'insoluble': [3783], 'material': [3784], 'determined': [3786], 'measure': [3789], 'Scholar).Annexin': [3845], 'Binding': [3847], 'Hoechst': [3849, 3925, 3959], 'Staining': [3850], 'Examining': [3852], 'Apoptotic': [3853], 'Cells—Mesangial': [3854], '6-well': [3859], 'plates': [3860], 'GFP': [3865, 3944], 'Apoptosis': [3872], 'measured': [3874, 3920], 'kit,': [3879], 'utilizes': [3881], 'V-FITC': [3883], 'propidium': [3885, 3916], 'iodide': [3886, 3917], 'fluorescence,': [3887], 'vendor.': [3892], 'flow': [3898], 'cytometry': [3899], 'excitation': [3902], 'wavelength': [3903], '488': [3905], 'nm.': [3906, 3914, 3923], 'FITC': [3908], 'detected': [3911], '518': [3913], 'fluorescence': [3918], '620': [3922], 'staining,': [3926], 'chamber': [3929, 4070], 'slides': [3930, 4071], 'fixed': [3952], '4%': [3954], 'paraformaldehyde': [3955], 'stained': [3957], '33258': [3960], '(47Ghosh': [3964], 'Zhang': [3967], 'J-H.': [3968], 'Biophys.': [3974], 'Commun.': [3976], '286:': [3978], '1183-1190Crossref': [3979], '(7)': [3982], 'Scholar).Protein-Protein': [3984], 'Interaction—Protein': [3985], 'association': [3986], 'incubating': [3990], 'immunoprecipitates.': [3995, 4162], 'After': [3996, 4051], 'incubation,': [3997, 4052], 'beads': [3999, 4054], 'washed': [4001, 4056, 4078], 'three': [4002], 'times': [4003], 'buffer,': [4007], 'twice': [4008], '0.5': [4010], 'm': [4011, 4015], 'LiCl': [4012], '0.1': [4014], 'once': [4020], 'analyzing': [4024], 'autoradiography.': [4029], 'some': [4031], 'experiments,': [4032], 'full-length': [4038], 'fused': [4044], 'GST': [4046], 'immobilized': [4047], 'GSH-Sepharose': [4049], 'beads.': [4050], 'above': [4059], 'gel': [4063], 'autoradiography.Immunofluorescence': [4066], 'Microscopy—Confluent': [4067], 'starved': [4074], 'PBS,': [4080], 'fixed,': [4081], 'double-stained': [4083], 'rabbit': [4085], 'anti-PDGFR': [4086], 'Cy3-conjugated': [4088], 'donkey': [4089, 4099], 'anti-rabbit': [4090], 'anti-PTEN': [4094], 'monoclonal': [4095], 'FITC-tagged': [4098], 'anti-mouse': [4100], 'secondary': [4101], 'antibodies.': [4102], 'visualized': [4107], 'confocal': [4110, 4118], 'laser': [4111], 'microscopy': [4112], '(Olympus': [4114], 'Fluoview': [4115], '500).': [4116], 'images': [4119], 'FluoView': [4123], 'software': [4124], 'determine': [4126], 'colocalization': [4128], 'PTEN.PTEN': [4132], 'Lipid': [4133], 'Phosphatase': [4134], 'Assay—Radiolabeled': [4135], '3-32P': [4137, 4157], 'prepared': [4139], 'PDGF-stimulated': [4149], 'radioactive': [4155], 'reaction': [4164], 'products': [4165], 'extracted': [4167], 'chloroform/methanol/12': [4169], 'n': [4170, 4176], 'HCl': [4171, 4177], '(50:100:1)': [4172], 'methanol/1': [4175], '(1:1).': [4178], 'organic': [4180], 'layer': [4181], 'separated': [4183], 'TLC': [4185], 'Scholar).RESULTSPTEN': [4238], 'Inhibits': [4239], 'Synthesis': [4242], 'Absence': [4245], 'Apoptosis—Depending': [4247], 'type,': [4251], 'either': [4254], 'directly': [4264], 'poorly': [4367], 'understood.': [4368], 'W': [4369]}, 'cited_by_api_url': 'https://api.openalex.org/works?filter=cites:W2085641812', 'counts_by_year': [{'year': 2023, 'cited_by_count': 1}, {'year': 2021, 'cited_by_count': 1}, {'year': 2020, 'cited_by_count': 2}, {'year': 2019, 'cited_by_count': 1}, {'year': 2018, 'cited_by_count': 3}, {'year': 2017, 'cited_by_count': 1}, {'year': 2016, 'cited_by_count': 6}, {'year': 2015, 'cited_by_count': 4}, {'year': 2014, 'cited_by_count': 3}, {'year': 2013, 'cited_by_count': 4}, {'year': 2012, 'cited_by_count': 14}], 'updated_date': '2024-09-19T14:45:28.931786', 'created_date': '2016-06-24'}

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