Title: SPD-2/CEP192 and CDK Are Limiting for Microtubule-Organizing Center Function at the Centrosome
Abstract: The centrosome acts as the microtubule-organizing center (MTOC) during mitosis in animal cells. Microtubules are nucleated and anchored by γ-tubulin ring complexes (γ-TuRCs) embedded within the centrosome’s pericentriolar material (PCM). The PCM is required for the localization of γ-TuRCs, and both are steadily recruited to the centrosome, culminating in a peak in MTOC function in metaphase [1Dictenberg J.B. Zimmerman W. Sparks C.A. Young A. Vidair C. Zheng Y. Carrington W. Fay F.S. Doxsey S.J. Pericentrin and gamma-tubulin form a protein complex and are organized into a novel lattice at the centrosome.J. Cell Biol. 1998; 141: 163-174Crossref PubMed Scopus (415) Google Scholar]. In differentiated cells, the centrosome is often attenuated as an MTOC and MTOC function is reassigned to non-centrosomal sites such as the apical membrane in epithelial cells, the nuclear envelope in skeletal muscle, and down the lengths of axons and dendrites in neurons [2Feldman J.L. Priess J.R. A role for the centrosome and PAR-3 in the hand-off of MTOC function during epithelial polarization.Curr. Biol. 2012; 22: 575-582Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar, 3Tassin A.M. Maro B. Bornens M. Fate of microtubule-organizing centers during myogenesis in vitro.J. Cell Biol. 1985; 100: 35-46Crossref PubMed Scopus (233) Google Scholar, 4Baas P.W. Deitch J.S. Black M.M. Banker G.A. Polarity orientation of microtubules in hippocampal neurons: uniformity in the axon and nonuniformity in the dendrite.Proc. Natl. Acad. Sci. USA. 1988; 85: 8335-8339Crossref PubMed Scopus (585) Google Scholar, 5Meads T. Schroer T.A. Polarity and nucleation of microtubules in polarized epithelial cells.Cell Motil. Cytoskeleton. 1995; 32: 273-288Crossref PubMed Scopus (156) Google Scholar, 6Brodu V. Baffet A.D. Le Droguen P.M. Casanova J. Guichet A. A developmentally regulated two-step process generates a noncentrosomal microtubule network in Drosophila tracheal cells.Dev. Cell. 2010; 18: 790-801Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar]. Hyperactive MTOC function at the centrosome is associated with epithelial cancers and with invasive behavior in tumor cells [7Lingle W.L. Lutz W.H. Ingle J.N. Maihle N.J. Salisbury J.L. Centrosome hypertrophy in human breast tumors: implications for genomic stability and cell polarity.Proc. Natl. Acad. Sci. USA. 1998; 95: 2950-2955Crossref PubMed Scopus (433) Google Scholar, 8Lingle W.L. Salisbury J.L. Altered centrosome structure is associated with abnormal mitoses in human breast tumors.Am. J. Pathol. 1999; 155: 1941-1951Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar, 9Pihan G.A. Purohit A. Wallace J. Malhotra R. Liotta L. Doxsey S.J. Centrosome defects can account for cellular and genetic changes that characterize prostate cancer progression.Cancer Res. 2001; 61: 2212-2219PubMed Google Scholar, 10Salisbury J.L. Lingle W.L. White R.A. Cordes L.E.M. Barrett S. Microtubule nucleating capacity of centrosomes in tissue sections.J. Histochem. Cytochem. 1999; 47: 1265-1273Crossref PubMed Scopus (19) Google Scholar, 11Godinho S.A. Picone R. Burute M. Dagher R. Su Y. Leung C.T. Polyak K. Brugge J.S. Théry M. Pellman D. Oncogene-like induction of cellular invasion from centrosome amplification.Nature. 2014; 510: 167-171Crossref PubMed Scopus (282) Google Scholar]. Little is known about the mechanisms that limit MTOC activation at the centrosome. Here, we find that MTOC function at the centrosome is completely inactivated during cell differentiation in C. elegans embryonic intestinal cells and MTOC function is reassigned to the apical membrane. In cells that divide after differentiation, the cellular MTOC state switches between the membrane and the centrosome. Using cell fusion experiments in live embryos, we find that the centrosome MTOC state is dominant and that the inactive MTOC state of the centrosome is malleable; fusion of a mitotic cell to a differentiated or interphase cell results in rapid reactivation of the centrosome MTOC. We show that conversion of MTOC state involves the conserved centrosome protein SPD-2/CEP192 and CDK activity from the mitotic cell.