Title: Phosphotyrosyl peptides targeted to the SH2 domain are potent inhibitors of the kinase activity of pp60c-src
Abstract: (Src) is the prototype enzyme of the src-family of protein tyrosine kinases (PTKs). Src participates in several signal transduction cascades, growth signaling, and because of its elevated activity in a wide variety of human cancers is a target for the development of inhibitors for chemotherapeutics [1]. Src is composed of an N-terminal myristoyl site, a unique region of approximately 85 amino acids, an SH3 domain, an SH2 domain, and the catalytic or SH1 domain. The SH2 domain binds phosphotyrosine residues which is proposed to mediate the localization of this PTK to its signal transduction partners. Src kinase activity is down-regulated by intra-molecular binding of the SH2 domain to phosphorylated Tyr, located in the C-terminal tail of the catalytic domain [2]. The crystal structure of the inactivated enzyme [3] illustrates the interactions between the linker region and the SH3 domain with the catalytic domain and the resulting distortions in the latter. Src is activated by phosphorylation on Tyr in the so-called activation loop [2]. The phosphotyrosine peptide from the middle T antigen, EQpYEEIPIYL, has been shown to be a high affinity ligand selective for Src family SH2 domains [4]. This peptide was also shown to activate Src that was autoinhibited by phosphorylation on Tyr [5], presumably by disrupting the intramolecular interaction between the SH2 domain and the phosphorylated C-terminal tail, causing the linker region and SH3 domain to dissociate from the catalytic domain resulting the refolding of the latter to an active conformation. In this study, we show that EQpYEEIPIYL can also be a potent inhibitor of the kinase activity of Src.
Publication Year: 2006
Publication Date: 2006-05-16
Language: en
Type: book-chapter
Indexed In: ['crossref']
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