The when and how of Src regulation

摘要: Jonathan A. Cooper and Brian Howell Fred Hutchinson Cancer Research Center Seattle, Washington 98104 With the discovery of yrk (Sudol et al., 1993). there are now nine members src gene family. Alternative translational initiation codons tissue-specific splicing result in more than 14 different src-related products being selectively expressed various cell types (reviewed by Cooper, 1990; Bolen 1992). These proteins all protein-tyrosine kinases. The family resemblances extend over but first 60-80 residues total length around 500-530 residues. conserved regions can be divided into five sequence blocks. From N-terminus, these extreme N-terminal myristoylation signal, Src homology (SH) 3 SH2 regions, kinase domain, C-terminal noncatalytic tail. structural similarities allow for common methods regulation. In this essay we focus on structures mechanisms that confer negative regulation discuss how inhibition is relaxed or overridden to activation. Repressed Activated Forms An indication a possible mechanism reversible regu- lation came from observation activated phosphatases present lysates (Courtneidge, 1985). inhibitory tyrosine phosphoryla- tion site was identified tail, Tyr-527 (Cooper 1986) which other members. most naturally occurring, mutants Src, either missing under- phosphorylated compared with wild type, catalytic domain (residue 416) becomes highly Jove Hanafusa, 1987). vitro experiments show changes phosphorylation induce activity: phosphotylation inhibitory, stimula- tory (Kmiecik 1988). phosphorylations viewed as stabilizing an re- pressed conformation altering relative free en- ergies states (see Figure 1, bottom). Each confor- mation stable, molecule flip between them via small energy barrier. cell, appears rapid turnover phosphate at both residues, so would “breathe” two pro- posed conformations. For Src-related kinases, diagrams have same general form, shapes account effects stimulatory phosphorylations. mutations activate been mapped many sites SH3 domains, tail Parsons Weber, 1989). This suggests normal, repressed state maintained cooperative intramolecular interactions in- volving entire part protein. Activating divergent region not described, probably integrated