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J Biol Chem. 1993 Jan 15;268(2):1132-40.

Evidence for autoinhibitory regulation of the c-src gene product. A possible interaction between the src homology 2 domain and autophosphorylation site.

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  • 1Laboratory of Molecular Biology, Kobe University, Japan.


In the previous study (Sato, K., Miki, S., Tachibana, H., Hayashi, F., Akiyama, T., and Fukami, Y. (1990) Biochem. Biophys. Res. Commun. 171, 1152-1159), we found a synthetic peptide, termed peptide A, that inhibited the kinase activity of p60v-src. The peptide A sequence corresponds to residues 137 to 157 of p60v-src which are included in the amino-terminal portion of the src homology 2 domain. In this study, we attempted to specify the inhibitory sequence in this domain and to identify its target site. The most potent peptide A derivative was one that corresponds to residues 140 through 157. The target site of peptide A was assumed to reside in the autophosphorylation site of p60v-src, since synthetic peptides containing the sequence Phe424-Pro-Ile-Lys-Trp428 which is present downstream of the autophosphorylated Tyr416 partially counteracted the inhibitory effect of peptide A. An antibody was prepared against one of such target peptides, termed pepY. Cross-linking experiments showed that 125I-labeled peptide A could bind to p60v-src blotted on a membrane, and the binding was blocked by the anti-pepY antibody but not by other anti-p60v-src antibodies. Conversely, immunoblotting of p60v-src with anti-pepY antibody was blocked by the cross-linking of peptide A to p60v-src. To our surprise, anti-pepY antibody did not affect the p60v-src activity. Furthermore, p60c-src was activated 2- to 6-fold by this antibody. These results suggest that the pepY region in the catalytic domain of p60v-src or of p60c-src is not essential for the catalytic activity but rather is involved in the negative regulation of the kinase activity of p60c-src.

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