A novel non-catalytic mechanism employed by the C-terminal Src-homologous kinase to inhibit Src-family kinase activity

Abstract

Although C-terminal Src kinase (CSK)-homologous kinase (CHK) is generally believed to inactivate Src-family tyrosine kinases (SFKs) by phosphorylating their consensus C-terminal regulatory tyrosine (TyrT), exactly how CHK inactivates SFKs is not fully understood. Herein, we report that in addition to phosphorylating TyrT, CHK can inhibit SFKs by a novel non-catalytic mechanism. First, CHK directly binds to the SFK members Hck, Lyn, and Src to form stable protein complexes. The complex formation is mediated by a non-catalytic TyrT-independent mechanism because it occurs even in the absence of ATP or when TyrT of Hck is replaced by phenylalanine. Second, the non-catalytic CHK-SFK interaction a..