pp60c-Src (Src) is the prototype non-receptor tyrosine kinase Src was the first proto-oncogenic protein discovered. The 9 members of the Src family include Src, Lyn, Fyn, Yes, Lck, Hck, Blk, Fgr, and Yrk. They share common structural characteristics that include an N-terminal anchor sequence that allows the protein to the membrane followed by both an SH3 and an SH2 domain, a catalytic domain, an activation loop, and finally a C-term region that binds to the SH2 domain when phosphorylated (Tyr527 in Src that is phosphorylated by Csk). This binding causes Src to adopt an inactive conformation. Mutation of Tyr527 to phenylalanine removes the SH2-binding target, and results in a constitutively active kinase. A second mutation at the conserved lysine residue at the ATP-binding site abolishes kinase activity, but without Tyr527, the conformation of the protein is open, allowing interaction with endogenous activators. Consequently, this double-mutant exhibits a dominant-negative phenotype. Homology to Src in three regions is shared by a number of proteins, SH1 being the catalytic domain, SH2 being a phospho-tyrosine binding domain, and SH3 being a proline-binding domain.
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