SH2 domains and non-receptor tyrosine kinases

The activation of receptor tyrosine kinases results in the recruitment of signaling proteins, principally those containing SH2 domains, leading to the onward transmission of the signal. Our group was the first to report the structure of an SH2 domain bound to a phosphopeptide (Waksman et al., Nature 1992). This was followed by the elucidation of the structure of the auto-inhibited form of a Src-family tyrosine kinase, Hck (Sicheri et al., Nature 1997). This landmark structure, and a similar one determined at the same time in the laboratory of Stephen C. Harrison, revealed how the two targeting domains of the Src family kinases, the SH2 and SH3 domains, control the catalytic activity of the kinase domain when the SH2 domain docks on a phosphotyrosine residue in the C-terminal tail. More recently, we worked out how the tyrosine kinase Csk recognizes Src-family kinases with high specificity and inactivates them by phosphorylation (Levinson et al., Cell 2008). Another important advance concerning SH2 domains was the first report of the structure of the STAT transcription factor bound to DNA, showing how the STATs are activated by a clasping interaction between the SH2 domains and their phosphorylated C-terminal tails (Chen et al., Cell 1998).

Our structural analysis of the Abl tyrosine kinase has been instrumental in explaining the unexpected specificity of the cancer drug Gleevec, an effective treatment for chronic myelogenous leukemia. Our definition of the conformational states of the Abl kinase have laid the intellectual framework for understanding the molecular basis for resistance to Gleevec and for the development of next generation CML treatments by others (Schindler et al., Science 2000; Nagar et al., Cell 2003).

Our work also provided the first view of the autoinhibited structure of the T-cell tyrosine kinase, ZAP-70, explaining how the tandem SH2 domains of this kinase regulate activity (Deindl et al., Cell 2007).

Freedom and Phosphorylation -- An Interview with Src