SH2 domain-mediated interactions represent a crucial step in transmembrane
signaling by receptor tyrosine kinases. SH2 domains recognize phosphotyrosine
(pY) in the context of particular sequence motifs in receptor phosphorylation
sites. However, the modest binding affinity of SH2 domains to pY containing
peptides may not account for and likely represents an oversimplified mechanism
for regulation of selectivity of signaling pathways in living cells. Here we
describe the crystal structure of the activated tyrosine kinase domain of FGFR1
in complex with a phospholipase Cgamma fragment. The structural and biochemical
data and experiments with cultured cells show that the selectivity of
phospholipase Cgamma binding and signaling via activated FGFR1 are determined by
interactions between a secondary binding site on an SH2 domain and a region in
FGFR1 kinase domain in a phosphorylation independent manner. These experiments
reveal a mechanism for how SH2 domain selectivity is regulated in vivo to
mediate a specific cellular process.
