EphrinB ligands recruit GRIP family PDZ adaptor proteins into raft membrane microdomains

Transmembrane ephrinB proteins have important functions during embryonic pa tterning as ligands for Eph receptor tyrosine kinases and presumably as sig nal-transducing receptor-like molecules. Consistent with "reverse" signalin g, ephrinB1 is localized in sphingo-lipid/cholesterol-enriched raft microdo mains, platforms for the localized concentration and activation of signalin g molecules. Glutamate receptor-interacting protein (GRIP) and a highly rel ated protein, which we have termed GRIP2, are recruited into these rafts th rough association with the c-terminal PDZ target site of ephrinB1. Stimulat ion of ephrinB1 with soluble EphB2 receptor ectodomain causes the formation of large raft patches that also contain GRIP proteins. Moreover, a GRIP-as sociated serine/threonine kinase activity is recruited into ephrinB1-GRIP c omplexes. Our findings suggest that GRIP proteins provide a scaffold for th e assembly of a multiprotein signaling complex downstream of ephrinB ligand s.