THE ROLE OF A LYMPHOID-RESTRICTED, GRB2-LIKE SH3-SH2-SH3 PROTEIN IN T-CELL RECEPTOR SIGNALING

We have characterized an SH3-SH2-SH3 linker protein that is prominentl y expressed in lymphoid tissues, This protein has 58% sequence identit y to Grb2, An identical protein called Grap has been found in hematopo ietic cells, In Jurkat cells, T cell receptor activation leads to the association of Grap with phosphoproteins p36/38 and, to a lesser degre e, Shc. This interaction is mediated by the Grap SH2 domain, which has similar binding specificity to the Grb2 SH2 domain, Grap also associa tes via its SH3 domains with Sos, the Ras guanine nucleo tide exchange factor; with dynamin, a GTPase involved in membrane protein trafficki ng; and with Sam68, a nuclear RNA-binding protein that serves as a sub strate of Src kinases during mitosis, T cell activation effects an inc rease in Grap association with p36/38, Shc, Sos, and dynamin, Sam68 bi nding is constitutive, Phospholipase C-gamma 1 and Fyn are also found in activated Grap signaling complexes, although these interactions may not be direct, We conclude that Grap is a prominent component of lymp hocyte receptor signaling, Based on the known functions of bound effec tor molecules, Grap-mediated responses to antigen challenge may includ e endocytosis of the T cell receptor, cellular proliferation, and regu lated entry into the cell cycle.