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EGF stimulates transient tyrosine-phosphorylation of Tom1L1 by the Src family kinases, resulting in transient interaction of Tom1L1 with the activated EGFR bridged by Grb2.Cytosolic Tom1L1 is recruited onto the plasma membrane and subsequently redistributes with EGFR into the early endosome.Mutant forms of Tom1L1 defective in Tyr-phosphorylation or interaction with Grb2 are incapable of interaction with EGFR, suggesting that Tyr-phosphorylation and interaction with Grb2 are important for transient interaction of TomlL1 with EGFR.These mutants behave as dominantnegative mutants to inhibit endocytosis of EGFR.RNAi-mediated knockdown of Tom1L1 inhibits endocytosis of EGFR.The C-terminal tail of Tom1L1 contains a novel clathrin-interacting motif responsible for interaction with the C-terminal region of clathrin heavy chain, which is important for exogenous Tom1L1 to rescue endocytosis of EGFR in Tom1L1 knocked-down cells.These results suggest that EGF triggers a transient Grb2-mediated association of EGFR with Tyr-phosphorylated Tom 1 L 1 to engage the endocytic machinery for endocytosis of the ligand-receptor complex.