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  current news   Press   selected story    
     
  8th October 2009  
 

Participation of Tom1L1 in EGF-stimulated endocytosis of EGF receptor

 
 




Author
Ning Sheng Liu, Li Shen Loo, Eva Loh, Li-Fong Seet and Wanjin Hong

Abstract
The EMBO Journal advance online publication 1 October 2009; doi:10.1038/emboj.2009.282 Although many proteins have been shown to participate in ligand-stimulated endocytosis of EGF receptor (EGFR), the adaptor protein responsible for interaction of activated EGFR with endocytic machinery remains elusive. We show here that 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 and Shc. Cytosolic Tom1L1 is recruited onto the plasma membrane and subsequently redistributes into the early endosome. Mutant forms of Tom1L1 defective in Tyr-phosphorylation or interaction with Grb2 are incapable of interaction with EGFR. These mutants behave as dominant-negative 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/Shc-mediated association of EGFR with Tyr-phosphorylated Tom1L1 to engage the endocytic machinery for endocytosis of the ligand–receptor complex.

 
 

 
 


Figure Legend: Tom1L1 contains a novel clathrin-binding motif important for endocytosis of EGFR. A working model for Tom1L1 to act as a regulated adaptor mediating EGF-stimulated endocytosis of EGFR. On EGF stimulation, EGFR dimerizes, leading to the activation of its cytoplasmic kinase domain and Tyr-phosphorylation at multiple sites, which then serve as docking sites for various signalling proteins such as Shc/Grb2 and Src kinases; activated Src family kinases phosphorylate Y460 of Tom1L1, causing a transient interaction of pTom1L1 with the activated EGFR through Grb2/Shc. By interacting with clathrin, pTom1L1 can bring endocytic machinery to mediate the segregation of activated EGFR into clathrin-coated structures for endocytosis. Other proteins such as dynamin and c-Cbl may be independently recruited to complete the endocytosis. After endocytosis, pTom1L1 becomes dephosphorylated and the dephosphorylated Tom1L1 is retained on the early endosome probably through its interaction with Hrs and TSG101 (Puertollano, 2005), in which it may potentially facilitate the sorting of EGFR into the MVB .

Published in The EMBO Journal online publication ( 1 October 2009/emboj 2009282)

For more information on WanJin HONG’s Lab, Please Click here.