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Title: The function of TOM1-L1 in bridging EGFR signaling and endocytosis
Keywords: TOM1-L1, EGFR, endocytosis, signaling
Issue Date: 13-Jul-2009
Citation: LIU NINGSHENG (2009-07-13). The function of TOM1-L1 in bridging EGFR signaling and endocytosis. ScholarBank@NUS Repository.
Abstract: The molecular mechanism governing ligand-stimulated endocytosis of receptor tyrosine kinases remains elusive. I show here that EGF stimulates transient tyrosine-phosphorylation of TOM1-L1(TOM-Like 1) by the Src family kinases, resulting in its transient interaction with the activated EGF (Epidermal Gowth Factor) receptor (EGFR) bridged by the receptor-bound Grb2 (Growth Factor Receptor-Bound protein 2). Cytosolic TOM1-L1 is recruited onto the plasma membrane and subsequently redistributes with EGFR into the early endosome. Mutant forms of TOM1-L1 defective in tyrosine-phosphorylation or interaction with Grb2 is incapable of interaction with EGFR and inhibits endocytosis of EGFR. In addition, siRNA (small interference RNA)-mediated knockdown of TOM1-L1 inhibits endocytosis of EGFR. The C-terminal tail of TOM1-L1 contains a novel clathrin-interacting motif, which is important for exogenous TOM1-L1 to rescue endocytosis of EGFR in TOM1-L1 knocked-down cells. These results suggest that EGF triggers a transient association of EGFR with TOM1-L1 to engage the endocytic machinery for endocytosis of the ligand-receptor complex. Moreover, TOM1-L1 interacts with ubiquitin and ESCRT (Endosomal Sorting Complex Required for Transport) family proteins, such as: Hrs (Hepatocyte growth factor Receptor tyrosine kinase Substrate), TSG101 (Tumor Susceptibility Gene 101), STAM1/2 (Signal Transuding Adaptor Molecule 1/2), and it is recruited to endosome upon over-expression HA-Hrs. These results suggest that TOM1-L1 could participate in the machinery for EGFR sorting and degradation. In addition, TOM1-L1 negatively regulates Ras activation upon EGF stimulation and A431 colony formation, which indicate that it may play a negative role in Src kinase signaling.
Appears in Collections:Ph.D Theses (Open)

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