Collagen-homology domain 1 deletion mutant of Shc suppresses transformation mediated by neu through a MAPK-independent pathway.
Shc proteins are implicated in coupling receptor tyrosine kinase to the mitogen-activated protein kinase (MAPK) pathway by recruiting Grb2/SOS to the plasma membrane. To better understand the role of Shc in the oncogenesis by point-mutation activated neu (p185*), we transfected a Shc mutant (ShcdeltaCHI), which lacks the Grb2 binding site Y317 by deletion of collagen-homology domain 1, into p185*-transformed NIH3T3 cells. The cellular transformation phenotypes were found to be largely suppressed by expression of ShcdeltaCH1. Although ShcdeltaCH1 still retained another Grb2 binding site (Y239/240), we did not detect its physical association with Grb2. We also found that ShcdeltaCH1 could associate with p185*; however, this association did not interfere with the endogenous Shc-p185* interaction or the Shc-Grb2 interaction. In addition, p185*-mediated MAPK and Elk activation likewise were not inhibited by ShcdeltaCH1 expression. Taken together, these data demonstrate that ShcdeltaCH1 suppresses the transformation induced by activated neu through a MAPK-independent pathway, indicating that Shc may be involved in other signal pathway(s) critical for cellular transformation in addition to the MAPK pathway.
Li
K
K
Department of Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
Shao
R
R
Hung
M C
MC
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D001665:Binding Sites / Q000235:genetics; D002471:Cell Transformation, Neoplastic; D003094:Collagen / Q000235:genetics*; D004789:Enzyme Activation; D051380:GRB2 Adaptor Protein; D017354:Point Mutation; D011485:Protein Binding; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D017384:Sequence Deletion; D017386:Sequence Homology, Amino Acid; D055765:Shc Signaling Adaptor Proteins; D014162:Transfection
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D003094:Collagen; D051380:GRB2 Adaptor Protein; D011506:Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D055765:Shc Signaling Adaptor Proteins