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 mit ogen-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 (Shc Del ta CH1), which lacks the Grb2 binding site Y317 by deletion of collagen-hom ology domain 1, into p185*-transformed NIH3T3 cells. The cellular transform ation phenotypes mere found to be largely suppressed by expression of Shc D elta CH1. Although Shc Delta CH1 still retained another Grb2 binding site ( Y239/240), we did not detect its physical association with Grb2. We also fo und that Shc Delta CH1 could associate with p185*; however, this associatio n did not interfere,vith the endogenous Shc-p185* interaction or the Shc-Gr b2 interaction. In addition, p185*-mediated MAPK and Elk activation likewis e were not inhibited by Shc Delta CH1 expression. Taken together, these dat a demonstrate that Shc Delta CH1 suppresses the transformation induced by a ctivated neu through a MAPK-independent pathway, indicating that Shc may be involved in other signal pathway(s) critical for cellular transformation i n addition to the MAPK pathway.