6464

SHC1

SHC (Src homology 2 domain containing) transforming protein 1;SHC1;SHC (Src homology 2 domain containing) transforming protein 1

SH2 domain protein C1|SHC (Src homology 2 domain-containing) transforming protein 1|SHC-transforming protein 1|SHC-transforming protein 3|SHC-transforming protein A

1q21

protein-coding

The ErbB2 and TGFbeta signaling pathways cooperate to promote the migratory, invasive, and metastatic behavior of breast cancer cells. We previously demonstrated that ShcA is necessary for these synergistic interactions. Through a structure/function approach, we now show that the phosphotyrosine-binding, but not the Src homology 2, domain of ShcA is required for TGFbeta-induced migration and invasion of ErbB2-expressing breast cancer cells. We further demonstrate that the tyrosine phosphorylation sites within ShcA (Tyr(239)/Tyr(240) and Tyr(313)) transduce distinct and non-redundant signals that promote these TGFbeta-mediated effects. We demonstrate that Grb2 is required specifically downstream of Tyr(313), whereas the Tyr(239)/Tyr(240) phosphorylation sites require the Crk adaptor proteins to augment TGFbeta-induced migration and invasion. Furthermore, ShcA Tyr(313) phosphorylation enhances tumor cell survival, and ShcA Tyr(239)/Tyr(240) signaling promotes endothelial cell recruitment into ErbB2-expressing breast tumors in vivo, whereas all three ShcA tyrosine residues are required for efficient breast cancer metastasis to the lungs. Our data uncover a novel ShcA-dependent signaling axis downstream of TGFbeta and ErbB2 that requires both the Grb2 and Crk adaptor proteins to increase the migratory and invasive properties of breast cancer cells. In addition, signaling downstream of specific ShcA tyrosine residues facilitates the survival, vascularization, and metastatic spread of breast tumors.

p66(Shc), one of the SHC1 gene encoding proteins, promotes cell death and reports cell anchorage status, mediating anoikis in vitro and functioning as a metastasis suppressor in vivo. However, very little is known about p66(Shc) gene regulation in cancer cells. Here, we show that methylation of a specific CpG site in the early post-transcriptional region correlates with p66(Shc) repression in clinical human lung cancer samples and cancer cell lines. We also find that the stress related transcription factor Nrf2 associates with p66(Shc) gene promoter in the methylated region, and promotes p66(Shc) transcription. However, p66(Shc) induction by Nrf2 requires demethylation of the Nrf2 binding site in p66(Shc) promoter. Knock-down of p66(Shc) leads to a positive feedback upregulation of Nrf2 expression and accordingly, Nrf2 is found to be highly expressed in tumors with low p66(Shc) expression. Further, Nrf2 expression level positively correlates with tumor grade of patients. Thus, we propose that epigenetic repression of p66(Shc) in cancer cells might be a key factor leading to Nrf2 upregulation, increased cell survival, and tumor progression.