Signalling pathways involved in cell transformation and conversion of phenotype

Polypeptides encoded by several oncogenes or tumor suppressor genes are involved in signalling pathways/networks mediating the transformation and phenotype conversion of cells. p185neu, a member of the ErbB family of receptor tyrosine kinases (RTKs), contributes to transformation by its capability to dimerize with itself and other receptors as well as via its kinase activity. A single residue, tyrosine882, may be important because of its location in the kinase domain. Substitution of tyrosine882 with phenylalanine, which diminished the enzymatic tyrosine kinase activity of p185neu, significantly decreased the transforming potential of activated oncogenic p185 neu.; To understand the growth inhibitory activity of BRCA1, a breast/ovarian cancer suppressor gene, we analyzed the relationship of the products of neu and BRCA1, both known to be important in the transformation of breast cells. BRCA1 was identified as a tyrosine phosphorylated protein localized primarily in the nucleus of several breast cancer cell lines. The tyrosine phosphorylation pattern of BRCA1 was also related to events in the cell cycle. In transformed murine and human cells, phosphorylated-tyrosine levels of BRCA1 were inversely correlated with the activity of the erbB family receptor-tyrosine-kinases as well as with the transformed growth features of these cells. More directly, BRCA1 inhibited transformation mediated by oncogenic neu in focus formation assays. Further analysis revealed that c-myc, a proto-oncogene, was unexpectedly required for neu-mediated transformation. Interestingly, c-Myc polypeptides can directly associate with BRCA1. BRCA1 represses Myc-mediated transcription and reverses the phenotype of embryonic fibroblasts transformed by the activation of Myc and Ras.; Taken together, our data suggest that neu, BRCA1, and c-myc are three critical elements involved in a linked signalling pathway involved in cell transformation and phenotype conversion. Acting as a growth repressor in this pathway, BRCA1 can interact and block functional c-Myc which is required for neu mediated transformation. BRCA1 also associates with VCP (Valise containing protein), an ATP binding protein that may transport ATP molecules for recognition of mis-matched DNA. Combined with other observations that BRCA1 can interact with some proteins involved in DNA repair, our studies also suggest that BRCA1 may connect this putative signalling pathway to DNA damage repair.