Role of the erbB3 Gene Product in Breast Cancer Cell Proliferation

摘要

The role of the heregulin receptor ErbB3 in breast cancer cell proliferation was examined. In the first year of funding, we discovered that ErbB3, although possessing a protein tyrosine kinase (PTK) homology domain, is in fact devoid of intrinsic PTK activity. In year two, we demonstrated the critical dependence of heregulin signaling upon the PTK activity of ErbB2 and characterized the interaction of ErbB3 with phosphoinositide (PI) 3-kinase in breast cancer cells. In year three, we identified a single tyrosine residue in ErbB3 responsible for binding the Shc adapter protein, clarified the role of Shc in activation of the Ras/mitogen-activated protein kinase (MAPK) pathway, and began an examination of other ErbB3 tyrosine residues. In the fourth year, we implicated six specific ErbB3 tyrosine residues in mediating interactions with PI 3-kinase and activating its downstream signaling target, the protein kinase Akt. In the fifth year of the project, we investigated a novel mechanism by which the Akt kinase was activated in the absence of a direct interaction of PT 3-kinase with either ErbB2 or ErbB3. Subsequently, we compared the respective contributions of the Ras/MAP% and PI 3- kinase signaling pathways in mediating the cell proliferation and transformation responses resulting from ErbB2/ErbB3 activation.