A MECHANISM FOR C-SRC ACTIVATION IN OVARIAN CANCER

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We have discovered that increased expression of two proteins in ovarian tumors, cSrc and a binding partner and activator for cSrc called AFAP-110, occur together in differentiated and invasive ovarian carcinomas, and that over expression of both these proteins occur in the same tumor cells. As cSrc is known to be activated in ovarian cancer and can promote either invasion or resistance to chemotherapy, the concomitant over expression of a cSrc activating protein indicates a possible mechanism for cSrc activation. AFAP-110 will activate cSrc in response to input signals, which in turn directs tumors to become invasive. Interestingly, we identified in ovarian tumor cells a polymorphic variant of AFAP-110, called AFAP-110403C, which when overexpressed, can activate cSrc independent of an input signal, unlike AFAP-110. It is both a novel and innovative finding to identify a polymorphic variant of a protein (AFAP-110403C) that, under conditions of high expression, has an increased capacity to promote signals that direct tumor progression relative to the more commonly expressed counterpart, (AFAP-110). Thus, we hypothesize that increased expression of both AFAP-110403C and cSrc (together) will result in cSrc activation and promote subsequent tumor invasion in ovarian cancer. In this proposal, we will address the mechanism by which AFAP-110403C is able to independently direct cSrc activation