Reciprocal Signaling Between BCAR3 and the Cas Controls Protein Function and Expression

Guerrero, Michael Steven, Department of Microbiology, Immunology, and Cancer Biology, University of Virginia
Bouton, Amy, Department of Microbiology, Immunology, and Cancer Biology, University of Virginia
Parsons, Sarah, Department of Microbiology
Brautigan, David, Department of Microbiology, University of Virginia
Shupnik, Margaret, Department of Medicine, Endocrinology and Metabolism, University of Virginia
Kashatus, David, Department of Microbiology, University of Virginia

Adaptor proteins play a central role in relaying signals downstream of activated cell surface receptors. Adaptors have evolved as catalytically inert molecules that consist only of domains that facilitate protein-protein interactions. These proteins greatly influence signal transduction by serving as molecular scaffolds that physically and functionally bridge other signaling molecules. Through this ability, adaptors regulate many cell processes in a broad range of biological contexts. Their aberrant expression can therefore deregulate critical functions so to promote pathogenic cell behaviors and human diseases such as cancer. The research performed during the completion of this thesis project describes novel aspects of the physical and functional relationship between two adaptor proteins, Breast Cancer Antiestrogen Resistance-3 (BCAR3) and p130 Cas (Cas). These two proteins are components of signaling pathways that regulate cell growth and motility, two processes important to both normal and cancer cells. Moreover, in many human cancers an inverse correlation exists between elevated Cas expression and relapse-free and overall survival times. The work presented here shows that BCAR3 expression augments the activity of Cas signaling pathways, and, reciprocally, Cas acts to positively regulate the expression of BCAR3. We also show that BCAR3 is constitutively bound to Cas and that the two proteins display similar degradation kinetics. These findings suggest that the function of these two proteins are intimately linked and that Cas may cyclically perpetuate its own activity through the promotion of BCAR3 expression. BCAR3 cooperates with Cas to activate c-Src (Src), a tyrosine kinase associated with malignant growth and development. Therefore, the iii results described in this thesis may provide important insights into the mechanism of how the aberrant expression of non-catalytic proteins could influence malignant progression. Lastly, these data provide rationale and support for future work with the specific goal of elucidating the physiological and pathological significance of the signaling relationship between BCAR3 and Cas. Such work will help to determine whether these proteins are viable candidates for use as biomarkers to better direct therapy and improve disease outcome.

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PHD (Doctor of Philosophy)
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