Ack-1 Tyrosine Kinase Regulates Integrin Signaling Leading to Breast Cell Migration
Annual Summary rept. 1 Mar 2003-28 Feb 2004
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Appropriate interactions between breast cells and the ECM via alpha2beta1 integrin help to establish normal cellular structure and differentiation. During transformation to a carcinoma, these normal interactions with the ECM are profoundly altered, resulting in cells that lose their specialization and lose control of their growth. Ultimately, these cells become invasive, and then migrate through the connective tissue environment to form distant metastases. We have previously found that Ack-l tyrosine kinase enhances alpha2beta1 integrin-induced cell migration and regulates signaling components downstream of the integrin. In the course of this research I have determined that Ack-l interacts with pl30Cas and FAK via its SH3 domain, and that the interactions with pl30Cas and Crk occur via its proline rich region. I have also determined that the interaction between Ack-l and Crk occurs in T47D cells in a collagen dependent manner. Additionally, I find that Ack-l binds to C3G, an exchange factor for the small GTPases Rap and R-Ras. Ack-1 not only binds to these molecules but also modulates their phosphorylation, since over expression of wild type Ack-1 results in hyper-phosphorylation of pl30Cas, FAK and C3G. Since phosphorylation of these molecules is crucial for their function and activation of downstream signaling pathways, I am investigating the role of Ack-1 in these processes.