Research Interests: The primary focus of our laboratory is to determine molecular mechanisms that integrate signal transduction events with changes in cortical actin dynamics and the role these events play in the motility of normal and transformed cells. Cellular signaling pathways involving activation of tyrosine and serine/threonine kinases as well as small GTPases function cooperatively in reorganizing the actin cytoskeleton in response to extracellular cues or genetic alterations. Actin-associated proteins that govern the formation of actin structures and that also serve as kinase targets likely play important roles in mediating and integrating kinase and GTPase signals. We are currently focusing on the function of one such protein, cortactin.

Cortactin associates with and activates the actin-related (Arp) 2/3 complex, the molecular "machine" that is responsible for the formation of branched actin networks at the leading edge of migrating cells. Arp 2/3 activity is essential for the extension of filopodia and lamellipodia, membrane protrusions that are required for cell movement. Cortactin is also a substrate for several tyrosine kinases; and most notably displays elevated tyrosine phosphorylation levels in v-Src transformed cells. Additionally, tyrosine phosphorylation of cortactin occurs following engagement of a number of transmembrane growth factor and adhesion receptors, events that also trigger cortical actin reorganization. While the precise function of cortactin remains largely unknown, these observations suggest that cortactin plays an important role in mediating (or integrating) tyrosine phosphorylation-based signals involved in cortical actin remodeling. We are currently examining the participation of the small GTPases Cdc42 and Rac, two proteins that also regulate Arp2/3 activity, and their role in regulating the spatial and temporal context of cortactin tyrosine phosphorylation. In addition, we are seeking to identify novel cortactin interacting proteins and to determine their impact on cortactin function. Finally, the amplification of the cortactin locus is found in a number of human tumors, most frequently in squamous cell carcinomas of the oral cavity. To this end we are examining the impact of cortactin overexpression on tyrosine kinase and actin signaling in tumor cell lines that overproduce cortactin.