This K22 Faculty Transition Award is intended to provide the initial support for the independent research program of the candidate, Scott A. Weed. Dr. Weed was appointed to a tenure track position at the University of Colorado Health Sciences Center following completion of his postdoctoral training. He is continuing his studies on the cytoskeletal and signaling protein, cortactin. Dr. Weed's appointment in the Department of Basic Sciences and Oral Research in the School of Dentistry allows him access to all forms of major modern instrumentation for his studies and provides an intellectually stimulating environment. Dr. Weed and his laboratory are involved in a variety of research group meetings involving all Departmental laboratories, he has access to all members of the School of Medicine research community at UCHSC through a joint appointment. His long-term goals involve further elucidation of the role of cortactin and associated proteins in lamellipodia function as it pertains to normal cell signal transduction and motility, and how this protein is malregulated in oral cancer. This proposal specifically addresses the function of cortactin in tyrosine kinase-based cell signaling events. Cortactin is a substrate for Src and is overexpressed in 30 percent of head and neck squamous cell carcinomas (HNSCCs). Based on his preliminary data, it is hypothesized that tyrosine phosphorylation of cortactin involves multiple signaling pathways including in part activation of the Rho GTPases, Rac and Cdc 42. The studies described here will use biochemical and cell biological analysis of fibroblast cell lines to explore the hypothesis that tyrosine phosphorylation of cortactin is central to the assembly of signaling complexes important for cortical actin assembly and motility.
In AIM 1 he will address if cortactin binding to Src activates Src kinase activity, if Rac-induced Src translocation is required for compartmentalization with cortactin in lamellipodia, and to identify proteins interacting with phosphotyrosine residues.
AIM2 will examine the role cortactin plays in ACK phosphorylation events by determining if cortactin is an ACK substrate, if ACK-mediated cortactin phosphorylation effects the actin cytoskeleton, and if phosphorylation of cortactin by ACK is involved in Cdc42-mediated cell motility.
AIM3 will examine the role of the EGF receptor in cortactin tyrosine phosphorylation by determining the kinases involved in EGFR-mediated cortactin phosphorylation, the role cortactin plays in EGF phosphorylation events, and the identity and function of a l25kDa phosphoprotein complexed with cortactin following EGFR activation.
|Kelley, Laura C; Weed, Scott A (2012) Cortactin is a substrate of activated Cdc42-associated kinase 1 (ACK1) during ligand-induced epidermal growth factor receptor downregulation. PLoS One 7:e44363|
|Evans, Jason V; Ammer, Amanda G; Jett, John E et al. (2012) Src binds cortactin through an SH2 domain cystine-mediated linkage. J Cell Sci 125:6185-97|
|Greer Jr, Robert O; Said, Sherif; Shroyer, Kenneth R et al. (2007) Overexpression of cyclin D1 and cortactin is primarily independent of gene amplification in salivary gland adenoid cystic carcinoma. Oral Oncol 43:735-41|
|Rothschild, Brian L; Shim, Ann H; Ammer, Amanda Gatesman et al. (2006) Cortactin overexpression regulates actin-related protein 2/3 complex activity, motility, and invasion in carcinomas with chromosome 11q13 amplification. Cancer Res 66:8017-25|
|Helwani, Falak M; Kovacs, Eva M; Paterson, Andrew D et al. (2004) Cortactin is necessary for E-cadherin-mediated contact formation and actin reorganization. J Cell Biol 164:899-910|
|McWilliams, Ryan R; Gidey, Elizabeth; Fouassier, Laura et al. (2004) Characterization of an ankyrin repeat-containing Shank2 isoform (Shank2E) in liver epithelial cells. Biochem J 380:181-91|
|Fan, Lingzhi; Di Ciano-Oliveira, Caterina; Weed, Scott A et al. (2004) Actin depolymerization-induced tyrosine phosphorylation of cortactin: the role of Fer kinase. Biochem J 380:581-91|
|Abell, Amy N; DeCathelineau, Aimee M; Weed, Scott A et al. (2004) Rac2D57N, a dominant inhibitory Rac2 mutant that inhibits p38 kinase signaling and prevents surface ruffling in bone-marrow-derived macrophages. J Cell Sci 117:243-55|
|Kinley, Andrew W; Weed, Scott A; Weaver, Alissa M et al. (2003) Cortactin interacts with WIP in regulating Arp2/3 activation and membrane protrusion. Curr Biol 13:384-93|
|Head, Julie A; Jiang, Dongyan; Li, Min et al. (2003) Cortactin tyrosine phosphorylation requires Rac1 activity and association with the cortical actin cytoskeleton. Mol Biol Cell 14:3216-29|