Semester

Spring

Date of Graduation

2013

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Microbiology, Immunology, and Cell Biology

Committee Chair

Scott A. Weed

Committee Co-Chair

Laura Gibson

Committee Member

Jun Liu

Committee Member

Karen Martin

Committee Member

Yong Qian

Committee Member

Robert Wysulmerski

Abstract

Src and cortactin are cytoplasmic proteins that are implicated in cancer progression and metastasis. Src is a non-receptor tyrosine kinase that also regulates normal cell homeostasis through phosphorylation of multiple downstream substrates. Cortactin is an actin binding protein and nucleation promoting factor that promotes the formation of stable branching networks within the actin cytoskeleton. Together, these proteins work in concert to promote the invasive and metastatic potential of tumor cells due to tyrosine phosphorylation of cortactin by Src. However, the mechanistic details of the interaction between Src and cortactin have never been elucidated. Collectively, this work aims to define how Src and cortactin interact to drive tumor cell invasion. The first study examines the mechanism of interaction between Src and cortactin, whereby the Src SH2 domain interacts with cortactin via a disulfide bond formation and that this binding event is necessary for the formation of pro-invasive invadopodia. The work here also defines a paradigm shift in how SH2 domain-containing proteins interact with reciprocal binding partners. The second study characterizes potential structural changes in cortactin resultant from phosphorylation by extracellular regulated protein kinases (ERKs) in order to gain structural insight into how cortactin conformation is regulated downstream of growth factor-mediated signaling events. The final study focuses on the creation of cortactin biosensor to directly monitor changes in cortactin conformation using FRET-based imaging. Taken together, these studies provide novel insights into the molecular events involved in regulating invasive tumor cell signal transduction and overall control of cortical actin dynamics during tumor metastasis.

Download

Share

COinS