Disulfide Bridging the Gap between Src and Cortactin: A New Paradigm in SH2 Domain-mediated Signaling

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.

Name thesis:degree_name

PhD

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Microbiology, Immunology, and Cell Biology

Year dc:date.available

2013

Author dc:creator

• Evans, Jason VanBuren

Contributors dc:contributor

• Scott A. Weed
• Laura Gibson
• Jun Liu
• Karen Martin
• Yong Qian
• Robert Wysulmerski

• Biochemistry
• Cellular biology

Identifier

https://researchrepository.wvu.edu/etd/427

OAI identifier oai:identifier

oai:researchrepository.wvu.edu:etd-1430