Date of Graduation
5-2015
Document Type
Dissertation (PhD)
Program Affiliation
Biomedical Sciences
Degree Name
Doctor of Philosophy (PhD)
Advisor/Committee Chair
JOHN E. LADBURY
Committee Member
SWATHI ARUR
Committee Member
CARMEN W. DESSAUER
Committee Member
JESSICA K. TYLER
Committee Member
NAOTO T. UENO
Abstract
Cells respond to environmental changes by converting extracellular signals into intracellular events. Scaffolding proteins play important roles in generating specificity in intracellular signaling through the combinatorial use of protein domains and posttranslational modifications. Using the scaffold Shc (Src-homology collagen-like) as a model system, we explored novel mechanisms whereby this class of protein shapes signaling output. In the present work, we focused on the role of Shc in the MAP kinase Erk signaling both prior to and post-growth factor stimulation. Prior to growth factor stimulation, we found Erk to be a direct interacting partner of Shc. The two proteins associate through a non-canonical interface. This interaction blocks the phosphorylation of Erk and restricts its nuclear translocation. Post-growth factor stimulation, Erk is released from Shc through an allosteric mechanism facilitated by the binding between Shc and the activated growth factor receptor. Furthermore, fully activated Erk phosphorylates Shc on three threonine residues. These phosphorylated residues on Shc subsequently serve as platforms to mediate both a positive feedforward loop in prolonging Erk activity and crosstalk with Akt signaling through protein recruitment.
Keywords
SIGNALING, EGF RECEPTOR, ERK, MAPK, AKT
Included in
Biochemistry, Biophysics, and Structural Biology Commons, Medicine and Health Sciences Commons