Investigation Of The Role Of The Scaffold Protein Shc In Erk Signaling

Author

kin man suen, The University of Texas Graduate School of Biomedical Sciences at HoustonFollow

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