Date of Award

Spring 5-15-2017

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Biochemistry)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

The epidermal growth factor receptor and its three orthologues, HER2, HER3 and HER4 have been the subject of intensive basic, clinical and translational research due to their involvement in cancers. These proteins are part of elaborate networks that interact with a myriad of other molecules to effect diverse signaling pathways and affect cellular processes such as migration, apoptosis, cell differentiation and so on. In addition to the formation of preformed dimers, it is well established that ligand engagement leads to receptor dimerization in all family members, except HER2. In the past decade, it has been shown that their intracellular domains dimerize in an asymmetric fashion where the C-lobe of the donor kinase interacts extensively with the Nlobe of the receiver kinase. This structural model is critical for activation of the receiver kinase and subsequent phosphorylation of the C-terminal tail. While the structures of the different domains have been solved, minimum structural and biophysical studies have been performed on the C-terminal tails. In this thesis, we use multiple approaches to characterize the C-terminal tails of EGFR and HER3, and show that they are intrinsically disordered regions of these receptors. We also developed a strategy that has been employed to site-specifically fluorophore-label the EGFR kinase domain, and would serve as a biological probe to directly measure EGFR kinase domain dimerization on lipid surfaces.

Language

English (en)

Chair and Committee

Ron Bose

Committee Members

Linda J. Pike, Carl Frieden, Roberto Galletto, Thomas Brett,

Comments

Permanent URL: https://doi.org/10.7936/K7RJ4GX0

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