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Title page for ETD etd-09022009-164115


Type of Document Dissertation
Author Red Brewer, Monica
URN etd-09022009-164115
Title Mechanisms of epidermal growth factor receptor tyrosine kinase activation and nuclear trafficking
Degree PhD
Department Biochemistry
Advisory Committee
Advisor Name Title
Graham Carpenter Committee Chair
Bruce Carter Committee Member
Carlos Arteaga Committee Member
Daniel Liebler Committee Member
Scott Hiebert Committee Member
Keywords
  • Epidermal Growth Factor Receptor
  • Juxtamembrane
  • p97
  • Tyrosine Kinase
Date of Defense 2009-08-26
Availability unrestricted
Abstract
In several growth factor receptors, the intracellular juxtamembrane (JM) region participates in autoinhibitory interactions that must be disrupted for tyrosine kinase activation. Using alanine scanning mutagenesis, I define a domain within the JM region of the epidermal growth factor receptor (EGFR) that plays an activating role. This region is termed the juxtamembrane activation domain (JMAD). The JMAD encompasses residues 664-682 and is encoded by a portion of exon 18, which also encodes part of the tyrosine kinase domain N-lobe. I describe how an uncharacterized lung cancer mutation within the JMAD (V665M) constitutively activates EGFR by augmenting its capacity to act as an acceptor in the asymmetric dimer. This JM mutant promotes cellular transformation by EGFR in vitro and is tumorigenic in a xenograft assay. The biochemical, biological, and structural data presented within this dissertation illustrates the importance of the JMAD in EGFR tyrosine kinase activation and inhibition.

In a related, but distinct project, I examine the role of the p97 AAA-ATPase in mediating nuclear localization of the EGFR. I demonstrate maximal ligand-dependent association of p97 and EGFR at a time point consistent with a previously described trafficking phenomenon which involves retrotranslocation of mature EGFR to the endoplasmic reticulum and then to the nucleus. Additionally, disruption of ligand-dependent nuclear trafficking of EGFR upon knockdown of p97 is shown. Data presented in this dissertation suggests that p97 is required for ligand-dependent nuclear localization of the EGFR.

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