Analysis of ErbB Receptors: Regulation of ErbB-1 Kinase Activation and Localization of ErbB-4 to Membrane Microdomains

Abstract

The ErbB family of receptor tyrosine kinases regulates cell growth, differentiation, and tumorigenesis. This dissertation contains two independent studies of ErbB-1 and ErbB-4. In one study, the intracellular juxtamembrane region of ErbB-1 was investigated for its role in kinase activation. By creating deletions and mutations in the juxtamembrane region of ErbB-1, the data defined an essential requirement for the juxtamembrane region in the allosteric mechanism of tyrosine kinase activation. The second study focused on proteolytic processing of ErbB-4. Activation of ErbB-4 results in ectodomain and transmembrane domain cleavage events, but the parameters that must be fulfilled to initiate ectodomain proteolysis remain poorly defined. The localization of ErbB-4 and its sheddase to membrane microdomains was evaluated as a regulatory step in sequential proteolytic processing.