Mechanisms of ErbB receptor oligomerization

Multicellular organisms rely on intracellular communication to govern a wide variety of cellular processes, including metabolism, proliferation, motility and apoptosis. Receptor tyrosine kinases (RTKs) play central roles in signal transduction by detecting extracellular hormones and growth factors and transmitting these signals to cytosolic effector proteins. These proteins must be tightly controlled as perturbations leading to deregulated kinase activity often result in malignant transformation.; All RTKs contain a large extracellular ligand-binding domain (known as the ectodomain), a single alpha-helical transmembrane domain and a cytoplasmic domain. The cytoplasmic region consists of the protein tyrosine kinase domain as well as regulatory regions that, when phosphorylated on tyrosines, recruit downstream signaling proteins. Activation of the kinase domain is mediated through ligand-induced receptor oligomerization.; The four members of the ErbB family of RTKs (also known as the EGF, HER or Type I RTK family) have been shown to play important roles in normal development and physiology, and all are implicated in the pathogenesis of a large number of human cancers. While the receptors all share similar sequence identity, they are markedly different in their ligand-binding characteristics and their complement of tyrosine phosphorylation sites. Signaling by the ErbB receptors is enhanced and diversified by their ability to form homo- and heterodimeric complexes.; This thesis describes experiments aimed at understanding the molecular mechanisms underlying the ligand-induced oligomerization of the ErbB receptors. We examined the stoichiometry of the receptors in functional signaling complexes, the ability of ErbB3 to undergo homodimerization when bound to its cognate growth factor, and the structural and energetic determinants of ErbB1 homodimerization. We find that, as predicted in the classical model of receptor activation, the ErbB receptors signal through homo- and heterodimers, as opposed to higher order oligomers. In addition, we show that ErbB3 is unique in that it binds growth factors, but does not respond by homodimerization. Finally, we have begun to generate a more thorough model of ligand-induced homodimerization of the ErbB1 ectodomain.