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Analysis of Ligand Binding ErbB Receptor Tyrosine Kinases

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Annual summary rept. 1 Jul 1998-30 Jun 2001

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Growth factor-receptor tyrosine kinases RTKs play a central role in the coordination of cell growth, differentiation and other activities in multicellular organism. Molecular lesions in andor aberrant expression of RTKs can lead to cancer. There is a particularly strong correlation between the erbB2 neuHER-2 receptor and breast cancer. The cell-surface location of the erbB2 receptor makes it an obvious target for novel therapies. The purpose of this research is to gain insight into the structure of the extracellular domain of this receptor and its mode of activation in order to aid in the development of new antagonists. ErbB2 is one of a family of 4 RTKs which also includes the epidermal growth factor receptor erbB1EGFR. The first step in the stimulation of a response by a growth factor is dimerization of the receptor upon binding of the cognate ligand. We have crystals of the EGF induced homodimer of the soluble extracellular domain of erbB1. Determination of this structure is in progress. This structure will provide insight into the specific molecular events that drive erbB receptor dimerization. A key question is whether the dimerization is mediated only by receptor-receptor contacts, or whether the ligand is bivalent in nature, simultaneously contacting both receptor molecules in the dimer.

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  • Biochemistry
  • Medicine and Medical Research

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