SIGNAL TRANSDUCTION BY EGF RECEPTORS/ERBB FAMILY MEMBERS

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The epidermal growth factor (EGF) receptor is the prototype of the ErbB family of polypeptide growth factor receptors, whose members include ErbB1-4 (also HER1-4). Receptors in this family play critical roles in the control of normal cellular growth, and are believed to be involved in the abnormal proliferation of cancer cells. For example, member so the ErbB receptors family are frequently over expressed in breast cancer cells, and the EGF receptor (EGFR) is often activated by mutation in human brain cancers. The heregulins constitute a newly discovered family of EGF- related polypeptides that bind to and activate ErbB family members. Heregulines play essential roles in cardiac and neural development, and may also be involved in tumorigenesis. Recently it has been determined that EGF and heregulines activate pairs of ErbB family members functioning as coreceptors, for example the ErbB2/ErbB3 heregulin corecptor. The long term goals of the proposed work are to dissect the signal transduction mechanisms used by ErbB family coreceptors, and to determine how corecptor constituents cooperate in the promotion of normal and cancerous cellular growth. This proposal focuses on the signaling mechanisms of the ErbB3 protein, which is unique among ErbB family members in its ability to recruit intracellular signal transducing proteins in response to either EGF or heregulin. Because receptor phosphorylation is a key first event in receptor signaling that triggers the recruitment of signal- transducers, the pattern of tyrosine residue phosphorylation in the ErbB3 receptor will be examined in the contexts of both EGFR/ErbB3 and ErbB2/ErbB3 coreceptors. Secondly, the mechanism by which the unique structural elements of ErbB3 are used in the recruitment and activation of phosphatidylinositiol (PI) 3-kinase will be investigated. Finally, the potential cooperation of the Shc/Ras/mitogen-activate protein kinase (MAPK) and PI 3-kinase pathways, two key signaling pathways know to be activated by ErbB3, will be investigated through the use of recombinant ErbB3 proteins designed to selectively activate each of these signaling pathways. Potential collaboration of these pathways in the stimulation of DNA synthesis, the activation and nuclear translocation of MAPK, and the activation of the recently characterized signal-transducer, protein kinase B (PKB/Akt), will be examined. Through these efforts it is hope that a clearer understanding of the factors that control both normal and cancerous cellular growth will be achieved.