Receptor systems are instrumental in the communication of cells with their surroundings. Information communicated through receptor signaling pathways control many key biological processes. Ligand regulation and availability, receptor down-regulation and trafficking, and crosstalk between signaling pathways are among the most important aspects of cell receptor signaling processes, and these aspects are _ell exemplified by the epidermal growth factor receptor (EGFR) system. The EGFR belongs to the HER (also called the ErbB) family of receptor tyrosine kinases, where it is the first type receptor. Four members of the HER family are highly related but have distinct functional properties and many cell types express multiple members of the HER family. Signaling behavior of EGFR is known to be modified by the other members of the HER family through the formation of receptor dimers and possibly oligomers. High expression levels of EGFR and HER2 have been observed in human cancers, particularly the breast and ovarian cancers. Overexpression of HER2 has been implicated in cancer promotion as well as in leading to poor prognosis. HER receptors are believed to contribute to the cancer development by leading to aberrant cell behavior such as increased sensitivity to mitogenic stimuli and cell transformation. Their importance is exemplified by the development of HER2 inhibitor Herceptin as an effective drug, and members of the HER family of receptors are often the chosen target of the tyrosine kinase inhibitor drug candidates. In this project we will use multi-compartment cell models and combine modeling approaches with experiments to systematically investigate how the interactions between EGFR and other members of the HER family modify each other's signaling behavior. We will achieve our goal by measuring the cellular responses in a library of transfected human mammary epithelial cells in which HER family of receptors are expressed at various levels. Proposed modeling studies will play an important part in designing new sets of experiments for this important system.
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