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Modeling Cell Receptor Signaling Pathways

Haluk Resat, Principal Investigator

Funding Agency: National Institutes of Health, National Institute of General Medical Sciences

Receptor systems are instrumental for cells to communicate 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 well exemplified by the epidermal growth factor receptor (EGFR) system. EGFR belongs to the HER (also called the ErbB) family of receptor tyrosine kinases, in which it is the first type receptor (HER-1). 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 HER-2 have been observed in human cancers, particularly breast and ovarian cancers. Overexpression of HER-2 has been implicated in cancer promotion as well; its presence indicates a poor prognosis. HER receptors are believed to contribute to 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 HER-2 inhibitor, Herceptin, as an effective drug, and members of the HER family of receptors are often the chosen targets of tyrosine kinase inhibitor drug candidates.

The Modeling Cell Receptor Signaling Pathways project team at Pacific Northwest National Laboratory (PNNL) is using multi-compartment cell models and combining 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 are working toward this goal by measuring the cellular responses in a library of transfected human mammary epithelial cells (HMEC), in which the HER family of receptors is expressed at various levels. Our proposed modeling studies will play an important part in designing new sets of experiments for this important system.

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