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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM072821-02
Application #
7018535
Study Section
Special Emphasis Panel (ZRG1-MABS (01))
Program Officer
Anderson, Richard A
Project Start
2005-03-01
Project End
2008-02-29
Budget Start
2006-03-01
Budget End
2007-02-28
Support Year
2
Fiscal Year
2006
Total Cost
$285,936
Indirect Cost
Name
Battelle Pacific Northwest Laboratories
Department
Type
DUNS #
032987476
City
Richland
State
WA
Country
United States
Zip Code
99352
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Speth, Zachary; Islam, Tanzila; Banerjee, Kasturi et al. (2017) EGFR signaling pathways are wired differently in normal 184A1L5 human mammary epithelial and MDA-MB-231 breast cancer cells. J Cell Commun Signal 11:341-356
Islam, Tanzila; Resat, Haluk (2017) Quantitative investigation of MDA-MB-231 breast cancer cell motility: dependence on epidermal growth factor concentration and its gradient. Mol Biosyst 13:2069-2082
Banerjee, Kasturi; Resat, Haluk (2016) Constitutive activation of STAT3 in breast cancer cells: A review. Int J Cancer 138:2570-8
Gong, Chunhong; Zhang, Yi; Shankaran, Harish et al. (2015) Integrated analysis reveals that STAT3 is central to the crosstalk between HER/ErbB receptor signaling pathways in human mammary epithelial cells. Mol Biosyst 11:146-58
Shankaran, Harish; Zhang, Yi; Tan, Yunbing et al. (2013) Model-based analysis of HER activation in cells co-expressing EGFR, HER2 and HER3. PLoS Comput Biol 9:e1003201
Shankaran, Harish; Zhang, Yi; Chrisler, William B et al. (2012) Integrated experimental and model-based analysis reveals the spatial aspects of EGFR activation dynamics. Mol Biosyst 8:2868-82
Archuleta, Michelle N; McDermott, Jason E; Edwards, Jeremy S et al. (2012) An adaptive coarse graining method for signal transduction in three dimensions. Fundam Inform 118:
Resat, Haluk; Costa, Michelle N; Shankaran, Harish (2011) Spatial aspects in biological system simulations. Methods Enzymol 487:485-511
Resat, Haluk; Petzold, Linda; Pettigrew, Michel F (2009) Kinetic modeling of biological systems. Methods Mol Biol 541:311-35

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