Receptor systems are instrumental in the communication of cells with their surroundings. Through the engagement of intracellular signal transduction networks, receptors can drive cellular decisions that are critical to both physiological and pathological processes. Characterizing the fundamental regulatory mechanisms in receptor-mediated signaling can help identify potential therapeutic targets. This however is a difficult task due to the complexity of the biological systems and necessitates the use of an integrated computational and experimental approach. The human epidermal growth factor receptor (HER) family of receptor tyrosine kinases regulates proliferation, pro-survival, and cell motility mechanisms, and it plays critical roles in development and tumorigenesis. Overexpression of HER family receptors can contribute to poor prognosis in various types of cancer. There are four members in the HER family (HER1/EGFR and HER2-4) and they interact with each other through dimerization. HER2 mediates the crosstalk among the family members and the HER2-HER3 dimer is particularly potent in leading to pathological responses. The HER family regulates cellular processes by activating the Erk and PI3K/Akt pathways. Erk activation is the primary mediator of cellular proliferation and the Akt pathway is central to pro-survival responses. Thus, HER signaling interlinks cellular growth and survival mechanisms, which need to be properly balanced and regulated for normal cell physiology. The dimerization ability of the HER receptors and their frequent co-expression in both developmental and pathological scenarios imply that the individual receptors cannot be studied in isolation. The ability of each HER dimer type to elicit a unique signaling pattern contributes to the complexity of the HER family. The important role of dimer identity in driving the cellular response is exemplified by the HER2-HER3 heterodimer, whose potency is thought to stem from its prolonged signaling and from the unique ability of HER3 to efficiently engage the pro-survival Akt pathway. Interactions between the members of the HER family are known to contribute to drug resistance when specific inhibitors are used against a single type of HER receptor in tumor therapy. Therefore, the use of combination therapeutics that target multiple HER family members is advocated as an effective treatment strategy for a variety of tumors. In this research, using a unified computational and experimental methodology, we will investigate the hypothesis that when HER3 is overexpressed, it leads to a distinct pattern of Erk and Akt activation, which can result in the loss of normal cell regulation and promote abnormal cellular responses. We will also investigate whether synergistic effects between HER2 and HER3 reduce the HER3 expression level necessary for the onset of abnormal responses when these receptors are coexpressed. Based on such knowledge, therapeutic treatment regimen can be personalized according to a patient's HER receptor expression profile.

Public Health Relevance

Receptors enable cells to sense and respond to their environment. The human epidermal growth factor receptor (HER) family is particularly important since it mediates a variety of cellular responses that are important both in normal physiology and in tumor formation. Combining computational approaches with experiments, this project will investigate how the interactions between the members of this important receptor family initiate and regulate cellular responses.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Modeling and Analysis of Biological Systems Study Section (MABS)
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Maas, Stefan
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Battelle Pacific Northwest Laboratories
United States
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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
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
Zhang, Yi; Opresko, Lee; Shankaran, Harish et al. (2009) HER/ErbB receptor interactions and signaling patterns in human mammary epithelial cells. BMC Cell Biol 10:78
Shankaran, Harish; Ippolito, Danielle L; Chrisler, William B et al. (2009) Rapid and sustained nuclear-cytoplasmic ERK oscillations induced by epidermal growth factor. Mol Syst Biol 5:332
Shankaran, Harish; Zhang, Yi; Opresko, Lee et al. (2008) Quantifying the effects of co-expressing EGFR and HER2 on HER activation and trafficking. Biochem Biophys Res Commun 371:220-4
Zhang, Y; Shankaran, H; Opresko, L et al. (2008) System theoretical investigation of human epidermal growth factor receptor-mediated signalling. IET Syst Biol 2:273-84
Shankaran, Harish; Wiley, H Steven; Resat, Haluk (2007) Receptor downregulation and desensitization enhance the information processing ability of signalling receptors. BMC Syst Biol 1:48
Shankaran, Harish; Resat, Haluk; Wiley, H Steven (2007) Cell surface receptors for signal transduction and ligand transport: a design principles study. PLoS Comput Biol 3:e101
Shankaran, Harish; Wiley, H Steven; Resat, Haluk (2006) Modeling the effects of HER/ErbB1-3 coexpression on receptor dimerization and biological response. Biophys J 90:3993-4009