In breast cancer, tumorigenesis occurs through an accumulation of genetic and epigenetic changes in epithelial cells involving both the activation of oncogenes and the inactivation of tumor suppressor genes. The Syk protein-tyrosine kinase, known best for its roles in the immune system, has recently been identified as a tumor suppressor in breast cancer;its expression being inversely correlated with malignant cell growth and metastasis. This is an unusual property for a tyrosine kinase, enzymes more typically found as the products of oncogenes. Thus, an understanding of how Syk functions to suppress the malignant phenotype of breast cancer cells is of considerable importance to our understanding of the critical pathways involved in growth control in breast epithelial cells and to the identification of possible, novel therapeutic targets. Preliminary studies have led to the hypothesis that Syk regulates two important aspects of of epithelial cell function: 1) cellular responses to tumor necrosis factor (TNF), a factor that regulates cell death/cell survival decisions and 2) cell adhesion and motility. These hypotheses are based on the identification of Syk- interacting proteins that participate in each of these pathways. The research proposed in this project will 1) characterize the physical and functional interactions between Syk and components of the TNF-signaling pathway with an emphasis on the characterization of a novel Syk-interacting protein thought to participate in this pathway;2) characterize the critical structural features and mechanisms by which Syk, through its interacting partners, regulates cell adhesion and motility;and 3) characterize through phosphoproteomics studies the substrates and binding partners important for Syk's regulatory functions in breast epithelial cells. Methodologies to be employed include 1) genetic, biochemical and microscopic evaluations of protein- protein interactions and the consequences of their disruption and 2) state-of-the-art analyses of the phosphoproteome of Syk-expressing cells.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Tumor Cell Biology Study Section (TCB)
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Jhappan, Chamelli
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Purdue University
Schools of Pharmacy
West Lafayette
United States
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Krisenko, Mariya O; Cartagena, Alexander; Raman, Arvind et al. (2015) Nanomechanical property maps of breast cancer cells as determined by multiharmonic atomic force microscopy reveal Syk-dependent changes in microtubule stability mediated by MAP1B. Biochemistry 54:60-8
Krisenko, Mariya O; Higgins, ReneƩ L; Ghosh, Soumitra et al. (2015) Syk Is Recruited to Stress Granules and Promotes Their Clearance through Autophagy. J Biol Chem 290:27803-15
Krisenko, Mariya O; Geahlen, Robert L (2015) Calling in SYK: SYK's dual role as a tumor promoter and tumor suppressor in cancer. Biochim Biophys Acta 1853:254-63
Cartagena-Rivera, Alexander X; Wang, Wen-Horng; Geahlen, Robert L et al. (2015) Fast, multi-frequency, and quantitative nanomechanical mapping of live cells using the atomic force microscope. Sci Rep 5:11692
Huang, Rong; Oh, Hyunju; Arrendale, Allison et al. (2013) Intracellular targets for a phosphotyrosine peptidomimetic include the mitotic kinesin, MCAK. Biochem Pharmacol 86:597-611
Yu, Shuai; Huang, He; Iliuk, Anton et al. (2013) Syk inhibits the activity of protein kinase A by phosphorylating tyrosine 330 of the catalytic subunit. J Biol Chem 288:10870-81
Fei, Bei; Yu, Shuai; Geahlen, Robert L (2013) Modulation by Syk of Bcl-2, calcium and the calpain-calpastatin proteolytic system in human breast cancer cells. Biochim Biophys Acta 1833:2153-64
Hu, Lianghai; Yang, Li; Lipchik, Andrew M et al. (2013) A quantitative proteomics-based competition binding assay to characterize pITAM-protein interactions. Anal Chem 85:5071-7
Xue, Liang; Geahlen, Robert L; Tao, W Andy (2013) Identification of direct tyrosine kinase substrates based on protein kinase assay-linked phosphoproteomics. Mol Cell Proteomics 12:2969-80
Pan, Li; Iliuk, Anton; Yu, Shuai et al. (2012) Multiplexed quantitation of protein expression and phosphorylation based on functionalized soluble nanopolymers. J Am Chem Soc 134:18201-4

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