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Robert L. Geahlen

Robert L. Geahlen Profile Picture
Professor of Medicinal Chemistry
Ph.D. - 1978 - University of Wyoming

Contact Info:

Training Group(s):
Molecular Signaling and Cancer Biology

Current Research Interests:

Our laboratory is interested in the molecular mechanisms by which cytoplasmic protein-tyrosine kinases modulate cellular responses to environmental signals. Our major focus is the kinase, Syk (spleen tyrosine kinase), a 72-kDa protein-tyrosine kinase originally discovered in our laboratory. We use chemical, biochemical and genetic approaches to understand the role of Syk in signal transduction pathways in two primary model systems: B cells activated through antigen and other stimulatory or inhibitory co-receptors and breast cancer cells interacting with other cells or with the extracellular matrix.

Structure-Function Analysis of Syk in B Cells. Signals transduced by the binding of antigens to receptors on B cells take the form of increased tyrosine phosphorylation of intracellular proteins. Since the components of the receptor complex itself lack intrinsic enzymatic activity, these responses are mediated instead by cytoplasmic protein-tyrosine kinases that associate with the liganded receptor, including Syk. B cells fail to develop properly in mice lacking the gene for Syk due to the inability of antigen receptors to signal in its absence. Receptor engagement leads to the recruitment of Syk, its phosphorylation on multiple sites and its association with effectors of downstream signaling pathways. We have been mapping these sites of phosphorylation and elucidating their roles in the regulation of the kinase's activity and in its interactions with other proteins. Through the use of genetic and biochemical screens, we are identifying and characterizing novel Syk-interacting proteins that are involved in these signal transduction pathways. In collaboration with Dr. Carol Post, we are examining the structural bases for these interactions. Ligation of B cell antigen receptors recruits Syk from both the cytoplasmic and nuclear compartments to the site of the clustered receptor. We are exploring the mechanisms by which Syk is translocated into and out of the nucleus and the roles that this translocation plays in regulating cellular responses to receptor engagement. In collaboration with Dr. Kavita Shah, we also are developing chemical genetic approaches to understanding Syk's function in B cells.

Analysis of Syk in Cancer Cells. Syk is expressed in a variety of non-hematopoietic cells including many epithelial cells. The expression of Syk has interesting and often opposing effects on the growth and survival of  cancer cells.  In many cancer cell types (e.g., leukemia, retinoblastoma, pancreatic carcinoma), Syk functions as a pro-survival factor while in other cancers (e.g., breast cancer, malanoma), the expression of Syk is inversely correlated with invasive growth and metastatic behavior.  We are studying the molecular mechanisms by which Syk regulates the growth properties of cancer cells and the nature of the proteins with which it interacts and the substrates that it phosphorylates. In collaboration with Dr. Andy Tao, we are using proteomics approaches to identify Syk interacting proteins and substrates in cancer cells.

Inhibitors of Protein-Tyrosine Kinases. We are interested in the development of chemical probes that act selectively to inhibit the activity of cytoplasmic protein-tyrosine kinases. The most recent targets to be investigated are the SH2 domains that mediate protein-protein interactions. In collaboration with Dr. Richard Borch, we are analyzing the effects of metabolically activated, cell permeable, SH2 domain ligands on the growth properties of leukemia cells.

Selected Publications:

Arrendale, A., Kim, K., Choi, J.Y., Li, W., Geahlen, R., and Borch, R.F. (2012) Synthesis of a phosphoserine mimetic prodrug with potent 14-3-3 protein inhibitory activiy. Chem. Biol. 19, 764-771.

Xue, L., Wang W.H., Iliuk, A., Hu, L., Galan, J.A., Yu, S., Hans, M., Geahlen, R.L., and Tao, W.A. (2012) Sensitive kinase assay linked with phosphoproteomics for identifying direct kinase substrates. Proc. Natl. Acad. Sci. USA 109, 5615-5620.

Maritin, V.A., Wang, W.H., Lipchik, A.M., Parker, L.L., He, Y., Zhang, S., Zhang, Z.Y., and Geahlen, R.L. (2012) Akts inhibits the activatin of NFAT in lymphocytes by modulating calcium release from intracellular stores. Cell. Signal. 24, 1064-1073. 

Chen, C.H., Martin, V.A., gorenstein, N.M., Geahlen, R.L., and Post, C.B. (2011) Two closely spaced tyrosines regulate NFAT signaling in B cells via Syk association with Vav. Mol. Cell. Biol. 31, 2984-2996.

Paris, L.L., Hu, J., Galan, J., Ong, S.S., Ma, H., Tao, W.A., Harrison, M.L., and Geahlen, R.L. (2010) Regulation of Syk by phosphorylation on serine in the linker insert, J. Biol. Chem. 285, 39844-39854.

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