Department of Medicinal Chemistry and Molecular Pharmacology Personnel - Robert L. Geahlen
Specialization: Biochemistry and Molecular Biology
EducationB.S. - 1975 - University of Southern Colorado
Ph.D. - 1978 - University of Wyoming
Postdoc - 1978-82 - University of Washington
Research: Biochemistry and Molecular Biology
Signals transduced by the binding of antigens to receptors on hematopoietic cells take the form of increased tyrosine phosphorylation of intracellular proteins. This response is mediated by cytoplasmic protein-tyrosine kinases that associate with the liganded receptor. The major focus of our laboratory is on understanding how these kinases are regulated and how, once activated, they regulate the multiple biochemical pathways that are activated by receptor engagement. The kinase of particular interest is Syk, a 72-kDa, cytoplasmic protein-tyrosine kinase originally discovered in our laboratory. We use chemical, biochemical and genetic approaches to understanding the role of each of these enzymes in signal transduction pathways downstream from B cell antigen receptors. Recent studies indicate additional roles for Syk in modulating the growth properties of many types of cancer cells. Syk is a prominent promoter of the survival of multiple tumor cells including many leukemias, lymphomas, retinoblastomas and pancreatic carcinomas. In contrast, Syk is frequently lost from many highly metastatic cells including breast cancers and melanomas. The molecular mechanisms by which Syk functions both as a tumor promoter and a tumor suppressor are of major interest to the lab.
Functional Analyses of Syk in B Cells and Cancer Cells: B cells fail to develop properly in mice lacking the gene for Syk due to the inability of the B cell antigen receptor (BCR) to signal in the absence of the kinase. How Syk mediates signaling through the BCR is a major question being investigated. We have mapped multiple sites of phosphorylation on Syk that are important for its ability to function in B cells. By site-directed mutagenesis and expression studies, we are exploring the role of these phosphorylations in the ability of Syk to complement signaling in Syk-deficient cells. We have also identified regions of Syk required for its translocation into and out of the nucleus. The role that Syk's nucleocytoplasmic translocation plays in modulating the properties of B cells and cancer cells is actively under investigation. In collaboration with Dr. Andy Tao, we are making extensive use of phosphoproteomics approaches to identify novel Syk substrates in both B cells and breast cancer cells. The analysis of novel substrates identified through these approaches is currently underway.
Interactions of Syk with Intracellular Proteins: Through the use of genetic, biochemical and proteomic screens, we are identifying and characterizing novel Syk-interacting proteins that are involved in the signal transduction pathways operating downstream of the activated kinase. In collaboration with Dr. Carol Post, we are examining the structural bases for the interactions between Syk and Syk-binding proteins, especially those containing SH2 and other phosphotyrosine-binding domains.
Inhibitors of Protein-Tyrosine Kinases: In collaboration with Dr. Richard Borch, we are developing and characterizing chemical probes that target the SH2 domains of protein-tyrosine kinases that mediate protein-protein interactions.
Arrendale, A., Kim, K., Choi, J.Y., Li, W., Geahlen, R.L., and Borch, R.F. (2012) Synthesis of a phosphoserine mimetic prodrug with potent 14-3-3 protein inhibitory activity, 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. U.S.A. 109, 5615-5620.
Martin V.A., Wang, W.-H., Lipchik, A.M., Parker, L.L., He, Y., Zhang, S., Zhang, Z.-Y., and Geahlen, R.L. (2012) Akt2 inhibits the activation 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.
Moon, K.D., Zhang, X., Zhou, Q., and Geahlen, R.L. (2012) The protein-tyrosine kinase Syk interacts with the C-terminal region of tensin2, BBA – Mol. Cell Res. 1823, 199-205.
Paris, LL., 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.
Geahlen, R.L. (2009) Syk and pTyr'd: Signaling through the B cell antigen receptor. BBA – Mol. Cell Res. 1793, 1115-1127.
Zhang, X., Shrikhande, U., Zhou, Q., and Geahlen, R.L. (2009) A role for the protein-tyrosine kinase, Syk, in regulating cell-cell adhesion and motility in breast cancer cells. Mol. Cancer Res. 7, 634-644.
Oh, H., Ozkirimli E., Shah, K., Harrison, M.L., and Geahlen, R.L. (2007) Generation of an analog-sensitive Syk tyrosine kinase for the study of signaling dynamics from the B cell antigen receptor. J. Biol. Chem. 282, 33760-33768.
This record was last updated on Aug 19, 2013 at 3:56 PM