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.
Lab Members:Soumitra Ghosh (Pulse Graduate Student)
Shana Denise Hardy (Graduate Student)
Wen-Hung Wang (Post-Doctoral Research Associate)
Mark Lee Westbroek (Graduate Student)
Cartagena, A., Wang, W.-H., Geahlen, R.L., and Raman, A. (2015) Fast, multi-frequency, quantitative nanomechanical mapping of live cells using the atomic force microscope. Sci. Rep. 5:11692.
Krisenko, M.O. and Geahlen, R.L. (2015) Calling in SYK: SYK's dual role as a tumor promoter and tumor suppressor in cancer. Biochim. Biophys. Acta 1853, 254-263.
Wang, W.-H., Childress, M.O., and Geahlen, R.L. (2014) Syk interacts with and phosphorylates nucleolin to stabilize Bcl-xL mRNA and promote cell survival. Mol. Cell. Biol. 34, 3788-3799.
Krisenko, M.O., Cartagena, A., Raman, A., and Geahlen, R.L. (2014) Nanomechanical property maps of breast cancer cells by multi-harmonic atomic force microscopy reveal Syk-dependent changes in microtubule stability mediated by MAP1B. Biochemistry 54. 60-68.
Geahlen, R.L. (2014) Getting Syk: Spleen tyrosine kinase as a therapeutic target. Trends Pharmacol. Sci. 35, 414-422.
Jayasundera, K.B., Iliuk, A.B., Nguyen, A., Higgins, R., Geahlen, R.L., and Tao, W. A. (2014) Global phosphoproteomics of activated B cells using complementary metal ion functionalized soluble nanopolymers. Anal. Chem. 86, 6363-6371.
Xue, L., Geahlen, R.L., and Tao, W.A. (2013) Identification of direct kinase substrates based on protein kinase assay-linked phosphoproteomics. Mol. Cell. Proteomics 12, 2969-2980.
Huang, R., Oh, H., Arrendale, A., Martin, V.A., Galan, J., Workman, R.J., Stout, J.R., Walczak, C.E., Tao, W.A., Borch, R.F., and Geahlen, R.L. (2013) Intracellular targets for a phosphotyrosine peptidomimetic include the mitotic kinesin, MCAK. Biochem. Pharmacol. 86, 597-611.
Yu, S., Huang, H., Iliuk, A., Wang, W.-H., Jayasundera,K.B., Tao, W.A., Post, C.B., and Geahlen, R.L. (2013) Syk inhibits the activity of protein kinase A by phosphorylating tyrosine 330 of the catalytic subunit. J. Biol. Chem. 288, 10870-10881.
Lipchik, A.M., Killins, R.L., Geahlen, R.L., and Parker, L.L. (2012) Detection of intracellular Syk kinase activation using a novel peptide substrate. Biochemistry 51, 7525-7524.
Pan, L; Iliuk, A., Yu, S., Geahlen, R., and Tao, W.A. (2012) Multiplexed quantitation of protein expression and phosphorylation based on functionalized soluble nanopolymers. J. Am. Chem. Soc. 134, 18201-18204.
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.
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.
This record was last updated on Aug 21, 2015 at 12:36 PM