Thomas W. Sturgill

    Professor of Medicine and Pharmacology

    • Phone: (434)924-9191
    • Fax: (434)924-9659
    • Office: Room 7021, Seventh Floor Hospital West Health Sciences Center
    • Email: tws7w@virginia.edu
    • Homepage: Click Here

Research Interest

Regulation of MAP Kinase Activity

Mammalian cells express receptors for various peptide growth factors. Growth factor receptors are proteins in the plasma membrane that bind specifically a particular peptide, generating signals for changes in metabolism, gene expression, and/or cell division. Expression of these receptors (as well as receptors for other hormonal substances) provides for external control of individual cell activity.

My laboratory is studying the protein kinases in the pathways used for signal transduction by peptide growth factors. MAP (mitogen-activated protein) kinases are serine/threonine kinases that are regulated positively by tyrosine and threonine phosphorylation. Two closely related 42 kDa and 44 kDa MAP kinases are expressed ubiquitously in mammalian cells. MAP kinases function in cascades important for mediating some of the actions of many peptide growth factors. The sites recognized by MAP kinases in target proteins all conform minimally to the amino acid sequence serine (or threonine) followed by proline.

We are interested in several aspects of MAP kinase regulation and function. Several proteins have been identified as candidates for regulation by MAP kinase, these include important regulatory proteins, e.g. protein kinases, cytoplasmic phospholipase A2, and several transactivating factors. We are attempting to identify additional proteins regulated by MAP kinase. This protein is translocated into the nucleus but lacks an apparent nuclear localization domain, thus the mechanism of its transport to the nucleus is an interesting problem. MAP kinases are activated by a new family of protein kinases with dual specificity for the regulatory tyrosine and threonine amino acid residues in MAP kinases, the MAP kinase kinases (MKKs). These enzymes are remarkably specific for their MAP kinase substrates. MKKs are activated also by phosphorylation. Present evidence suggests that several protein kinases including Raf-1 and the MEK kinase may activate MKKs. The mechanism of activation of Raf-1 and MEK kinase is unknown and is a major interest at present. The mechanisms for communication with other pathways remains to be explored. Recently, cAMP has been shown to regulate negatively the MAP kinase pathways. Finally, and perhaps most exciting of all, there must exist interactions of the MAP kinase pathway with the cell cycle machinery.

Representative Recent Publications

  1. Dent, P., Reardon, D.B., Morrison, D.K., and Sturgill, T.W. 1995. Regulation of raf-1 and raf-1 mutants by ras-dependent and ras-independent mechanisms in vitro. Molec.Cell.Biol. 15:4125-4135.
  2. Dent, P., Jelinek, T., Morrison, D.K., Weber, M.J. and Sturgill, T.W. 1995. Reversal of raf-1 activation by purified and membrane-associated protein phosphatases. Science 268:1902-1906.
  3. Chow, Y.H., Pumiglia, K., Jun, T.H., Dent, P., Sturgill, T.W. and R. Jove. 1995. Functional mapping of the N-terminal regulatory domain in the human raf-1 protein kinase. J.Biol.Chem. 270:14100-14106.
  4. Wu, J., Spiegel, S., and Sturgill, T.W. 1995. Sphingosine-1-phosphate rapidly activates the MAP kinase pathway by a G-protein dependent mechanism. J.Biol.Chem. 270:11484-11488.
  5. Aziz, N., Miglarese, M.R., Hendrickson, R.C., Sturgill. T.W., Hunt, D.F., and T.P. Bender. 1995. Modulation of c-Myb-induced transcripton activation by a phosphorylation site in the negative regulatory domain. Proc.Natl.Acad.Sci. 92:6429-6433.
  6. Jelinek, T., Dent, P., Sturgill, T.W., and Weber, M.J. 1996. Ras-induced activation of Raf-1 is dependent on tyrosine phosphorylation. Molec. Cell. Biol.16:1027-1034.
  7. Dent, P., Reardon, D.B., Wood, S.L., Lindorfer, M.A., Graber, S.G., Garrison, J.C., Brautigan, D.L., and Sturgill, T.W. 1996. Inactivation of Raf-1 by a protein-tyrosine phosphatase stimulated by GTP and reconstituted by G•i/o subunits. J. Biol. Chem. 271:3119-3123.
  8. Reardon, D.B., Wood, S.L., Brautigan, D.L., Bell, G.I., Dent, P., and Sturgill, T.W. 1996. Activation of a protein tyrosine phosphatase and inactivation of Raf-1 by somatostatin. Biochem. J. 314:401-404.
  9. Trofimova, M., Sprenkle, A.B., Green, M., Sturgill, T.W., Goebl, M.G., and Harrington, M.A. 1996. Developmental and tissue-specific expression of mouse pelle-like protein kinase. J. Biol. Chem. 271:17609-17612.
  10. Kasid, U., Suy, S., Dent, P., Ray, S., Whiteside, T.L., and Sturgill, T.W. 1996. Activation of Raf by ionizing radiation. Nature 382: 813-816.
  11. Sprenkle, A.B., Davies, S.P., Carling, D., Hardie, D.G., and Sturgill, T.W. 1997. Identification of Raf-1 Ser621 kinase activity from NIH-3T3 cells as AMP-activated protein kinase. FEBS Lett 403/3:254-258.
  12. Reardon, D.B., Dent, P., Wood, S.L., Kong, T., and Sturgill, T.W. 1997. Activation in vitro of somatostatin receptor subtypes 2,3, or 4 stimulates protein tyrosine phosphatase activity in membranes from transfected ras-transformed NIH 3T3 cells: co-expression with catalytically-inactive SHP-2 blocks responsiveness. Molec. Endo. 8:1062-1069.
  13. Burack, W.R. and Sturgill, T.W. 1997. The activating dual-phosphorylation of MAPK by MEK is nonprocessive. Biochem. 36:5929-5933.
  14. Rani, C.S.S., Wang, F., Fuior, E., Berger, A., Wu, J., Sturgill, T.W., Beitner-Johnson, D., LeRoith, D., Varticovski, L., and Spiegel, S. 1997. Divergence in signal transduction pathways of platelet-derived growth factor (PDGF) and epidermal growth factor (EGF) receptors: Involvement of sphingosine 1-phosphate in PDGF but not EGF signaling. J. Biol. Chem. 272:10777-10783.
  15. Dent, P., Wang, Y., Gu, Y-Z., Wood, S.L., Reardon, D.B., Mangues, R., Pellicer, A., Schonbrunn, A., and Sturgill, T.W. 1997. S49 cells endogenously express subtype 2 somatostatin receptors which couple to increase protein tyrosine phosphatase activity in membranes and down-regulate Raf-1 activity in situ. Cell. Signal. 9:539-549.
  16. Stancato, L.F., Sakatsume, M., David, M., Dent, P., Dong, F., Petricoin, E.F., Krolewski, J.J., Silvennoinen, O., Saharinen, P., Pierce, J., Marshall, C.J., Sturgill, T., Finbloom, D.S., and Larner, A.C. 1997. Beta interferon and oncostatin M activate Raf-1 and mitogen-activated protein kinase through a JAK1-dependent pathway. Molec. Cell Biol 17:3833-3840.
  17. Malarkey, K., Coker, K.J., and Sturgill, T.W. 1998. Ribosomal S6 kinase is activated as an early event in preemergence development of encysted embryos of Artemia salina. Eur. J. Biochem. In press.
  18. Joel, P., Smith, J., Sturgill, T.W., Fisher, T.L., Blenis, J., and Lannigan, D.A. 1998. Molec. Cell. Biol. pp90rsk1 regulates estrogen receptor-mediated transcription through phosphorylation of Ser-167. Accepted for publication.
  19. Santiago J. Sturgill TW. Identification of the S6 kinase activity stimulated in quiescent brine shrimp embryos upon entry to preemergence development as p70 ribosomal protein S6 kinase: isolation of Artemia franciscana p70S6k cDNA. [Journal Article] Biochemistry & Cell Biology. 79(2):141-52, 2001. HEALTH SCIENCES LIBRARY OWNS - CLICK ON LIBRARY HOLDINGS UI: 21204474
  20. Smith JA. Poteet-Smith CE. Lannigan DA. Freed TA. Zoltoski AJ. Sturgill TW. Creation of a stress-activated p90 ribosomal S6 kinase. The carboxyl-terminal tail of the MAPK-activated protein kinases dictates the signal transduction pathway in which they function. [Journal Article] Journal of Biological Chemistry. 275(41):31588-93, 2000 Oct 13. HSL OWNS PRINT & ONLINE hslnet.med.virginia.edu/ejrnl.html UI: 20493526
  21. McPherson RA. Taylor MM. Hershey ED. Sturgill TW. A different function for a critical tryptophan in c-Raf and Hck. [Journal Article] Oncogene. 19(32):3616-22, 2000 Jul 27. HEALTH SCIENCES LIBRARY OWNS - CLICK ON LIBRARY HOLDINGS UI: 20406541
  22. Poteet-Smith CE. Smith JA. Lannigan DA. Freed TA. Sturgill TW. Generation of constitutively active p90 ribosomal S6 kinase in vivo. Implications for the mitogen-activated protein kinase-activated protein kinase family. [erratum appears in J Biol Chem 1999 Nov 26;274(48):34506]. [Journal Article] Journal of Biological Chemistry. 274(32):22135-8, 1999 Aug 6. HSL OWNS PRINT & ONLINE hslnet.med.virginia.edu/ejrnl.html UI: 99357730
  23. Smith JA. Poteet-Smith CE. Malarkey K. Sturgill TW. Identification of an extracellular signal-regulated kinase (ERK) docking site in ribosomal S6 kinase, a sequence critical for activation by ERK in vivo. [Journal Article] Journal of Biological Chemistry. 274(5):2893-8, 1999 Jan 29. HSL OWNS PRINT & ONLINE hslnet.med.virginia.edu/ejrnl.html UI: 99115635

For more information email tws7w@virginia.edu.