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FRISC: The Faculty Research Interests Science Comparator |
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Professor of Pharmacology
Biological Chemistry
Cell Regulation
Office: (214) 648-3627
FAX: (214) 648-3811
Email: mcobb@mednet.swmed.edu
Interests in my laboratory revolve around the function and
regulation of protein kinases in signal transduction pathways. A major goal is to identify
and understand the regulation and function of mitogen-activated protein kinases (MAPKs).
Over a dozen members of the protein kinase subfamily are known in mammals including the
ERKs (ERK1, 2, 5, 7), the stress-sensitive c-Jun N-terminal kinases (JNKs 1, 2, 3), and
the p38 MAPKs (a, b, g, d). These protein kinases are important participants in
controlling cellular events such as proliferation, differentiation, homeostasis, and cell
death. MAPKs are activated by upstream protein kinase cascades that are controlled by
growth factors, G protein-coupled receptors, cytokine receptors, small G proteins,
cell-cell and cell-matrix contacts, and cellular stresses. Current work focuses on five
problems:
The role of MAPK cascades in the biology of beta cells of
the islets of Langerhans. These cells produce and secrete insulin. We are learning how
MAPKs help to coordinate these processes.
Functions of MAPK cascades in the immune system. A number
of drugs that act as anti-inflammatory agents target components of MAPK cascades. We are
most interested in how MAPKs help mediate the inflammatory response of macrophages to
lipopolysaccharide (LPS), a biologically active product released during infection by gram
negative bacteria.
Mechanisms controlling signaling specificity. Many ligands
activate an overlapping array of signaling pathways. We are defining protein-protein
interactions and mechanisms of subcellular localization of signal transducers to
understand how distinct outputs are generated by different hormones and other agents.
Genetic analysis of protein kinase cascades in the nematode
C. elegans . To aid in delineating the functions of MAPKs and other signaling
pathways, we are using forward and reverse genetics in the nematode. The completed genome
sequence and the ease of introducing mutants into the organism facilitates our study of
nematode protein kinases.
Structure-function relationships of MAPK cascades. In
collaboration with Betsy Goldsmith, we use mutagenesis and X-ray crystallography to
understand regulatory mechanisms in these cascades.
Selected Publications:
Swantek, J.L., Christerson, L., and Cobb, M.H. (1999).
Lipopolysaccharide-induced tumor necrosis factor-alpha promoter activity is inhibitor of
nuclear factor-kappaB kinase-dependent. J Biol Chem 274, 11667-11671.
Yin, M.J., Christerson, L.B., Yamamoto, Y., Kwak, Y.T.,
Xu, S., Mercurio, F., Barbosa, M., Cobb, M.H., and Gaynor, R.B. (1998). HTLV-I Tax protein
binds to MEKK1 to stimulate IkappaB kinase activity and NF-kappaB activation. Cell 93,
875-884.
Robinson, M. J., Stippec, S. A., Goldsmith E., White, M.
A., and Cobb, M. H. (1998) Constitutively active ERK2 MAP kinase is sufficient for neurite
outgrowth and cell transformation when targeted to the nucleus. Current Biology
8, 1141-1150.
Khokhlatchev, A., Canagarajah, B., Wilsbacher, J.,
Robinson, M., Atkinson, M., Goldsmith, E., and Cobb, M.H. (1998). Phosphorylation of the
MAP kinase ERK2 promotes its homodimerization and nuclear translocation. Cell 93,
605-615.
Hutchison, M., Berman, K., and Cobb, M. H. (1998)
Isolation of TAO1, a protein kinase that activates MEKs in stress-activated protein kinase
cascades. J Biol Chem 273, 28625-28632.
Frost, J. A., Khokhlatchev, A., White, M. A., and Cobb, M.
H. (1998) Differential effect of PAK1 activating mutations reveal protein-protein
interactions required for cytoskeletal regulation. J Biol Chem 273, 28253-28260.
10-20-98.
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Last updated: 17 Nov 2000
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