The goal of this application is to characterize the kinases that are activated by chemotactic factors, specifically those kinases which are not activated by protein kinase C dependent mechanisms , and to identify the substrates of these kinases. The ultimate goal is to understand the role of these kinase pathways in neutrophil activation and function in response to chemotactic factors, cytokines or crosslinking of Ff receptors.
The specific aims are, first, to continue to define the protein Kinases that are activated in response to the above mentioned stimuli and specifically those which are not protein kinase dependent. The specific projects will concentrate upon activation and regulation of three kinases in this Specific Aim. 1) MAPKAP-kinase 2, 2) (PKH4) protein kinase histone 4 and 3) calcium-calmodulin-dependent protein kinase II (CAMPKII).
Specific aim 2 will concentrate on further definition on the phosphoproteins of these kinases. Much of this work concentrate on the recently identified substrate of the MAPKAP-kinase, (LSP1) lymphocytes specific protein 1. In addition, various assays of neutrophil function will be performed, using relatively specific inhibitors of different kinases and intrinsic kinase activity of these kinases in control cells in stimulated cells will be performed using immunoprecipitation and in vitro kinase assays.
|Wu, Yue; Zhan, Lijun; Ai, Youxi et al. (2007) MAPKAPK2-mediated LSP1 phosphorylation and FMLP-induced neutrophil polarization. Biochem Biophys Res Commun 358:170-5|
|Hannigan, Michael; Zhan, Lijun; Li, Zhong et al. (2002) Neutrophils lacking phosphoinositide 3-kinase gamma show loss of directionality during N-formyl-Met-Leu-Phe-induced chemotaxis. Proc Natl Acad Sci U S A 99:3603-8|
|Mathews, Clayton E; Dunn, Brian D; Hannigan, Michael O et al. (2002) Genetic control of neutrophil superoxide production in diabetes-resistant ALR/Lt mice. Free Radic Biol Med 32:744-51|
|Hannigan, M O; Zhan, L; Ai, Y et al. (2001) Abnormal migration phenotype of mitogen-activated protein kinase-activated protein kinase 2-/- neutrophils in Zigmond chambers containing formyl-methionyl-leucyl-phenylalanine gradients. J Immunol 167:3953-61|
|Hannigan, M; Zhan, L; Ai, Y et al. (2001) Leukocyte-specific gene 1 protein (LSP1) is involved in chemokine KC-activated cytoskeletal reorganization in murine neutrophils in vitro. J Leukoc Biol 69:497-504|
|Huang, C K; Zhan, L; Hannigan, M O et al. (2000) P47(phox)-deficient NADPH oxidase defect in neutrophils of diabetic mouse strains, C57BL/6J-m db/db and db/+. J Leukoc Biol 67:210-5|
|Zu, Y L; Qi, J; Gilchrist, A et al. (1998) p38 mitogen-activated protein kinase activation is required for human neutrophil function triggered by TNF-alpha or FMLP stimulation. J Immunol 160:1982-9|
|Hannigan, M; Zhan, L; Ai, Y et al. (1998) The role of p38 MAP kinase in TGF-beta1-induced signal transduction in human neutrophils. Biochem Biophys Res Commun 246:55-8|
|Huang, C K; Zhan, L; Ai, Y et al. (1997) LSP1 is the major substrate for mitogen-activated protein kinase-activated protein kinase 2 in human neutrophils. J Biol Chem 272:17-9|
|Zu, Y L; Ai, Y; Gilchrist, A et al. (1997) High expression and activation of MAP kinase-activated protein kinase 2 in cardiac muscle cells. J Mol Cell Cardiol 29:2159-68|
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