Mitogen-activated protein kinases (MAPKs) are serine-threonine protein kinases that are activated by diverse stimuli ranging from cytokines, neurotransmitters, hormones, cellular stress and cell adherence. The basic assembly of MAPK pathways is a three-component module conserved from yeast to humans. The MAPK module includes three kinases that establish a sequential activation pathway comprising MAPK kinase kinase (MKKK), MAPK kinase (MKK), and MAPK. Currently, the mammalian MAPKs can be subdivided into five families: ERK1/2, p38alpha, Beta, Gamma, delta, JNK1 ,2,3, ERK3/4 and ERK5. Each family of MAPKs has distinct biological regulatory functions. The number of different MKKKs in MAPK modules allows for a diversity of inputs capable of activating specific MAPK pathways. The hypothesis that is the foundation of the research described in this proposal is that multiple MKKKs regulate common MKK/MAPK modules. MKKKs are differentially regulated by upstream signals allowing common MAPK pathways to be selectively regulated by the specific MKKK within the MAPK module. The composition of MAPK modules involves scaffolding proteins and interaction domains encoded in each MKKK, MKK and MAPK. The targeted gene disruption of each MKKK will therefore have a selective loss in the regulation of MAPK pathways in response to a set of specific stimuli. The phenotypic consequence of specific MKKK gene disruptions will therefore have unique defects in cellular regulation. My laboratory first cloned four of the MKKKs referred to as MEKK1, 2, 3 & 4. MEKKs regulate the JNK pathway. MEKK2 and 3 also regulate the ERK5 pathway. Targeted gene disruption of MEKK1, 2, 3 & 4 by homologous recombination has been completed. The MEKK1, 2 and 3 knockouts have unique phenotypes, signaling defects and pathologies. MEKK4 knockout is being characterized. MEKK1-/- animals have defects in cytokine expression, protease regulation and organ homeostasis. MEKK2-/- animals have immune defects with loss of cytokine expression and deficient T cell migration to lymph nodes. MEKK3-/- embryos die at day E4-7 and are postulated to have defects in trophoblast signaling in response to FGF4 or HB-EGF (heparin-binding EGF).
Specific aims i nclude: define the pathophysiology of mice having the targeted disruption of MEKK genes, define the signaling and functional abnormalities in cells deficient for each MEKK, and characterize the function of scaffold proteins we cloned that bind MEKK2 & 3. Cumulatively, the studies are defining the role of MEKKs in the control of physiological processes including wound healing, cardiac hypertrophy, lung inflammation, immune response and signaling controlling embryo development.
| Graves, Lee M; Duncan, James S; Whittle, Martin C et al. (2013) The dynamic nature of the kinome. Biochem J 450:1-8 |
| Wu, Congying; Asokan, Sreeja B; Berginski, Matthew E et al. (2012) Arp2/3 is critical for lamellipodia and response to extracellular matrix cues but is dispensable for chemotaxis. Cell 148:973-87 |
| Duncan, James S; Whittle, Martin C; Nakamura, Kazuhiro et al. (2012) Dynamic reprogramming of the kinome in response to targeted MEK inhibition in triple-negative breast cancer. Cell 149:307-21 |
| Cronan, M R; Nakamura, K; Johnson, N L et al. (2012) Defining MAP3 kinases required for MDA-MB-231 cell tumor growth and metastasis. Oncogene 31:3889-900 |
| Johnson, Gary L (2011) Defining MAPK interactomes. ACS Chem Biol 6:18-20 |
| Huang, Weichun; Umbach, David M; Vincent Jordan, Nicole et al. (2011) Efficiently identifying genome-wide changes with next-generation sequencing data. Nucleic Acids Res 39:e130 |
| Abell, Amy N; Jordan, Nicole Vincent; Huang, Weichun et al. (2011) MAP3K4/CBP-regulated H2B acetylation controls epithelial-mesenchymal transition in trophoblast stem cells. Cell Stem Cell 8:525-37 |
| Jordan, Nicole Vincent; Johnson, Gary L; Abell, Amy N (2011) Tracking the intermediate stages of epithelial-mesenchymal transition in epithelial stem cells and cancer. Cell Cycle 10:2865-73 |
| Nakamura, Kazuhiro; Kimple, Adam J; Siderovski, David P et al. (2010) PB1 domain interaction of p62/sequestosome 1 and MEKK3 regulates NF-kappaB activation. J Biol Chem 285:2077-89 |
| Konhilas, John P; Boucek, Dana M; Horn, Todd R et al. (2010) The role of MEKK1 in hypertrophic cardiomyopathy. Int Heart J 51:277-84 |
Showing the most recent 10 out of 111 publications
