title: JNK1 differentially regulates osteopontin-induced nuclear factor-inducing kinase/MEKK1-dependent activating protein-1-mediated promatrix metalloproteinase-9 activation.
abstract: We have recently demonstrated that nuclear factor-inducing kinase (NIK) plays a crucial role in osteopontin (OPN)-induced mitogen-activated protein kinase/I kappa B alpha kinase-dependent nuclear factor kappa B (NF kappa B)-mediated promatrix metalloproteinase-9 activation (Rangaswami, H., Bulbule, A., and Kundu, G. C. (2004) J. Biol. Chem. 279, 38921-38935). However, the molecular mechanism(s) by which OPN regulates NIK/MEKK1-dependent activating protein-1 (AP-1)-mediated promatrix metalloproteinase-9 activation and whether JNK1 plays any role in regulating both these pathways that control the cell motility are not well defined. Here we report that OPN induces alpha v beta3 integrin-mediated MEKK1 phosphorylation and MEKK1-dependent JNK1 phosphorylation and activation. Overexpression of NIK enhances OPN-induced c-Jun expression, whereas overexpressed NIK had no role in OPN-induced JNK1 phosphorylation and activation. Sustained activation of JNK1 by overexpression of wild type but not kinase negative MEKK1 resulted in suppression of ERK1/2 activation. But this did not affect the OPN-induced NIK-dependent ERK1/2 activation. OPN stimulated both NIK and MEKK1-dependent c-Jun expression, leading to AP-1 activation, whereas NIK-dependent AP-1 activation is independent of JNK1. OPN also enhanced JNK1-dependent/independent AP-1-mediated urokinase type plasminogen activator (uPA) secretion, uPA-dependent promatrix metalloproteinase-9 (MMP-9) activation, cell motility, and invasion. OPN stimulates tumor growth, and the levels of c-Jun, AP-1, urokinase type plasminogen activator, and MMP-9 were higher in OPN-induced tumor compared with control. To our knowledge this is first report that OPN induces NIK/MEKK1-mediated JNK1-dependent/independent AP-1-mediated pro-MMP-9 activation and regulates the negative crosstalk between NIK/ERK1/2 and MEKK1/JNK1 pathways that ultimately controls the cell motility, invasiveness, and tumor growth.
authors.affiliation: National Center for Cell Science, Pune 411 007, India.
authors.forename: Hema
authors.initials: H
authors.lastname: Rangaswami
authors.forename: Anuradha
authors.initials: A
authors.lastname: Bulbule
authors.forename: Gopal C
authors.initials: GC
authors.lastname: Kundu
mesh_terms: D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement; D002467:Cell Nucleus / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic; D017930:Genes, Reporter; D006801:Humans; D047468:Immunoprecipitation; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008156:Luciferases / Q000378:metabolism; D048728:MAP Kinase Kinase Kinase 1 / Q000378:metabolism*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism / Q000502:physiology*; D008954:Models, Biological; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D053495:Osteopontin; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012795:Sialoglycoproteins / Q000378:metabolism*; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism
chemical_list: D039302:Integrin alphaVbeta3; D047908:Intracellular Signaling Peptides and Proteins; C506895:SPP1 protein, human; D012795:Sialoglycoproteins; C506896:Spp1 protein, mouse; D018808:Transcription Factor AP-1; D053495:Osteopontin; D004247:DNA; D008156:Luciferases; C117090:MAP4K4 protein, human; D017346:Protein Serine-Threonine Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048055:Mitogen-Activated Protein Kinase 8; D048728:MAP Kinase Kinase Kinase 1; D014568:Urokinase-Type Plasminogen Activator; D020780:Matrix Metalloproteinase 9