title: MAPKK-independent activation of p38alpha mediated by TAB1-dependent autophosphorylation of p38alpha.
abstract: Phosphorylation of mitogen-activated protein kinases (MAPKs) on specific tyrosine and threonine sites by MAP kinase kinases (MAPKKs) is thought to be the sole activation mechanism. Here, we report an unexpected activation mechanism for p38alpha MAPK that does not involve the prototypic kinase cascade. Rather it depends on interaction of p38alpha with TAB1 [transforming growth factor-beta-activated protein kinase 1 (TAK1)-binding protein 1] leading to autophosphorylation and activation of p38alpha. We detected formation of a TRAF6-TAB1-p38alpha complex and showed stimulus-specific TAB1-dependent and TAB1-independent p38alpha activation. These findings suggest that alternative activation pathways contribute to the biological responses of p38alpha to various stimuli.
authors.affiliation: Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Baoxue
authors.initials: B
authors.lastname: Ge
authors.forename: Hermann
authors.initials: H
authors.lastname: Gram
authors.forename: Franco
authors.initials: F
authors.lastname: Di Padova
authors.forename: Betty
authors.initials: B
authors.lastname: Huang
authors.forename: Liguo
authors.initials: L
authors.lastname: New
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Ulevitch
authors.forename: Ying
authors.initials: Y
authors.lastname: Luo
authors.forename: Jiahuai
authors.initials: J
authors.lastname: Han
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D001665:Binding Sites; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D029721:Drosophila Proteins; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D048669:MAP Kinase Kinase 6; D020935:MAP Kinase Signaling System; D008562:Membrane Glycoproteins / Q000378:metabolism; D048308:Mitogen-Activated Protein Kinase 14; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D010449:Peptide Mapping; D030421:Peroxynitrous Acid / Q000494:pharmacology; D010766:Phosphorylation; D011506:Proteins / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D048029:TNF Receptor-Associated Factor 6; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D020798:Two-Hybrid System Techniques; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D029721:Drosophila Proteins; D004791:Enzyme Inhibitors; D007093:Imidazoles; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D011506:Proteins; D011725:Pyridines; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins; C099510:TAB1 protein, MAPKKK activator, vertebrate; C486300:TAB1 protein, human; D048029:TNF Receptor-Associated Factor 6; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D030421:Peroxynitrous Acid; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048308:Mitogen-Activated Protein Kinase 14; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048669:MAP Kinase Kinase 6; C482566:MAP2K6 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases; C093642:SB 203580