title: TAB3, a new binding partner of the protein kinase TAK1.
abstract: We have identified a new binding partner of the TGFbeta (transforming growth factor-beta)-activated protein kinase (TAK1), termed TAB3 (TAK1-binding protein-3), which shares 48% amino acid sequence identity with TAB2. Our results indicate that two distinct TAK1 complexes are present in cells. One comprises TAK1 complexed with TAB1 and TAB2, and the other TAK1 complexed with TAB1 and TAB3. Both complexes are activated in response to tumour necrosis factor-alpha or interleukin-1 in human epithelial KB cells or bacterial lipopolysaccharide in RAW264.7 macrophages, and are subject to feedback control by stress-activated protein kinase 2a (SAPK2a; also called p38alpha). The electrophoretic mobility of TAB2 and TAB3 decreases in response to these agonists or osmotic shock, and is reversed by treatment with protein phosphatase-1. The decrease in mobility of TAB3 is prevented if the cells are incubated with SB 203580 before stimulation, but treatment with SB 203580 produces forms of TAB2 with a mobility intermediate between that observed for TAB2 in unstimulated and stimulated cells. Similar results were obtained in embryonic fibroblasts from mice deficient in SAPK2a/p38alpha. Our results indicate that TAB3 is phosphorylated via the SAPK2a/p38alpha pathway, whereas TAB2 is phosphorylated at two or more sites by both an SAPK2a/p38alpha-dependent and an SB 203580-independent kinase. The SAPK2a/p38alpha-mediated phosphorylation of TAB2 and TAB3 may contribute to the SAPK2a/p38alpha-mediated feedback control of TAK1 activity that also involves the phosphorylation of TAB1. We also show that the agonist-induced activation of TAK1 complexes requires the phosphorylation of the TAK1 catalytic subunit at a serine/threonine residue(s).
authors.affiliation: MRC Protein Phosphorylation Unit, School of Life Sciences, MSI/WTB Complex, Dow Street, University of Dundee, Dundee DD1 5EH, Scotland, UK.
authors.forename: Peter C F
authors.initials: PC
authors.lastname: Cheung
authors.forename: Angel R
authors.initials: AR
authors.lastname: Nebreda
authors.forename: Philip
authors.initials: P
authors.lastname: Cohen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism*; D002478:Cells, Cultured; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D046911:Macromolecular Substances; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008969:Molecular Sequence Data; D014018:Tissue Distribution; D048051:p38 Mitogen-Activated Protein Kinases; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D020930:MAP Kinase Kinase Kinases; D046911:Macromolecular Substances; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000099151:MAP Kinase Kinase Kinase 7; C099510:TAB1 protein, MAPKKK activator, vertebrate; C486300:TAB1 protein, human; C410585:TAB2 protein, human; C481053:TAB3 protein, human