Phosphatase Subfamily TAB1

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Phosphatase Classification: Fold PPM (PP2C): Superfamily PPM (PP2C): Family PPM (PP2C): Subfamily TAB1


The TAB1 subfamily is found throughout metazoa. It was lost in Drosophila, but is present in most other arthropods (see internal data). Its interacting kinases from the MAPK cascade, TAK1 and p38 emerged earlier, in holozoa and opisthokont, respectively. Interestingly, they are present in Drosophila, which suggests Drosophila may lose the TAB1 modulation of TAK1 and p38.

Human TAB1 can be phosphorylated at Ser-452, Ser-453, Ser-456, Ser-457 by TAK1 and p38 [1]. This stretch of serines is not found in invertebrates.


TAB1 has a PPM-fold phosphatase domain and a C-terminal TAK1-binding motif motif (PYVDxA/TxF) [2]. The phosphatase domain binds to X-linked inhibitor of apoptosis (XIAP) [3].


Human TAB1 is a pseudophosphatase but basal metazoan TAB1s are probably active

Human TAB1 is a pseudophosphatase. Several key residues required for dual metal-binding (D69N, D290E, D356E, N367D) and catalysis (H71Y) are substitued by other amino acids [4]. However, not all of the substitutions are conserved. D69 is found in invertebrates, including sponge, nematostella and sea urchin; D290 is found in metazoa except chordates, such as sponge, nematostella and C. elegans; D356 is found in metazoa, such as sponge, nematostella and sea urchin; H71 is found in basal metazoa, such as nematostella and sponge. Thus, TAB1s in basal metazoa are probably active, though human TAB1 is inactive.

TAB1 binds to TAK1 and induces its autophosphorylation

TAB1 physically associates with TAK1 [5] and induces TAK1 autoactivation, both in human [6, 7] and C. elegans [8, 9].

TAB1 has a conserved C-terminal region of about 30 AA, including a PYVDXA/TXF, motif, found to mediate TAK1 interaction in vertebrates and nematodes [2, 6]. This association is isoform specific: the TAB1β splice isoform replaces the the C-terminal 69 AA with an unrelated 27 AA sequence. This does not interact with TAK1 [10].

TAB1 binds to p38α and induces its autophosphorylation

Human TAB1 associates with p38α in complex with TRAF6 [11] and induces its autophosphorylation [12]. p38α binds to both the isoforms TAB1α and TAB1β [10].

  • p38α [11, 13, 14]. TAB1 functions as a scaffold protein in the activation of p38 [14]. The interaction between TAB1 and p38α is mediated by Pro-412 on TAB1 and a hydrophobic docking groove on p38α [15]. The Pro-412 of TAB1 does not localize in a conserved region, so it is hard to tell whether it is conserved.
Other interacting partners: XIAP and MEKK1
  • MEKK1 [16]. TAB1 is ubiquitinated by MEKK1 PHD domain.
  • X-chromosome-linked inhibitor of apoptosis protein (XIAP) [17].


  1. Wolf A, Beuerlein K, Eckart C, Weiser H, Dickkopf B, Müller H, Sakurai H, and Kracht M. Identification and functional characterization of novel phosphorylation sites in TAK1-binding protein (TAB) 1. PLoS One. 2011;6(12):e29256. DOI:10.1371/journal.pone.0029256 | PubMed ID:22216226 | HubMed [Wolf11]
  2. Ono K, Ohtomo T, Sato S, Sugamata Y, Suzuki M, Hisamoto N, Ninomiya-Tsuji J, Tsuchiya M, and Matsumoto K. An evolutionarily conserved motif in the TAB1 C-terminal region is necessary for interaction with and activation of TAK1 MAPKKK. J Biol Chem. 2001 Jun 29;276(26):24396-400. DOI:10.1074/jbc.M102631200 | PubMed ID:11323434 | HubMed [Ono01]
  3. Lu M, Lin SC, Huang Y, Kang YJ, Rich R, Lo YC, Myszka D, Han J, and Wu H. XIAP induces NF-kappaB activation via the BIR1/TAB1 interaction and BIR1 dimerization. Mol Cell. 2007 Jun 8;26(5):689-702. DOI:10.1016/j.molcel.2007.05.006 | PubMed ID:17560374 | HubMed [Lu07]
  4. Conner SH, Kular G, Peggie M, Shepherd S, Schüttelkopf AW, Cohen P, and Van Aalten DM. TAK1-binding protein 1 is a pseudophosphatase. Biochem J. 2006 Nov 1;399(3):427-34. DOI:10.1042/BJ20061077 | PubMed ID:16879102 | HubMed [Conner06]
  5. Shibuya H, Yamaguchi K, Shirakabe K, Tonegawa A, Gotoh Y, Ueno N, Irie K, Nishida E, and Matsumoto K. TAB1: an activator of the TAK1 MAPKKK in TGF-beta signal transduction. Science. 1996 May 24;272(5265):1179-82. DOI:10.1126/science.272.5265.1179 | PubMed ID:8638164 | HubMed [Shibuya96]
  6. Sakurai H, Miyoshi H, Mizukami J, and Sugita T. Phosphorylation-dependent activation of TAK1 mitogen-activated protein kinase kinase kinase by TAB1. FEBS Lett. 2000 Jun 2;474(2-3):141-5. DOI:10.1016/s0014-5793(00)01588-x | PubMed ID:10838074 | HubMed [Sakurai00]
  7. Scholz R, Sidler CL, Thali RF, Winssinger N, Cheung PC, and Neumann D. Autoactivation of transforming growth factor beta-activated kinase 1 is a sequential bimolecular process. J Biol Chem. 2010 Aug 13;285(33):25753-66. DOI:10.1074/jbc.M109.093468 | PubMed ID:20538596 | HubMed [Scholz10]
  8. Meneghini MD, Ishitani T, Carter JC, Hisamoto N, Ninomiya-Tsuji J, Thorpe CJ, Hamill DR, Matsumoto K, and Bowerman B. MAP kinase and Wnt pathways converge to downregulate an HMG-domain repressor in Caenorhabditis elegans. Nature. 1999 Jun 24;399(6738):793-7. DOI:10.1038/21666 | PubMed ID:10391246 | HubMed [Meneghini99]
  9. Smit L, Baas A, Kuipers J, Korswagen H, van de Wetering M, and Clevers H. Wnt activates the Tak1/Nemo-like kinase pathway. J Biol Chem. 2004 Apr 23;279(17):17232-40. DOI:10.1074/jbc.M307801200 | PubMed ID:14960582 | HubMed [Smit04]
  10. Ge B, Xiong X, Jing Q, Mosley JL, Filose A, Bian D, Huang S, and Han J. TAB1beta (transforming growth factor-beta-activated protein kinase 1-binding protein 1beta ), a novel splicing variant of TAB1 that interacts with p38alpha but not TAK1. J Biol Chem. 2003 Jan 24;278(4):2286-93. DOI:10.1074/jbc.M210918200 | PubMed ID:12429732 | HubMed [Ge03]
  11. Ge B, Gram H, Di Padova F, Huang B, New L, Ulevitch RJ, Luo Y, and Han J. MAPKK-independent activation of p38alpha mediated by TAB1-dependent autophosphorylation of p38alpha. Science. 2002 Feb 15;295(5558):1291-4. DOI:10.1126/science.1067289 | PubMed ID:11847341 | HubMed [Ge02]
  12. Tanno M, Bassi R, Gorog DA, Saurin AT, Jiang J, Heads RJ, Martin JL, Davis RJ, Flavell RA, and Marber MS. Diverse mechanisms of myocardial p38 mitogen-activated protein kinase activation: evidence for MKK-independent activation by a TAB1-associated mechanism contributing to injury during myocardial ischemia. Circ Res. 2003 Aug 8;93(3):254-61. DOI:10.1161/01.RES.0000083490.43943.85 | PubMed ID:12829618 | HubMed [Tanno03]
  13. Lanna A, Henson SM, Escors D, and Akbar AN. The kinase p38 activated by the metabolic regulator AMPK and scaffold TAB1 drives the senescence of human T cells. Nat Immunol. 2014 Oct;15(10):965-72. DOI:10.1038/ni.2981 | PubMed ID:25151490 | HubMed [Lanna14]
  14. Zhou H, Zheng M, Chen J, Xie C, Kolatkar AR, Zarubin T, Ye Z, Akella R, Lin S, Goldsmith EJ, and Han J. Determinants that control the specific interactions between TAB1 and p38alpha. Mol Cell Biol. 2006 May;26(10):3824-34. DOI:10.1128/MCB.26.10.3824-3834.2006 | PubMed ID:16648477 | HubMed [Zhou06]
  15. Charlaftis N, Suddason T, Wu X, Anwar S, Karin M, and Gallagher E. The MEKK1 PHD ubiquitinates TAB1 to activate MAPKs in response to cytokines. EMBO J. 2014 Nov 3;33(21):2581-96. DOI:10.15252/embj.201488351 | PubMed ID:25260751 | HubMed [Charlaftis14]
  16. Yamaguchi K, Nagai S, Ninomiya-Tsuji J, Nishita M, Tamai K, Irie K, Ueno N, Nishida E, Shibuya H, and Matsumoto K. XIAP, a cellular member of the inhibitor of apoptosis protein family, links the receptors to TAB1-TAK1 in the BMP signaling pathway. EMBO J. 1999 Jan 4;18(1):179-87. DOI:10.1093/emboj/18.1.179 | PubMed ID:9878061 | HubMed [Yamaguchi99]
  17. Zhu Y, Regunath K, Jacq X, and Prives C. Cisplatin causes cell death via TAB1 regulation of p53/MDM2/MDMX circuitry. Genes Dev. 2013 Aug 15;27(16):1739-51. DOI:10.1101/gad.212258.112 | PubMed ID:23934659 | HubMed [Zhu14]
All Medline abstracts: PubMed | HubMed