Phosphatase Subfamily TAB1

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

Domain

The TAB1 subfamily has a phosphatase domain of PPM fold.

Function

Human TAB1 is a pseudophosphatase but basal metazoa 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 [1]. However, not all of the substitutions are conserved in TAB1s. D69 is found in metazoa, such as 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-TAK1 complex

Human TAB1 associated with TAK1 [2]. The association induces TAK1 autoactivation [3].

• TRAF6 [].
• p38α [4, 5, 6]. TAB1 functions as a scaffold protein in the activation of p38 [6]. The interaction between TAB1 and p38α is mediated by Pro-412 on TAB1 and a hydrophobic docking groove on p38α [7]. The Pro-412 of TAB1 does not localize in a conserved region, so it is hard to tell whether it is conserved.

• MEKK1 [8]. TAB1 is ubiquitinated by MEKK1 PHD domain.

Human TAB1 can be dephosphorylated at Ser-452, Ser-453, Ser-456, Ser-457 by TAK1 and p38 [9]. These sites are not found in invertebrates.

References

1. 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 |
2. 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 |
3. 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 |
4. 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 |
6. 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 |
7. 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 |
8. 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 |
10. 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 |