Phosphatase Subfamily TAB1

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

Evolution

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 dephosphorylated at Ser-452, Ser-453, Ser-456, Ser-457 by TAK1 and p38 [1]. This stretch of series is not found in invertebrates.

Domain

The TAB1 subfamily has a phosphatase domain of PPM fold and a conserved C-terminal motif to bind TAK1, which has a pattern of PYVDXA/TXF [2].

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 [3]. 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 binds to TAK1 and induces its autophosphorylation

Human TAB1 associates with TAK1 [4] and induces TAK1 autoactivation [5, 6]. Similar results have been also observed in C. elegans, between tap-1 and mom-4, which are the orthologs of TAB1 and TAK1, respectively [7, 8].

TAB1 has a conserved C-terminal motif (last 30 amini acids), PYVDXA/TXF, among mammalian TAB1, Xenopus TAB1 and, C.elegans tap-1 [2, 5]. In addition, the association with TAK1 is isoform specific. TAB1α but not TAB1β interacts with TAK1. The two isoforms are identical except the C-terminal 69 amino acids of TAB1α were replaced with an unrelated 27-amino acid sequence [9]. Taken together, the interaction between TAB1α and TAK1 is mediated by the C-terminal motif.

TAB1 binds to p38α and induces its autophosphorylation

Human TAB1 associates with p38α in complex with TRAF6 [10] and induces its autophosphorylation [11]. In contrast with TAK1, which only binds to TAB1α, p38α binds to both the isoforms TAB1α and TAB1β [9].

• p38α [10, 12, 13]. TAB1 functions as a scaffold protein in the activation of p38 [13]. The interaction between TAB1 and p38α is mediated by Pro-412 on TAB1 and a hydrophobic docking groove on p38α [14]. 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 [15]. TAB1 is ubiquitinated by MEKK1 PHD domain.
• X-chromosome-linked inhibitor of apoptosis protein (XIAP) [16].

References

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