Phosphatase Family HP1

Phosphatase Classification: Histidine phosphatase superfamily: HP, branch1 family

Two subfamilies in this family have been reported as protein phosphatases. Refer to Pfam ID PF00300 for general information.

PGAM5

PGAM5 is first thought as an enzyme of intermediary metabolism that converts 3-phosphoglycerate to 2-phosphoglycerate in glycolysis. Later, Takeda et al. reported that PGAM5 dephosphorylates and activates MAP kinase kinase kinase ASK1 [1]. PGAM5 is anchored in the mitochondrial membrane and it lacks PGAM activity, but instead it associates with ASK1 and activates ASK1 by dephosphorylation of inhibitory sites. Mutation of an active site His-105 in PGAM5 abolished phosphatase activity with ASK1 and pThr peptides as substrates. The Drosophila and Caenorhabditis elegans orthologs of PGAM5 also exhibit specific Ser/Thr phosphatase activity and activate the corresponding Drosophila and C. elegans ASK1 kinases [1]. PGAM5 was also reported to dephosphorylate the serine 637 site of Drp1. The dephosphorylation activates the GTPase activity of Drp1 and causes mitochondrial fragmentation, an early and obligatory step for necrosis execution [2]. PGAM5 was recently reported to dephosphorylate FUNDC1 at Ser-13 and thereby activates mitophagy [3]. PGAM5 (phosphoglycerate mutase family member 5) is found in metazoan and many protists but is absent from fungi, plants, and amoebozoa.

STSs/TULAs

There are two TULAs in human, UBASH3A (STS-2 or TULA-1) and UBASH3B (STS-1 or TULA-2). Both TULAs negatively regulate the endocytosis of receptor tyrosine kinases. The UBA domain of TULA-1 and SH3-dependent Cbl-binding are required for this function. TULA-1 (STS-2) is a lymphoid protein, whereas TULA-2 (STS-1) is expressed ubiquitously. It has been shown that TULA-2 can dephosphorylate phospho-tyrosines on EGFR and Syk. The histidine phosphatase domain of TULA-2, but not of TULA-1, dephosphorylates the EGFR at multiple tyrosines, and thereby terminating its signalling and endocytosis [4]. TULA-2 decreases tyrosine phosphorylation of Syk in vivo and in vitro. Inactivated TULA-2 increases tyrosine phosphorylation of Syk in cells co-transfected to overexpress these proteins, thus acting as a dominant-negative form that suppresses dephosphorylation of Syk caused by endogenous TULA-2. However, the same assay on TULA-1 shows the phosphatase activity of TULA-1 is negligible compared to TULA-2 [5]. TULA-1 is present in lobe-finned fish, birds and mammals, but not other bony fishes. TULA-2 emerged earlier than TULA-1, which is found in most metazoan, from sponge to nematodes, insects, fishes, birds, and mammals.

References

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