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 (phosphoglycerate mutase family member 5) is found in metazoan and many protists but is absent from fungi, plants, and amoebozoa. 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].

TULAs

There are two TULAs in human, UBASH3A (STS-2 or TULA-1) and UBASH3B (STS-1 or TULA-2). 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. 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].

References

1. Takeda K, Komuro Y, Hayakawa T, Oguchi H, Ishida Y, Murakami S, Noguchi T, Kinoshita H, Sekine Y, Iemura S, Natsume T, and Ichijo H. Mitochondrial phosphoglycerate mutase 5 uses alternate catalytic activity as a protein serine/threonine phosphatase to activate ASK1. Proc Natl Acad Sci U S A. 2009 Jul 28;106(30):12301-5. DOI:10.1073/pnas.0901823106 |
2. Wang Z, Jiang H, Chen S, Du F, and Wang X. The mitochondrial phosphatase PGAM5 functions at the convergence point of multiple necrotic death pathways. Cell. 2012 Jan 20;148(1-2):228-43. DOI:10.1016/j.cell.2011.11.030 |
3. Chen G, Han Z, Feng D, Chen Y, Chen L, Wu H, Huang L, Zhou C, Cai X, Fu C, Duan L, Wang X, Liu L, Liu X, Shen Y, Zhu Y, and Chen Q. A regulatory signaling loop comprising the PGAM5 phosphatase and CK2 controls receptor-mediated mitophagy. Mol Cell. 2014 May 8;54(3):362-77. DOI:10.1016/j.molcel.2014.02.034 |
4. Raguz J, Wagner S, Dikic I, and Hoeller D. Suppressor of T-cell receptor signalling 1 and 2 differentially regulate endocytosis and signalling of receptor tyrosine kinases. FEBS Lett. 2007 Oct 2;581(24):4767-72. DOI:10.1016/j.febslet.2007.08.077 |
5. Agrawal R, Carpino N, and Tsygankov A. TULA proteins regulate activity of the protein tyrosine kinase Syk. J Cell Biochem. 2008 Jun 1;104(3):953-64. DOI:10.1002/jcb.21678 |
6. Rigden DJ. The histidine phosphatase superfamily: structure and function. Biochem J. 2008 Jan 15;409(2):333-48. DOI:10.1042/BJ20071097 |