Difference between revisions of "Phosphatase Subfamily STS"

Revision as of 17:35, 15 May 2016

Phosphatase Classification: Fold HP: Superfamily HP (histidine phosphatase): HP, branch1 family: Subfamily STS

STS is protein tyrosine phosphatase involved in T-cell receptor signaling. In particular, STS dephosphorylates kinases Syk and ZAP-70 of Syk subfamily. STS is conserved in metazoan.

Evolution

STS subfamily is found in most metazoa. Human has two STSs: STS-1 (TULA-2 or UBASH3B) and STS-2 (TULA-1 or UBASH3A). STS-2 is present in lobe-finned fish, birds and mammals, but not other bony fishes. STS-1 emerged earlier than STS-2, which is found in most metazoan, from sponge to insects, fishes, birds, and mammals. C. elegans has five STS genes, but all of them lack UBA (ubiquitin-associated domain), 2H phosphoesterase, and SH3 domains. Interestingly, STS substrates, Syk and ZAP-70, both of which belong to SYK kinase family, is absent from C. elegans.

Domain

Most STS have four domains: UBA (ubiquitin-associated domain), 2H phosphoesterase [1], SH3 and HP2 phosphatase domain. The UBA, 2H and SH3 domains are absent from all nematode members (see technical notes).

Functions

Human STS1 and STS2 bind to the Cbl protein via their SH3 domains and interact with several membrane-associated signaling proteins. In particular, STS regulates T Cell Receptor (TCR) signaling by acting on the Syk family kinases, Syk and ZAP-70. STS-2/TULA1/UBASH3A is predominantly in naive and mature T cells (white blood, spleen and small intestine, according to GTEx), whereas STS-1/TULA2/UBASH3B is expressed ubiquitously (according to GTEx, particularly abundant in cerebellum (not whole brain)).

STS-1 decreases tyrosine phosphorylation of Syk in vivo and in vitro [2, 3]. Inactivated STS-1 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 STS-1. However, the same assay on STS-2 shows the phosphatase activity of STS-2 is negligible compared to STS-1. The UBA domain of STS-2 and SH3-dependent Cbl-binding are required for this function [4]. In addition, both STS-1 and STS-2 regulate kinase ZAP-70 activation [3].

Human STS-1 can also dephosphorylate pTyr on EGFR [5] and is overexpressed in triple-negative breast cancer and promotes invasion and metastasis [6]. STS-1 dephosphorylated the EGFR at multiple tyrosines, terminating its signalling and endocytosis [5]. STS1 and STS2 also dephosphorylate the receptor tyrosine kinases Kit and Flt3, and double knockout mice show greatly expanded hematopoiesis [7].

Drosophila STS (CG13604) was shown to have activity on phosphorylated ecdysteroids, the storage form of these molting hormones, and the C. elegans homolog T07F12.1 also had activity [8]. A silkworm homolog was also shown to have ecdysteroid phosphatase activity [9]. An Unclassified HP1-family yeast phosphatase, DET1 has been implicated in sterol trafficking [10], but it is not known if phosphatase activity is involved.

Technical notes

Nematodes lost UBA, 2H and SH3 domain

We observed the absence of UBA, 2H and SH3 domain in C. elegans. We then asked whether the lose is conserved, which can be use to measure the reliability of the lose. We obtained STSs from our internal orthology database, which has 203 eukaryotic genomes and 9 nematode genomes. We then searched Pfam domain in the STSs using Pfam web server (E-value cutoff 1.0). We found none of the 24 DSPs from 9 nematode genomes has UBA, 2H or SH3 domain.

References

1. Mazumder R, Iyer LM, Vasudevan S, and Aravind L. Detection of novel members, structure-function analysis and evolutionary classification of the 2H phosphoesterase superfamily. Nucleic Acids Res. 2002 Dec 1;30(23):5229-43. DOI:10.1093/nar/gkf645 | PubMed ID:12466548 | HubMed [mazumder02]
2. Chen X, Ren L, Kim S, Carpino N, Daniel JL, Kunapuli SP, Tsygankov AY, and Pei D. Determination of the substrate specificity of protein-tyrosine phosphatase TULA-2 and identification of Syk as a TULA-2 substrate. J Biol Chem. 2010 Oct 8;285(41):31268-76. DOI:10.1074/jbc.M110.114181 | PubMed ID:20670933 | HubMed [chen10]
3. Carpino N, Turner S, Mekala D, Takahashi Y, Zang H, Geiger TL, Doherty P, and Ihle JN. Regulation of ZAP-70 activation and TCR signaling by two related proteins, Sts-1 and Sts-2. Immunity. 2004 Jan;20(1):37-46. DOI:10.1016/s1074-7613(03)00351-0 | PubMed ID:14738763 | HubMed [carpino04]
4. 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 | PubMed ID:18189269 | HubMed [STS_2]
5. 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 | PubMed ID:17880946 | HubMed [STS_1]
6. Lee ST, Feng M, Wei Y, Li Z, Qiao Y, Guan P, Jiang X, Wong CH, Huynh K, Wang J, Li J, Karuturi KM, Tan EY, Hoon DS, Kang Y, and Yu Q. Protein tyrosine phosphatase UBASH3B is overexpressed in triple-negative breast cancer and promotes invasion and metastasis. Proc Natl Acad Sci U S A. 2013 Jul 2;110(27):11121-6. DOI:10.1073/pnas.1300873110 | PubMed ID:23784775 | HubMed [Lee13]
7. pmid 26365512 [Zhang]
8. Davies L, Anderson IP, Turner PC, Shirras AD, Rees HH, and Rigden DJ. An unsuspected ecdysteroid/steroid phosphatase activity in the key T-cell regulator, Sts-1: surprising relationship to insect ecdysteroid phosphate phosphatase. Proteins. 2007 May 15;67(3):720-31. DOI:10.1002/prot.21357 | PubMed ID:17348005 | HubMed [Davies]
9. Yamada R and Sonobe H. Purification, kinetic characterization, and molecular cloning of a novel enzyme ecdysteroid-phosphate phosphatase. J Biol Chem. 2003 Jul 18;278(29):26365-73. DOI:10.1074/jbc.M304158200 | PubMed ID:12721294 | HubMed [Yamada]
10. Sullivan DP, Georgiev A, and Menon AK. Tritium suicide selection identifies proteins involved in the uptake and intracellular transport of sterols in Saccharomyces cerevisiae. Eukaryot Cell. 2009 Feb;8(2):161-9. DOI:10.1128/EC.00135-08 | PubMed ID:19060182 | HubMed [Sullivan]