Difference between revisions of "Phosphatase Subfamily STS"

Revision as of 20:06, 31 August 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 is found in most metazoa. Human has two STS: STS1 (TULA-2 or UBASH3B) and STS2 (TULA-1 or UBASH3A). STS1 is found in all vertebrates, while STS2 is not found in bony fish. 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, are 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 [2]. In particular, STS regulates T Cell Receptor (TCR) signaling by acting on the Syk family kinases, Syk and ZAP-70. STS2 is predominantly in naive and mature T cells (white blood, spleen and small intestine, according to GTEx), whereas STS1 is expressed ubiquitously (according to GTEx, particularly abundant in cerebellum).

STS1 decreases tyrosine phosphorylation of Syk in vivo and in vitro [3, 4], and this is reversed by transfection of an inactive STS1 mutant. In addition, both STS1 and STS2 regulate kinase ZAP-70 activation [4].

Human STS1 can also dephosphorylate pTyr on EGFR [5] and is overexpressed in triple-negative breast cancer and promotes invasion and metastasis [6]. STS1 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

Loss of UBA, 2H and SH3 domain was seen in all C. elegans STS. NCBI Blast, interrogation of an internal orthology database, and Pfam profiling were used to show that all other nematode STS proteins also lack these domains.

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. 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]
3. 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]
4. 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]
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. Zhang J, Vakhrusheva O, Bandi SR, Demirel Ö, Kazi JU, Fernandes RG, Jakobi K, Eichler A, Rönnstrand L, Rieger MA, Carpino N, Serve H, and Brandts CH. The Phosphatases STS1 and STS2 Regulate Hematopoietic Stem and Progenitor Cell Fitness. Stem Cell Reports. 2015 Oct 13;5(4):633-46. DOI:10.1016/j.stemcr.2015.08.006 | PubMed ID:26365512 | HubMed [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]