Difference between revisions of "Phosphatase Subfamily STS"

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[[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Fold_HP|Fold HP]]: [[Phosphatase_Superfamily_HP|Superfamily HP]] (histidine phosphatase):  [[Phosphatase_Family_HP1|HP, branch1 family]]: [[Phosphatase_Subfamily_STS|Subfamily STS]]
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__NOTOC__
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[[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Fold_HP|Fold HP]]: [[Phosphatase_Superfamily_HP|Superfamily HP]]:  [[Phosphatase_Family_HP1|HP, branch1 family]]: [[Phosphatase_Subfamily_STS|Subfamily STS]]
  
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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.
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STS is protein tyrosine phosphatase involved in T-cell receptor signaling by dephosphorylating the Syk and ZAP-70 kinases. STS is found throughout metazoa.
  
 
=== Evolution ===
 
=== Evolution ===
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STS subfamily is found in most [[Phosphatase_Glossary#metazoa|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''.
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STS is found in most [[Phosphatase_Glossary#metazoa|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 ===
 
=== Domain ===
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Typical STS consists of four domains: [[Phosphatase_Glossary#Domain_UBA|UBA]]  (ubiquitin-associated domain), 2H phosphoesterase <cite>mazumder02</cite>, [[Phosphatase_Glossary#Domain_SH3|SH3]] and HP2 phosphatase domain. The UBA, 2H and SH3 domains are absent from ''C. elegans'' STSs and from nematodes in general (see technical notes).
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Most STS have four domains: [[Phosphatase_Glossary#Domain_UBA|UBA]]  (ubiquitin-associated domain), 2H phosphoesterase <cite>mazumder02</cite>, [[Phosphatase_Glossary#Domain_SH3|SH3]] and HP2 phosphatase domain. The UBA, 2H and SH3 domains are absent from all nematode members (see technical notes).
  
 
=== Functions ===
 
=== Functions ===
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Human STS-1 and STS-2 are involved in T Cell Receptor (TCR) signaling pathways by regulating kinase Syk and ZAP-70, two members of Syk kinase subfamily. STS-2/TULA1/UBASH3A is predominantly in naive and mature T cells (white blood, spleen and small intestine, according to [http://www.gtexportal.org/home/gene/UBASH3A GTEx]), whereas STS-1/TULA2/UBASH3B is expressed ubiquitously (according to [http://www.gtexportal.org/home/gene/UBASH3B GTEx], particularly abundant in cerebellum (not whole brain)).
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Human STS1 and STS2 bind to the Cbl protein via their SH3 domains and interact with several membrane-associated signaling proteins  <cite>STS_2</cite>. In particular, STS regulates T Cell Receptor (TCR) signaling by acting on the [http://kinase.com/wiki/index.php/Kinase_Family_Syk Syk family] kinases, Syk and ZAP-70. STS2 is predominantly in naive and mature T cells (white blood, spleen and small intestine, according to [http://www.gtexportal.org/home/gene/UBASH3A GTEx]), whereas STS1 is expressed ubiquitously (according to [http://www.gtexportal.org/home/gene/UBASH3B GTEx], particularly abundant in cerebellum).
  
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STS-1 decreases tyrosine phosphorylation of Syk ''in vivo'' and ''in vitro'' <cite>chen10, carpino04</cite>. 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 <cite>STS_2</cite>. In addition, both STS-1 and STS-2 regulates kinase ZAP-70 activation <cite>carpino04</cite>.  
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STS1 decreases tyrosine phosphorylation of Syk ''in vivo'' and ''in vitro'' <cite>chen10, carpino04</cite>, and this is reversed by transfection of an inactive STS1 mutant. In addition, both STS1 and STS2 regulate kinase ZAP-70 activation <cite>carpino04</cite>.  
  
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Human STS-1 can also dephosphorylate phospho-tyrosines on EGFR <cite>STS_1</cite> and is overexpressed in triple-negative breast cancer and promotes invasion and metastasis <cite>Lee13</cite>. The histidine phosphatase domain of STS-1, but not of STS-2, dephosphorylates the EGFR at multiple tyrosines, and thereby terminating its signalling and endocytosis <cite>STS_1</cite>.
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Human STS1 can also dephosphorylate pTyr on EGFR <cite>STS_1</cite> and is overexpressed in triple-negative breast cancer and promotes invasion and metastasis <cite>Lee13</cite>. STS1 dephosphorylated the EGFR at multiple tyrosines, terminating its signalling and endocytosis <cite>STS_1</cite>. STS1 and STS2 also dephosphorylate the receptor tyrosine kinases Kit and Flt3, and double knockout mice show greatly expanded hematopoiesis <cite>Zhang</cite>.
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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 <cite><Davies</cite>. A silkworm homolog was also shown to have ecdysteroid phosphatase activity <cite>Yamada</cite>. An Unclassified HP1-family yeast phosphatase, [http://phosphatome.net/3.0/database/gene/uid/ScerP017 DET1] has been implicated in sterol trafficking <cite>Sullivan</cite>, but it is not known if phosphatase activity is involved.
  
 
=== Technical notes ===
 
=== Technical notes ===
 
===== Nematodes lost UBA, 2H and SH3 domain =====
 
===== Nematodes lost UBA, 2H and SH3 domain =====
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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.
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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===
 
===References===
 
<biblio>
 
<biblio>
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#Davies pmid=17348005
 
#STS_1 pmid=17880946
 
#STS_1 pmid=17880946
 
#STS_2 pmid=18189269
 
#STS_2 pmid=18189269
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#Lee13 pmid=23784775
 
#Lee13 pmid=23784775
 
#mazumder02 pmid=12466548
 
#mazumder02 pmid=12466548
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#Sullivan pmid=19060182
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#Yamada pmid=12721294
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#Zhang pmid=26365512
 
</biblio>
 
</biblio>

Latest revision as of 20:53, 10 July 2017

Phosphatase Classification: Fold HP: Superfamily HP: HP, branch1 family: Subfamily STS

STS is protein tyrosine phosphatase involved in T-cell receptor signaling by dephosphorylating the Syk and ZAP-70 kinases. STS is found throughout metazoa.

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]
All Medline abstracts: PubMed | HubMed
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