Protein tyrosine phosphatase explained

Protein-tyrosine-phosphatase
Ec Number:3.1.3.48
Cas Number:79747-53-8
Width:270

Protein tyrosine phosphatases (EC 3.1.3.48, systematic name protein-tyrosine-phosphate phosphohydrolase) are a group of enzymes that remove phosphate groups from phosphorylated tyrosine residues on proteins:

[a protein]-tyrosine phosphate + H2O = [a protein]-tyrosine + phosphate

Protein tyrosine (pTyr) phosphorylation is a common post-translational modification that can create novel recognition motifs for protein interactions and cellular localization, affect protein stability, and regulate enzyme activity. As a consequence, maintaining an appropriate level of protein tyrosine phosphorylation is essential for many cellular functions. Tyrosine-specific protein phosphatases (PTPase;) catalyse the removal of a phosphate group attached to a tyrosine residue, using a cysteinyl-phosphate enzyme intermediate. These enzymes are key regulatory components in signal transduction pathways (such as the MAP kinase pathway) and cell cycle control, and are important in the control of cell growth, proliferation, differentiation, transformation, and synaptic plasticity.[1] [2] [3] [4]

Functions

Together with tyrosine kinases, PTPs regulate the phosphorylation state of many important signalling molecules, such as the MAP kinase family.PTPs are increasingly viewed as integral components of signal transduction cascades, despite less study and understanding compared to tyrosine kinases.

PTPs have been implicated in regulation of many cellular processes, including, but not limited to:

Classification

By mechanism

PTP activity can be found in four protein families.[6] [7]

Links to all 107 members of the protein tyrosine phosphatase family can be found in the template at the bottom of this article.

Class I

The class I PTPs, are the largest group of PTPs with 99 members, which can be further subdivided into

Dual-specificity phosphatases (dTyr and dSer/dThr) dual-specificity protein-tyrosine phosphatases. Ser/Thr and Tyr dual-specificity phosphatases are a group of enzymes with both Ser/Thr and tyrosine-specific protein phosphatase activity able to remove the serine/threonine or the tyrosine-bound phosphate group from a wide range of phosphoproteins, including a number of enzymes that have been phosphorylated under the action of a kinase. Dual-specificity protein phosphatases (DSPs) regulate mitogenic signal transduction and control the cell cycle.

LEOPARD syndrome, Noonan syndrome, and metachondromatosis are associated with PTPN11.

Elevated levels of activated PTPN5 negatively affects synaptic stability and plays a role in Alzheimer's disease,[3] Fragile X syndrome,[4] schizophrenia,[8] and Parkinson's disease.[9] Decreased levels of PTPN5 has been implicated in Huntington's disease,[10] [11] brain ischemia,[12] alcohol use disorder,[13] [14] and stress disorders.[15] [16] Together these findings indicate that only at optimal levels of PTPN5 is synaptic function unimpaired.

Class II

LMW (low-molecular-weight) phosphatases, or acid phosphatases, act on tyrosine phosphorylated proteins, low-MW aryl phosphates and natural and synthetic acyl phosphates.[17] [18]

The class II PTPs contain only one member, low-molecular-weight phosphotyrosine phosphatase (LMPTP).

Class III

Cdc25 phosphatases (dTyr and/or dThr)

The Class III PTPs contains three members, CDC25 A, B, and C

Class IV

These are members of the HAD fold and superfamily, and include phosphatases specific to pTyr and pSer/Thr as well as small molecule phosphatases and other enzymes.[19] The subfamily EYA (eyes absent) is believed to be pTyr-specific, and has four members in human, EYA1, EYA2, EYA3, and EYA4. This class has a distinct catalytic mechanism from the other three classes.[20]

By location

Based on their cellular localization, PTPases are also classified as:

Common elements

All PTPases, other than those of the EYA family, carry the highly conserved active site motif C(X)5R (PTP signature motif), employ a common catalytic mechanism, and possess a similar core structure made of a central parallel beta-sheet with flanking alpha-helices containing a beta-loop-alpha-loop that encompasses the PTP signature motif.[23] Functional diversity between PTPases is endowed by regulatory domains and subunits.

Expression pattern

Individual PTPs may be expressed by all cell types, or their expression may be strictly tissue-specific. Most cells express 30% to 60% of all the PTPs, however hematopoietic and neuronal cells express a higher number of PTPs in comparison to other cell types. T cells and B cells of hematopoietic origin express around 60 to 70 different PTPs. The expression of several PTPS is restricted to hematopoietic cells, for example, LYP, SHP1, CD45, and HePTP.[24] The expression of PTPN5 is restricted to the brain, and differs between brain regions, with no expression in the cerebellum.[25] [26] [27]

External links

Notes and References

  1. Dixon JE, Denu JM . 2018 . Protein tyrosine phosphatases: mechanisms of catalysis and regulation . Curr Opin Chem Biol . 2 . 5 . 633–41 . 10.1016/S1367-5931(98)80095-1 . 9818190.
  2. Paul S, Lombroso PJ . 2020 . Receptor and nonreceptor protein tyrosine phosphatases in the nervous system . Cell. Mol. Life Sci. . 60 . 11 . 2465–82 . 10.1007/s00018-003-3123-7 . 14625689 . 10827975. 11138652 .
  3. Zhang Y, Kurup P, Xu J, Carty N, Fernandez SM, Nygaard HB, Pittenger C, Greengard P, Strittmatter SM, Nairn AC, Lombroso PJ . Nov 2018 . Genetic reduction of striatal-enriched tyrosine phosphatase (STEP) reverses cognitive and cellular deficits in an Alzheimer's disease mouse model . Proceedings of the National Academy of Sciences of the United States of America . 107 . 44 . 19014–9 . 2010PNAS..10719014Z . 10.1073/pnas.1013543107 . 2973892 . 20956308 . free.
  4. Goebel-Goody SM, Wilson-Wallis ED, Royston S, Tagliatela SM, Naegele JR, Lombroso PJ . Jul 2019 . Genetic manipulation of STEP reverses behavioral abnormalities in a fragile X syndrome mouse model . Genes, Brain and Behavior . 11 . 5 . 586–600 . 10.1111/j.1601-183X.2012.00781.x . 3922131 . 22405502.
  5. Kurup P, Zhang Y, Xu J, Venkitaramani DV, Haroutunian V, Greengard P, Nairn AC, Lombroso PJ . Apr 2022 . Abeta-mediated NMDA receptor endocytosis in Alzheimer's disease involves ubiquitination of the tyrosine phosphatase STEP61 . The Journal of Neuroscience . 30 . 17 . 5948–57 . 10.1523/JNEUROSCI.0157-10.2010 . 2868326 . 20427654.
  6. Sun JP, Zhang ZY, Wang WQ . 2017 . An overview of the protein tyrosine phosphatase superfamily . Curr Top Med Chem . 3 . 7 . 739–48 . 10.2174/1568026033452302 . 12678841.
  7. Alonso A, Sasin J, etal . 2020 . Protein tyrosine phosphatases in the human genome . Cell . 117 . 6 . 699–711 . 10.1016/j.cell.2004.05.018 . 15186772 . free.
  8. Carty NC, Xu J, Kurup P, Brouillette J, Goebel-Goody SM, Austin DR, Yuan P, Chen G, Correa PR, Haroutunian V, Pittenger C, Lombroso PJ . 2021 . The tyrosine phosphatase STEP: implications in schizophrenia and the molecular mechanism underlying antipsychotic medications . Translational Psychiatry . 2 . 7 . e137 . 10.1038/tp.2012.63 . 3410627 . 22781170.
  9. Kurup PK, Xu J, Videira RA, Ononenyi C, Baltazar G, Lombroso PJ, Nairn AC . Jan 2018 . STEP61 is a substrate of the E3 ligase parkin and is upregulated in Parkinson's disease . Proceedings of the National Academy of Sciences of the United States of America . 112 . 4 . 1202–7 . 2015PNAS..112.1202K . 10.1073/pnas.1417423112 . 4313846 . 25583483 . free.
  10. Saavedra A, Giralt A, Rué L, Xifró X, Xu J, Ortega Z, Lucas JJ, Lombroso PJ, Alberch J, Pérez-Navarro E . Jun 2021 . Striatal-enriched protein tyrosine phosphatase expression and activity in Huntington's disease: a STEP in the resistance to excitotoxicity . The Journal of Neuroscience . 31 . 22 . 8150–62 . 10.1523/JNEUROSCI.3446-10.2011 . 3472648 . 21632937.
  11. Gladding CM, Sepers MD, Xu J, Zhang LY, Milnerwood AJ, Lombroso PJ, Raymond LA . Sep 2020 . Calpain and STriatal-Enriched protein tyrosine phosphatase (STEP) activation contribute to extrasynaptic NMDA receptor localization in a Huntington's disease mouse model . Human Molecular Genetics . 21 . 17 . 3739–52 . 10.1093/hmg/dds154 . 3412376 . 22523092.
  12. Deb I, Manhas N, Poddar R, Rajagopal S, Allan AM, Lombroso PJ, Rosenberg GA, Candelario-Jalil E, Paul S . Nov 2020 . Neuroprotective role of a brain-enriched tyrosine phosphatase, STEP, in focal cerebral ischemia . The Journal of Neuroscience . 33 . 45 . 17814–26 . 10.1523/JNEUROSCI.2346-12.2013 . 3818554 . 24198371.
  13. Hicklin TR, Wu PH, Radcliffe RA, Freund RK, Goebel-Goody SM, Correa PR, Proctor WR, Lombroso PJ, Browning MD . Apr 2020 . Alcohol inhibition of the NMDA receptor function, long-term potentiation, and fear learning requires striatal-enriched protein tyrosine phosphatase . Proceedings of the National Academy of Sciences of the United States of America . 108 . 16 . 6650–5 . 2011PNAS..108.6650H . 10.1073/pnas.1017856108 . 3081035 . 21464302 . free.
  14. Darcq E, Hamida SB, Wu S, Phamluong K, Kharazia V, Xu J, Lombroso P, Ron D . Jun 2019 . Inhibition of striatal-enriched tyrosine phosphatase 61 in the dorsomedial striatum is sufficient to increased ethanol consumption . Journal of Neurochemistry . 129 . 6 . 1024–34 . 10.1111/jnc.12701 . 4055745 . 24588427.
  15. Yang CH, Huang CC, Hsu KS . May 2022 . A critical role for protein tyrosine phosphatase nonreceptor type 5 in determining individual susceptibility to develop stress-related cognitive and morphological changes . The Journal of Neuroscience . 32 . 22 . 7550–62 . 10.1523/JNEUROSCI.5902-11.2012 . 6703597 . 22649233 . free.
  16. Dabrowska J, Hazra R, Guo JD, Li C, Dewitt S, Xu J, Lombroso PJ, Rainnie DG . Dec 2020 . Striatal-enriched protein tyrosine phosphatase-STEPs toward understanding chronic stress-induced activation of corticotrophin releasing factor neurons in the rat bed nucleus of the stria terminalis . Biological Psychiatry . 74 . 11 . 817–26 . 10.1016/j.biopsych.2013.07.032 . 3818357 . 24012328.
  17. Wo YY, Shabanowitz J, Hunt DF, Davis JP, Mitchell GL, Van Etten RL, McCormack AL . 2023 . Sequencing, cloning, and expression of human red cell-type acid phosphatase, a cytoplasmic phosphotyrosyl protein phosphatase . J. Biol. Chem. . 267 . 15 . 10856–10865 . 10.1016/S0021-9258(19)50097-7 . 1587862 . free.
  18. Shekels LL, Smith AJ, Bernlohr DA, Van Etten RL . Identification of the adipocyte acid phosphatase as a PAO-sensitive tyrosyl phosphatase . Protein Sci. . 1 . 6 . 710–721 . 1992 . 1304913 . 2142247 . 10.1002/pro.5560010603.
  19. Chen MJ, Dixon JE, Manning G . April 2023 . Genomics and evolution of protein phosphatases . Science Signaling . 10 . 474 . eaag1796 . 10.1126/scisignal.aag1796 . 28400531 . 41041971.
  20. Book: Plaxton . William C. . Control of primary metabolism in plants . McManus . Michael T. . Wiley-Blackwell . 2020 . 978-1-4051-3096-7 . 130– . 12 December 2020 . vanc.
  21. Knapp S, Longman E, Debreczeni JE, Eswaran J, Barr AJ . The crystal structure of human receptor protein tyrosine phosphatase kappa phosphatase domain 1 . Protein Sci. . 15 . 6. 1500–1505. 2006 . 16672235 . 10.1110/ps.062128706 . 2242534.
  22. Perrimon N, Johnson MR, Perkins LA, Melnick MB . 2018 . The nonreceptor protein tyrosine phosphatase corkscrew functions in multiple receptor tyrosine kinase pathways in Drosophila . Dev. Biol. . 180 . 1 . 63–81 . 10.1006/dbio.1996.0285 . 8948575 . free.
  23. Barford D, Das AK, Egloff MP . 2021 . The structure and mechanism of protein phosphatase s: insights into catalysis and regulation . Annu. Rev. Biophys. Biomol. Struct. . 27 . 1 . 133–64 . 10.1146/annurev.biophys.27.1.133 . 9646865.
  24. Mustelin T, Vang T, Bottini N . 2018 . Protein tyrosine phosphatases and the immune response . Nat. Rev. Immunol. . 5 . 1 . 43–57 . 10.1038/nri1530 . 15630428 . 20308090.
  25. Lombroso PJ, Murdoch G, Lerner M . Aug 2021 . Molecular characterization of a protein-tyrosine-phosphatase enriched in striatum . Proceedings of the National Academy of Sciences of the United States of America . 88 . 16 . 7242–6 . 1991PNAS...88.7242L . 10.1073/pnas.88.16.7242 . 52270 . 1714595 . free.
  26. Bult A, Zhao F, Dirkx R, Sharma E, Lukacsi E, Solimena M, Naegele JR, Lombroso PJ . Dec 2021 . STEP61: a member of a family of brain-enriched PTPs is localized to the endoplasmic reticulum . The Journal of Neuroscience . 16 . 24 . 7821–31 . 10.1523/JNEUROSCI.16-24-07821.1996 . 6579237 . 8987810 . free.
  27. Lombroso PJ, Naegele JR, Sharma E, Lerner M . Jul 2021 . A protein tyrosine phosphatase expressed within dopaminoceptive neurons of the basal ganglia and related structures . The Journal of Neuroscience . 13 . 7 . 3064–74 . 10.1523/JNEUROSCI.13-07-03064.1993 . 6576687 . 8331384 . free.

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