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PTPN1

December 15, 2023

Tyrosine-protein phosphatase non-receptor type 1 also known as protein-tyrosine phosphatase 1B (PTP1B) is an enzyme that is the founding member of the protein tyrosine phosphatase (PTP) family. In humans it is encoded by the PTPN1 gene.[5] PTP1B is a negative regulator of the insulin signaling pathway and is considered a promising potential therapeutic target, in particular for treatment of type 2 diabetes.[6] It has also been implicated in the development of breast cancer and has been explored as a potential therapeutic target in that avenue as well.[7][8][9]

PTPN1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesPTPN1, PTP1B, protein tyrosine phosphatase, non-receptor type 1, protein tyrosine phosphatase non-receptor type 1
External IDsOMIM: 176885 MGI: 97805 HomoloGene: 2119 GeneCards: PTPN1
Orthologs
SpeciesHumanMouse
Entrez

5770

19246

Ensembl

ENSG00000196396

ENSMUSG00000027540

UniProt

P18031

P35821

RefSeq (mRNA)

NM_002827
NM_001278618

NM_011201

RefSeq (protein)

NP_001265547
NP_002818

NP_035331

Location (UCSC)Chr 20: 50.51 – 50.59 MbChr 2: 167.77 – 167.82 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Structure and function edit

PTP1B was first isolated from a human placental protein extract,[10][11] but it is expressed in many tissues.[12] PTP1B is localized to the cytoplasmic face of the endoplasmic reticulum.[13] PTP1B can dephosphorylate the phosphotyrosine residues of the activated insulin receptor kinase.[11][14][15] In mice, genetic ablation of PTPN1 results in enhanced insulin sensitivity.[16][17] Several other tyrosine kinases, including epidermal growth factor receptor,[18] insulin-like growth factor 1 receptor,[19] colony stimulating factor 1 receptor,[20] c-Src,[21] Janus kinase 2,[22] TYK2,[22] and focal adhesion kinase[23] as well as other tyrosine-phosphorylated proteins, including BCAR1,[24] DOK1,[25] beta-catenin[26] and cortactin[27] have also been described as PTP1B substrates.

The first crystal structure of the PTP1B catalytic domain revealed that the catalytic site exists within a deep cleft of the protein formed by three loops including the WPD loop with the Asp181 residue, a pTyr loop with the Tyr46 residue and a Q loop with the Gln262 residue.[28][29] The pTyr loop and Tyr46 residue are located on the surface of the protein, and thus help to determine the depth a substrate can obtain within the cleft. This acts as a means of driving selectivity, as substrates containing smaller phosphoresidues cannot reach the site of catalytic activity at the base of the cleft.[28] Upon substrate binding, PTP1B undergoes a structural modification in which the WPD loop closes around the substrate, introducing stabilizing pi stacking interactions between the aromatic rings of the phosphotyrosine (pTyr) substrate residue and the Phe182 residue on the WPD loop.[29]

Mechanism edit

The phosphatase activity of PTP1B occurs via a two-step mechanism.[28] The dephosphorylation of the pTyr substrate occurs in the first step, while the enzyme intermediates are broken down during the second step. During the first step, there is a nucleophilic attack at the phosphocenter by the reduced Cys215 residue, followed by subsequent protonation by Asp181 to yield the neutral tyrosine phenol. The active enzyme is regenerated after the thiophosphate intermediate is hydrolyzed, which is facilitated by the hydrogen bonding interactions of Gln262 and Asp181 that help to position in the water molecule at the desired site of nucleophillic attack.

 
Two step mechanism of PTP1B phosphatase activity.

Regulation edit

The Cys215 residue is essential for the enzymatic activity of PTP1B and similar cysteine residues are required for the activity of other members of the Class I PTP family.[30] The thiolate anion form is needed for nucleophilic activity but it is susceptible to oxidation by reactive oxygen species (ROS) in the cell which would render the enzyme non-functional. This cysteine residue has been shown to oxidize under increased cellular concentrations of hydrogen peroxide (H2O2), produced in response to EGF and insulin signaling.[31][32][33] The thiolate is oxidized to a sulfenic acid, which is converted to a sulfenyl amide after reacting with the adjacent Ser216 residue.[34] This modification of the Cys215 residue prevents further oxidation of the residue which would be irreversible, and also induces a structural change in the cleft of the active site such that substrates may not bind.[34][35] This oxidation can be reversed through reduction by glutathione and acts as a means of regulating PTP1B activity.[35] Phosphorylation of the Ser50 residue has also been shown as a point of allosteric regulation of PTP1B, in which the phosphorylated state of the enzyme is inactive.[36]

Interactions edit

PTPN1 has been shown to interact with BCAR1,[24] epidermal growth factor receptor,[37][38] Grb2[24][39] and IRS1.[36][39] Vascular endothelial growth factor Receptor-2[40] and Vascular endothelial growth factor via PGC1-alpha/ERR-alpha[41]

Clinical Significance edit

PTP1B has clinical implications in the treatment of type 2 diabetes as well as cancer. Gene knockout studies conducted in murine models has provided substantial evidence for the role PTP1B plays in the regulation of insulin signalling and the development of obesity.[16][17] PTPN1 knockout mice kept on high fat diets showed a resistance to obesity and an increased degree of insulin sensitivity as compared to their wild-type counterparts.[16][17] As such, the design and development of PTP1B inhibitors is a growing field of research for the treatment of type 2 diabetes and obesity.[42]

Although PTP1B is generally studied as a regulator of metabolism, some research suggest it may have a role in tumor development, though whether it is oncogenic or tumor suppressive is unclear, as there is data in support of both arguments. The high ROS concentrations within cancer cells provide an environment for potential constitutive inactivation of PTP1B and it has been shown in two human cancer cell lines HepG2 and A431, that up to 40% of the Cys215 residues in PTP1B can be selectively irreversibly oxidized under these cellular conditions resulting in non-functional PTP1B.[43] In addition, PTPN1 genetic ablation in p53 deficient mice resulted in an increased incidence of lymphomas and a decrease in overall survival rates.[44] In contrast, the PTPN1 gene has been shown to be overexpressed in conjunction with HER2 in breast cancer cases.[8] Murine models of HER2 overexpression in conjunction with PTPN1 knockout resulted in delayed tumor growth and with fewer observed metastases to the lung suggesting that PTPN1 may have an oncogenic role in breast cancer.[8][9]

See also edit

References[5] edit

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000196396 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000027540 - Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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  6. ^ Combs AP (March 2010). "Recent advances in the discovery of competitive protein tyrosine phosphatase 1B inhibitors for the treatment of diabetes, obesity, and cancer". J. Med. Chem. 53 (6): 2333–44. doi:10.1021/jm901090b. PMID 20000419.
  7. ^ Lessard L, Stuible M, Tremblay ML (2010). "The two faces of PTP1B in cancer". Biochim. Biophys. Acta. 1804 (3): 613–9. doi:10.1016/j.bbapap.2009.09.018. PMID 19782770.
  8. ^ a b c Bentires-Alj M, Neel BG (2007). "Protein-tyrosine phosphatase 1B is required for HER2/Neu-induced breast cancer". Cancer Res. 67 (6): 2420–4. doi:10.1158/0008-5472.CAN-06-4610. PMID 17347513.
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  10. ^ Tonks NK, Diltz CD, Fischer EH (May 1988). "Purification of the major protein-tyrosine-phosphatases of human placenta" (PDF). J. Biol. Chem. 263 (14): 6722–30. doi:10.1016/S0021-9258(18)68702-2. PMID 2834386.
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  22. ^ a b Myers MP, Andersen JN, Cheng A, Tremblay ML, Horvath CM, Parisien JP, Salmeen A, Barford D, Tonks NK (December 2001). "TYK2 and JAK2 are substrates of protein-tyrosine phosphatase 1B". J. Biol. Chem. 276 (51): 47771–4. doi:10.1074/jbc.C100583200. PMID 11694501.
  23. ^ Zhang Z, Lin SY, Neel BG, Haimovich B (January 2006). "Phosphorylated alpha-actinin and protein-tyrosine phosphatase 1B coregulate the disassembly of the focal adhesion kinase x Src complex and promote cell migration". J. Biol. Chem. 281 (3): 1746–54. doi:10.1074/jbc.M509590200. PMID 16291744.
  24. ^ a b c Liu F, Hill DE, Chernoff J (December 1996). "Direct binding of the proline-rich region of protein tyrosine phosphatase 1B to the Src homology 3 domain of p130(Cas)". J. Biol. Chem. 271 (49): 31290–5. doi:10.1074/jbc.271.49.31290. PMID 8940134.
  25. ^ Dubé N, Cheng A, Tremblay ML (February 2004). "The role of protein tyrosine phosphatase 1B in Ras signaling". Proc. Natl. Acad. Sci. U.S.A. 101 (7): 1834–9. Bibcode:2004PNAS..101.1834D. doi:10.1073/pnas.0304242101. PMC 357013. PMID 14766979.
  26. ^ Balsamo J, Arregui C, Leung T, Lilien J (October 1998). "The Nonreceptor Protein Tyrosine Phosphatase PTP1B Binds to the Cytoplasmic Domain of N-Cadherin and Regulates the Cadherin–Actin Linkage". J. Cell Biol. 143 (2): 523–32. doi:10.1083/jcb.143.2.523. PMC 2132848. PMID 9786960.
  27. ^ Stuible M, Dubé N, Tremblay ML (June 2008). "PTP1B regulates cortactin tyrosine phosphorylation by targeting Tyr446". J. Biol. Chem. 283 (23): 15740–6. doi:10.1074/jbc.M710534200. PMC 3259645. PMID 18387954.
  28. ^ a b c Tonks NK (Jul 3, 2003). "PTP1B: from the sidelines to the front lines!". FEBS Letters. 546 (1): 140–8. doi:10.1016/s0014-5793(03)00603-3. PMID 12829250. S2CID 21205538.
  29. ^ a b Barford D, Flint AJ, Tonks NK (March 1994). "Crystal structure of human protein tyrosine phosphatase 1B". Science. 263 (5152): 1397–404. Bibcode:1994Sci...263.1397B. doi:10.1126/science.8128219. PMID 8128219.
  30. ^ Alonso A, Sasin J, Bottini N, Friedberg I, Friedberg I, Osterman A, Godzik A, Hunter T, Dixon J, Mustelin T (2004). "Protein tyrosine phosphatases in the human genome". Cell. 117 (6): 699–711. doi:10.1016/j.cell.2004.05.018. PMID 15186772. S2CID 18072568.
  31. ^ Mahadev K, Zilbering A, Zhu L, Goldstein BJ (2001). "Insulin-stimulated hydrogen peroxide reversibly inhibits protein-tyrosine phosphatase 1b in vivo and enhances the early insulin action cascade". J. Biol. Chem. 276 (24): 21938–42. doi:10.1074/jbc.C100109200. PMID 11297536.
  32. ^ Lee SR, Kwon KS, Kim SR, Rhee SG (June 1998). "Reversible inactivation of protein-tyrosine phosphatase 1B in A431 cells stimulated with epidermal growth factor". J. Biol. Chem. 273 (25): 15366–72. doi:10.1074/jbc.273.25.15366. PMID 9624118.
  33. ^ Sundaresan M, Yu ZX, Ferrans VJ, Irani K, Finkel T (October 1995). "Requirement for generation of H2O2 for platelet-derived growth factor signal transduction". Science. 270 (5234): 296–9. Bibcode:1995Sci...270..296S. doi:10.1126/science.270.5234.296. PMID 7569979. S2CID 8065388.
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  35. ^ a b van Montfort RL, Congreve M, Tisi D, Carr R, Jhoti H (2003). "Oxidation state of the active-site cysteine in protein tyrosine phosphatase 1B". Nature. 423 (6941): 773–7. Bibcode:2003Natur.423..773V. doi:10.1038/nature01681. PMID 12802339. S2CID 4424814.
  36. ^ a b Ravichandran LV, Chen H, Li Y, Quon MJ (October 2001). "Phosphorylation of PTP1B at Ser(50) by Akt impairs its ability to dephosphorylate the insulin receptor". Mol. Endocrinol. 15 (10): 1768–80. doi:10.1210/mend.15.10.0711. PMID 11579209.
  37. ^ Sarmiento M, Puius YA, Vetter SW, Keng YF, Wu L, Zhao Y, Lawrence DS, Almo SC, Zhang ZY (July 2000). "Structural basis of plasticity in protein tyrosine phosphatase 1B substrate recognition". Biochemistry. 39 (28): 8171–9. doi:10.1021/bi000319w. PMID 10889023.
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  39. ^ a b Goldstein BJ, Bittner-Kowalczyk A, White MF, Harbeck M (February 2000). "Tyrosine dephosphorylation and deactivation of insulin receptor substrate-1 by protein-tyrosine phosphatase 1B. Possible facilitation by the formation of a ternary complex with the Grb2 adaptor protein". J. Biol. Chem. 275 (6): 4283–9. doi:10.1074/jbc.275.6.4283. PMID 10660596.
  40. ^ Lanahan AA, Lech D, Dubrac A, Zhang J, Zhuang ZW, Eichmann A, Simons M (September 2014). "PTP1b is a physiologic regulator of vascular endothelial growth factor signaling in endothelial cells". Circulation. 130 (11): 902–9. doi:10.1161/CIRCULATIONAHA.114.009683. PMC 6060619. PMID 24982127.
  41. ^ Figueiredo H, Figueroa AL, Garcia A, Fernandez-Ruiz R, Broca C, Wojtusciszyn A, et al. (June 2019). "Targeting pancreatic islet PTP1B improves islet graft revascularization and transplant outcomes". Science Translational Medicine. 11 (497): eaar6294. doi:10.1126/scitranslmed.aar6294. hdl:10609/103266. PMID 31217339. S2CID 195188512.
  42. ^ Thareja S, Aggarwal S, Bhardwaj TR, Kumar M (2012). "Protein tyrosine phosphatase 1B inhibitors: a molecular level legitimate approach for the management of diabetes mellitus". Med Res Rev. 32 (3): 459–517. doi:10.1002/med.20219. PMID 20814956. S2CID 23121386.
  43. ^ Tonks NK (2013). "Protein tyrosine phosphatases — from housekeeping enzymes to master regulators of signal transduction". FEBS J. 280 (2): 346–78. doi:10.1111/febs.12077. PMC 3662559. PMID 23176256.
  44. ^ Dubé N, Bourdeau A, Heinonen KM, Cheng A, Loy AL, Tremblay ML (2005). "Genetic ablation of protein tyrosine phosphatase 1B accelerates lymphomagenesis of p53-null mice through the regulation of B-cell development". Cancer Res. 65 (21): 10088–95. doi:10.1158/0008-5472.CAN-05-1353. PMID 16267035.

December 15, 2023
ptpn1, tyrosine, protein, phosphatase, receptor, type, also, known, protein, tyrosine, phosphatase, ptp1b, enzyme, that, founding, member, protein, tyrosine, phosphatase, family, humans, encoded, gene, ptp1b, negative, regulator, insulin, signaling, pathway, c. Tyrosine protein phosphatase non receptor type 1 also known as protein tyrosine phosphatase 1B PTP1B is an enzyme that is the founding member of the protein tyrosine phosphatase PTP family In humans it is encoded by the PTPN1 gene 5 PTP1B is a negative regulator of the insulin signaling pathway and is considered a promising potential therapeutic target in particular for treatment of type 2 diabetes 6 It has also been implicated in the development of breast cancer and has been explored as a potential therapeutic target in that avenue as well 7 8 9 PTPN1Available structuresPDBOrtholog search PDBe RCSBList of PDB id codes1A5Y 1AAX 1BZC 1BZH 1BZJ 1C83 1C84 1C85 1C86 1C87 1C88 1ECV 1EEN 1EEO 1G1F 1G1G 1G1H 1G7F 1G7G 1GFY 1I57 1JF7 1KAK 1KAV 1L8G 1LQF 1NL9 1NNY 1NO6 1NWE 1NWL 1NZ7 1OEM 1OEO 1OES 1OET 1OEV 1ONY 1ONZ 1PA1 1PH0 1PTT 1PTU 1PTV 1PTY 1PXH 1PYN 1Q1M 1Q6J 1Q6M 1Q6N 1Q6P 1Q6S 1Q6T 1QXK 1SUG 1T48 1T49 1T4J 1WAX 1XBO 2AZR 2B07 2B4S 2BGD 2BGE 2CM2 2CM3 2CM7 2CM8 2CMA 2CMB 2CMC 2CNE 2CNF 2CNG 2CNH 2CNI 2F6F 2F6T 2F6V 2F6W 2F6Y 2F6Z 2F70 2F71 2FJM 2FJN 2H4G 2H4K 2HB1 2HNP 2HNQ 2NT7 2NTA 2QBP 2QBQ 2QBR 2QBS 2VEU 2VEV 2VEW 2VEX 2VEY 2ZMM 2ZN7 3A5J 3A5K 3CWE 3D9C 3EAX 3EB1 3EU0 3I7Z 3I80 3QKP 3QKQ 3SME 3ZMP 3ZMQ 3ZV2 4BJO 4I8N 4QAH 4QAP 4QBE 4QBW 4Y14 4ZRTIdentifiersAliasesPTPN1 PTP1B protein tyrosine phosphatase non receptor type 1 protein tyrosine phosphatase non receptor type 1External IDsOMIM 176885 MGI 97805 HomoloGene 2119 GeneCards PTPN1Gene location Human Chr Chromosome 20 human 1 Band20q13 13Start50 510 321 bp 1 End50 585 241 bp 1 Gene location Mouse Chr Chromosome 2 mouse 2 Band2 2 H3Start167 773 977 bp 2 End167 821 305 bp 2 RNA expression patternBgeeHumanMouse ortholog Top expressed inupper lobe of left lungright lungspleenappendixmonocytelymph nodeascending aortaleft adrenal glandgastrocnemius muscleright coronary arteryTop expressed incorneal stromaspleenhair follicleankle jointyolk sacinternal carotid arteryright lung lobeexternal carotid arterylacrimal glandleft lungMore reference expression dataBioGPSn aGene ontologyMolecular functionphosphoprotein phosphatase activity insulin receptor binding phosphatase activity ephrin receptor binding receptor tyrosine kinase binding zinc ion binding protein binding protein tyrosine phosphatase activity protein phosphatase 2A binding enzyme binding hydrolase activity protein kinase binding RNA binding cadherin bindingCellular componentcytoplasm cytosol endoplasmic reticulum membrane membrane plasma membrane early endosome endoplasmic reticulum cytoplasmic side of endoplasmic reticulum membrane sorting endosome cytoplasmic vesicle protein containing complexBiological processregulation of endocytosis actin cytoskeleton reorganization insulin receptor signaling pathway negative regulation of endoplasmic reticulum stress induced intrinsic apoptotic signaling pathway growth hormone receptor signaling pathway via JAK STAT peptidyl tyrosine dephosphorylation involved in inactivation of protein kinase activity negative regulation of vascular endothelial growth factor receptor signaling pathway positive regulation of protein tyrosine kinase activity protein dephosphorylation regulation of hepatocyte growth factor receptor signaling pathway response to endoplasmic reticulum stress endoplasmic reticulum unfolded protein response regulation of intracellular protein transport positive regulation of IRE1 mediated unfolded protein response negative regulation of insulin receptor signaling pathway IRE1 mediated unfolded protein response regulation of type I interferon mediated signaling pathway regulation of signal transduction negative regulation of MAP kinase activity positive regulation of receptor catabolic process negative regulation of ERK1 and ERK2 cascade peptidyl tyrosine dephosphorylation negative regulation of PERK mediated unfolded protein response regulation of insulin receptor signaling pathway platelet derived growth factor receptor beta signaling pathway dephosphorylation negative regulation of signal transduction Unfolded Protein ResponseSources Amigo QuickGOOrthologsSpeciesHumanMouseEntrez577019246EnsemblENSG00000196396ENSMUSG00000027540UniProtP18031P35821RefSeq mRNA NM 002827NM 001278618NM 011201RefSeq protein NP 001265547NP 002818NP 035331Location UCSC Chr 20 50 51 50 59 MbChr 2 167 77 167 82 MbPubMed search 3 4 WikidataView Edit HumanView Edit Mouse Contents 1 Structure and function 2 Mechanism 3 Regulation 4 Interactions 5 Clinical Significance 6 See also 7 References 5 Structure and function editPTP1B was first isolated from a human placental protein extract 10 11 but it is expressed in many tissues 12 PTP1B is localized to the cytoplasmic face of the endoplasmic reticulum 13 PTP1B can dephosphorylate the phosphotyrosine residues of the activated insulin receptor kinase 11 14 15 In mice genetic ablation of PTPN1 results in enhanced insulin sensitivity 16 17 Several other tyrosine kinases including epidermal growth factor receptor 18 insulin like growth factor 1 receptor 19 colony stimulating factor 1 receptor 20 c Src 21 Janus kinase 2 22 TYK2 22 and focal adhesion kinase 23 as well as other tyrosine phosphorylated proteins including BCAR1 24 DOK1 25 beta catenin 26 and cortactin 27 have also been described as PTP1B substrates The first crystal structure of the PTP1B catalytic domain revealed that the catalytic site exists within a deep cleft of the protein formed by three loops including the WPD loop with the Asp181 residue a pTyr loop with the Tyr46 residue and a Q loop with the Gln262 residue 28 29 The pTyr loop and Tyr46 residue are located on the surface of the protein and thus help to determine the depth a substrate can obtain within the cleft This acts as a means of driving selectivity as substrates containing smaller phosphoresidues cannot reach the site of catalytic activity at the base of the cleft 28 Upon substrate binding PTP1B undergoes a structural modification in which the WPD loop closes around the substrate introducing stabilizing pi stacking interactions between the aromatic rings of the phosphotyrosine pTyr substrate residue and the Phe182 residue on the WPD loop 29 Mechanism editThe phosphatase activity of PTP1B occurs via a two step mechanism 28 The dephosphorylation of the pTyr substrate occurs in the first step while the enzyme intermediates are broken down during the second step During the first step there is a nucleophilic attack at the phosphocenter by the reduced Cys215 residue followed by subsequent protonation by Asp181 to yield the neutral tyrosine phenol The active enzyme is regenerated after the thiophosphate intermediate is hydrolyzed which is facilitated by the hydrogen bonding interactions of Gln262 and Asp181 that help to position in the water molecule at the desired site of nucleophillic attack nbsp Two step mechanism of PTP1B phosphatase activity Regulation editThe Cys215 residue is essential for the enzymatic activity of PTP1B and similar cysteine residues are required for the activity of other members of the Class I PTP family 30 The thiolate anion form is needed for nucleophilic activity but it is susceptible to oxidation by reactive oxygen species ROS in the cell which would render the enzyme non functional This cysteine residue has been shown to oxidize under increased cellular concentrations of hydrogen peroxide H2O2 produced in response to EGF and insulin signaling 31 32 33 The thiolate is oxidized to a sulfenic acid which is converted to a sulfenyl amide after reacting with the adjacent Ser216 residue 34 This modification of the Cys215 residue prevents further oxidation of the residue which would be irreversible and also induces a structural change in the cleft of the active site such that substrates may not bind 34 35 This oxidation can be reversed through reduction by glutathione and acts as a means of regulating PTP1B activity 35 Phosphorylation of the Ser50 residue has also been shown as a point of allosteric regulation of PTP1B in which the phosphorylated state of the enzyme is inactive 36 Interactions editPTPN1 has been shown to interact with BCAR1 24 epidermal growth factor receptor 37 38 Grb2 24 39 and IRS1 36 39 Vascular endothelial growth factor Receptor 2 40 and Vascular endothelial growth factor via PGC1 alpha ERR alpha 41 Clinical Significance editPTP1B has clinical implications in the treatment of type 2 diabetes as well as cancer Gene knockout studies conducted in murine models has provided substantial evidence for the role PTP1B plays in the regulation of insulin signalling and the development of obesity 16 17 PTPN1 knockout mice kept on high fat diets showed a resistance to obesity and an increased degree of insulin sensitivity as compared to their wild type counterparts 16 17 As such the design and development of PTP1B inhibitors is a growing field of research for the treatment of type 2 diabetes and obesity 42 Although PTP1B is generally studied as a regulator of metabolism some research suggest it may have a role in tumor development though whether it is oncogenic or tumor suppressive is unclear as there is data in support of both arguments The high ROS concentrations within cancer cells provide an environment for potential constitutive inactivation of PTP1B and it has been shown in two human cancer cell lines HepG2 and A431 that up to 40 of the Cys215 residues in PTP1B can be selectively irreversibly oxidized under these cellular conditions resulting in non functional PTP1B 43 In addition PTPN1 genetic ablation in p53 deficient mice resulted in an increased incidence of lymphomas and a decrease in overall survival rates 44 In contrast the PTPN1 gene has been shown to be overexpressed in conjunction with HER2 in breast cancer cases 8 Murine models of HER2 overexpression in conjunction with PTPN1 knockout resulted in delayed tumor growth and with fewer observed metastases to the lung suggesting that PTPN1 may have an oncogenic role in breast cancer 8 9 See also editProtein tyrosine phosphataseReferences 5 edit a b c GRCh38 Ensembl release 89 ENSG00000196396 Ensembl May 2017 a b c GRCm38 Ensembl release 89 ENSMUSG00000027540 Ensembl May 2017 Human PubMed Reference National Center for Biotechnology Information U S National Library of Medicine Mouse PubMed Reference National Center for Biotechnology Information U S National Library of Medicine a b Brown Shimer S Johnson KA Lawrence JB Johnson C Bruskin A Green NR Hill DE Aug 1990 Molecular cloning and chromosome mapping of the human gene encoding protein phosphotyrosyl phosphatase 1B Proc Natl Acad Sci USA 87 13 5148 52 Bibcode 1990PNAS 87 5148B doi 10 1073 pnas 87 13 5148 PMC 54279 PMID 2164224 Combs AP March 2010 Recent advances in the discovery of competitive protein tyrosine phosphatase 1B inhibitors for the treatment of diabetes obesity and cancer J Med Chem 53 6 2333 44 doi 10 1021 jm901090b PMID 20000419 Lessard L Stuible M Tremblay ML 2010 The two faces of PTP1B in cancer Biochim Biophys Acta 1804 3 613 9 doi 10 1016 j bbapap 2009 09 018 PMID 19782770 a b c Bentires Alj M Neel BG 2007 Protein tyrosine phosphatase 1B is required for HER2 Neu induced breast cancer Cancer Res 67 6 2420 4 doi 10 1158 0008 5472 CAN 06 4610 PMID 17347513 a b Julien SG Dube N Read M Penney J Paquet M Han Y Kennedy BP Muller WJ Tremblay ML 2007 Protein tyrosine phosphatase 1B deficiency or inhibition delays ErbB2 induced mammary tumorigenesis and protects from lung metastasis Nat Genet 39 3 338 46 doi 10 1038 ng1963 PMID 17259984 S2CID 33612091 Tonks NK Diltz CD Fischer EH May 1988 Purification of the major protein tyrosine phosphatases of human placenta PDF J Biol Chem 263 14 6722 30 doi 10 1016 S0021 9258 18 68702 2 PMID 2834386 a b Tonks NK Diltz CD Fischer EH May 1988 Characterization of the major protein tyrosine phosphatases of human placenta PDF J Biol Chem 263 14 6731 7 doi 10 1016 S0021 9258 18 68703 4 PMID 2834387 Chernoff J Schievella AR Jost CA Erikson RL Neel BG April 1990 Cloning of a cDNA for a major human protein tyrosine phosphatase Proc Natl Acad Sci U S A 87 7 2735 9 Bibcode 1990PNAS 87 2735C doi 10 1073 pnas 87 7 2735 PMC 53765 PMID 2157211 Frangioni JV Beahm PH Shifrin V Jost CA Neel BG February 1992 The nontransmembrane tyrosine phosphatase PTP 1B localizes to the endoplasmic reticulum via its 35 amino acid C terminal sequence Cell 68 3 545 60 doi 10 1016 0092 8674 92 90190 N PMID 1739967 S2CID 43430621 Cicirelli MF Tonks NK Diltz CD Weiel JE Fischer EH Krebs EG July 1990 Microinjection of a protein tyrosine phosphatase inhibits insulin action in Xenopus oocytes Proc Natl Acad Sci U S A 87 14 5514 8 Bibcode 1990PNAS 87 5514C doi 10 1073 pnas 87 14 5514 PMC 54355 PMID 2164686 Seely BL Staubs PA Reichart DR Berhanu P Milarski KL Saltiel AR Kusari J Olefsky JM October 1996 Protein tyrosine phosphatase 1B interacts with the activated insulin receptor Diabetes 45 10 1379 85 doi 10 2337 diabetes 45 10 1379 PMID 8826975 a b c Elchebly M Payette P Michaliszyn E Cromlish W Collins S Loy AL Normandin D Cheng A Himms Hagen J Chan CC Ramachandran C Gresser MJ Tremblay ML Kennedy BP March 1999 Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase 1B gene Science 283 5407 1544 8 Bibcode 1999Sci 283 1544E doi 10 1126 science 283 5407 1544 PMID 10066179 a b c Klaman LD Boss O Peroni OD Kim JK Martino JL Zabolotny JM Moghal N Lubkin M Kim YB Sharpe AH Stricker Krongrad A Shulman GI Neel BG Kahn BB August 2000 Increased Energy Expenditure Decreased Adiposity and Tissue Specific Insulin Sensitivity in Protein Tyrosine Phosphatase 1B Deficient Mice Mol Cell Biol 20 15 5479 89 doi 10 1128 MCB 20 15 5479 5489 2000 PMC 85999 PMID 10891488 Flint AJ Tiganis T Barford D Tonks NK March 1997 Development of substrate trapping mutants to identify physiological substrates of protein tyrosine phosphatases Proc Natl Acad Sci U S A 94 5 1680 5 Bibcode 1997PNAS 94 1680F doi 10 1073 pnas 94 5 1680 PMC 19976 PMID 9050838 Buckley DA Cheng A Kiely PA Tremblay ML O Connor R April 2002 Regulation of Insulin Like Growth Factor Type I IGF I Receptor Kinase Activity by Protein Tyrosine Phosphatase 1B PTP 1B and Enhanced IGF I Mediated Suppression of Apoptosis and Motility in PTP 1B Deficient Fibroblasts Mol Cell Biol 22 7 1998 2010 doi 10 1128 MCB 22 7 1998 2010 2002 PMC 133665 PMID 11884589 Heinonen KM Dube N Bourdeau A Lapp WS Tremblay ML February 2006 Protein tyrosine phosphatase 1B negatively regulates macrophage development through CSF 1 signaling Proc Natl Acad Sci U S A 103 8 2776 81 Bibcode 2006PNAS 103 2776H doi 10 1073 pnas 0508563103 PMC 1413784 PMID 16477024 Zhu S Bjorge JD Fujita DJ November 2007 PTP1B contributes to the oncogenic properties of colon cancer cells through Src activation Cancer Res 67 21 10129 37 doi 10 1158 0008 5472 CAN 06 4338 PMID 17974954 a b Myers MP Andersen JN Cheng A Tremblay ML Horvath CM Parisien JP Salmeen A Barford D Tonks NK December 2001 TYK2 and JAK2 are substrates of protein tyrosine phosphatase 1B J Biol Chem 276 51 47771 4 doi 10 1074 jbc C100583200 PMID 11694501 Zhang Z Lin SY Neel BG Haimovich B January 2006 Phosphorylated alpha actinin and protein tyrosine phosphatase 1B coregulate the disassembly of the focal adhesion kinase x Src complex and promote cell migration J Biol Chem 281 3 1746 54 doi 10 1074 jbc M509590200 PMID 16291744 a b c Liu F Hill DE Chernoff J December 1996 Direct binding of the proline rich region of protein tyrosine phosphatase 1B to the Src homology 3 domain of p130 Cas J Biol Chem 271 49 31290 5 doi 10 1074 jbc 271 49 31290 PMID 8940134 Dube N Cheng A Tremblay ML February 2004 The role of protein tyrosine phosphatase 1B in Ras signaling Proc Natl Acad Sci U S A 101 7 1834 9 Bibcode 2004PNAS 101 1834D doi 10 1073 pnas 0304242101 PMC 357013 PMID 14766979 Balsamo J Arregui C Leung T Lilien J October 1998 The Nonreceptor Protein Tyrosine Phosphatase PTP1B Binds to the Cytoplasmic Domain of N Cadherin and Regulates the Cadherin Actin Linkage J Cell Biol 143 2 523 32 doi 10 1083 jcb 143 2 523 PMC 2132848 PMID 9786960 Stuible M Dube N Tremblay ML June 2008 PTP1B regulates cortactin tyrosine phosphorylation by targeting Tyr446 J Biol Chem 283 23 15740 6 doi 10 1074 jbc M710534200 PMC 3259645 PMID 18387954 a b c Tonks NK Jul 3 2003 PTP1B from the sidelines to the front lines FEBS Letters 546 1 140 8 doi 10 1016 s0014 5793 03 00603 3 PMID 12829250 S2CID 21205538 a b Barford D Flint AJ Tonks NK March 1994 Crystal structure of human protein tyrosine phosphatase 1B Science 263 5152 1397 404 Bibcode 1994Sci 263 1397B doi 10 1126 science 8128219 PMID 8128219 Alonso A Sasin J Bottini N Friedberg I Friedberg I Osterman A Godzik A Hunter T Dixon J Mustelin T 2004 Protein tyrosine phosphatases in the human genome Cell 117 6 699 711 doi 10 1016 j cell 2004 05 018 PMID 15186772 S2CID 18072568 Mahadev K Zilbering A Zhu L Goldstein BJ 2001 Insulin stimulated hydrogen peroxide reversibly inhibits protein tyrosine phosphatase 1b in vivo and enhances the early insulin action cascade J Biol Chem 276 24 21938 42 doi 10 1074 jbc C100109200 PMID 11297536 Lee SR Kwon KS Kim SR Rhee SG June 1998 Reversible inactivation of protein tyrosine phosphatase 1B in A431 cells stimulated with epidermal growth factor J Biol Chem 273 25 15366 72 doi 10 1074 jbc 273 25 15366 PMID 9624118 Sundaresan M Yu ZX Ferrans VJ Irani K Finkel T October 1995 Requirement for generation of H2O2 for platelet derived growth factor signal transduction Science 270 5234 296 9 Bibcode 1995Sci 270 296S doi 10 1126 science 270 5234 296 PMID 7569979 S2CID 8065388 a b Salmeen A Andersen JN Myers MP Meng TC Hinks JA Tonks NK Barford D 2003 Redox regulation of protein tyrosine phosphatase 1B involves a sulphenyl amide intermediate Nature 423 6941 769 73 Bibcode 2003Natur 423 769S doi 10 1038 nature01680 PMID 12802338 S2CID 4416512 a b van Montfort RL Congreve M Tisi D Carr R Jhoti H 2003 Oxidation state of the active site cysteine in protein tyrosine phosphatase 1B Nature 423 6941 773 7 Bibcode 2003Natur 423 773V doi 10 1038 nature01681 PMID 12802339 S2CID 4424814 a b Ravichandran LV Chen H Li Y Quon MJ October 2001 Phosphorylation of PTP1B at Ser 50 by Akt impairs its ability to dephosphorylate the insulin receptor Mol Endocrinol 15 10 1768 80 doi 10 1210 mend 15 10 0711 PMID 11579209 Sarmiento M Puius YA Vetter SW Keng YF Wu L Zhao Y Lawrence DS Almo SC Zhang ZY July 2000 Structural basis of plasticity in protein tyrosine phosphatase 1B substrate recognition Biochemistry 39 28 8171 9 doi 10 1021 bi000319w PMID 10889023 Zhang ZY Walsh AB Wu L McNamara DJ Dobrusin EM Miller WT March 1996 Determinants of substrate recognition in the protein tyrosine phosphatase PTP1 J Biol Chem 271 10 5386 92 doi 10 1074 jbc 271 10 5386 PMID 8621392 a b Goldstein BJ Bittner Kowalczyk A White MF Harbeck M February 2000 Tyrosine dephosphorylation and deactivation of insulin receptor substrate 1 by protein tyrosine phosphatase 1B Possible facilitation by the formation of a ternary complex with the Grb2 adaptor protein J Biol Chem 275 6 4283 9 doi 10 1074 jbc 275 6 4283 PMID 10660596 Lanahan AA Lech D Dubrac A Zhang J Zhuang ZW Eichmann A Simons M September 2014 PTP1b is a physiologic regulator of vascular endothelial growth factor signaling in endothelial cells Circulation 130 11 902 9 doi 10 1161 CIRCULATIONAHA 114 009683 PMC 6060619 PMID 24982127 Figueiredo H Figueroa AL Garcia A Fernandez Ruiz R Broca C Wojtusciszyn A et al June 2019 Targeting pancreatic islet PTP1B improves islet graft revascularization and transplant outcomes Science Translational Medicine 11 497 eaar6294 doi 10 1126 scitranslmed aar6294 hdl 10609 103266 PMID 31217339 S2CID 195188512 Thareja S Aggarwal S Bhardwaj TR Kumar M 2012 Protein tyrosine phosphatase 1B inhibitors a molecular level legitimate approach for the management of diabetes mellitus Med Res Rev 32 3 459 517 doi 10 1002 med 20219 PMID 20814956 S2CID 23121386 Tonks NK 2013 Protein tyrosine phosphatases from housekeeping enzymes to master regulators of signal transduction FEBS J 280 2 346 78 doi 10 1111 febs 12077 PMC 3662559 PMID 23176256 Dube N Bourdeau A Heinonen KM Cheng A Loy AL Tremblay ML 2005 Genetic ablation of protein tyrosine phosphatase 1B accelerates lymphomagenesis of p53 null mice through the regulation of B cell development Cancer Res 65 21 10088 95 doi 10 1158 0008 5472 CAN 05 1353 PMID 16267035 Retrieved from https en wikipedia org w index php title PTPN1 amp oldid 1184029592, wikipedia, wiki, book, books, library,

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