PTPN6

La tirosina proteína fosfatasa no receptora tipo 6.

La tirosina-proteína fosfatasa no receptora tipo 6, también conocida como fosfatasa-1 que contiene la región 2 del dominio de homología de Src (SHP-1), es una enzima que en humanos está codificada por el gen PTPN6.[1]​

Función

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La proteína codificada por este gen es un miembro de la familia de la proteína tirosina fosfatasa (PTP). Se sabe que las PTP son moléculas de señalización que regulan una batería de procesos celulares que incluyen el crecimiento celular, la diferenciación, el ciclo mitótico y la transformación oncogénica. La parte N-terminal de esta PTP contiene dos dominios de homólogo de Src en tándem (SH2), que actúan como dominios de unión de la proteína fosfo-tirosina y median la interacción de esta PTP con sus sustratos. Esta PTP se expresa principalmente en células hematopoyéticas y funciona como un importante regulador de múltiples vías de señalización en células hematopoyéticas. Se ha demostrado que esta PTP interactúa con un amplio espectro de fosfo-proteínas involucradas en la señalización de células hematopoyéticas, a las que desfosforila (por ejemplo, la vía LYN-CD22-SHP-1). Se han descrito múltiples variantes de este gen con splicing alternativo, que codifican distintas isoformas.[2]​

Expresión

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El gen SHP-1 tiene dos promotores: P-1, activo en células epiteliales, y P-2, activo en células hemopoyéticas. Además, la expresión de SHP-1 es baja en células epiteliales y alta en células hemopoéticas. En cáncer, el nivel de SHP-1 en células epiteliales aumenta y en células hematopoyéticas disminuye.[3]​

Interacciones

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Se ha demostrado que PTPN6 interactúa con:

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* Gen BCR[4]​

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Referencias

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  1. ↑ «Chromosomal localization of an SH2-containing tyrosine phosphatase (PTPN6)». Genomics 13 (3): 869-72. August 1992. PMID 1639416. doi:10.1016/0888-7543(92)90172-O. 
  2. ↑ «Entrez Gene: PTPN6 protein tyrosine phosphatase, non-receptor type 6». 
  3. ↑ «Breast cancer cells proliferation is regulated by tyrosine phosphatase SHP1 through c-jun N-terminal kinase and cooperative induction of RFX-1 and AP-4 transcription factors». Mol. Cancer Res. 9 (8): 1112-25. agosto de 2011. PMID 21719561. doi:10.1158/1541-7786.MCR-11-0097. 
  4. ↑ a b Liedtke M, Pandey P, Kumar S, Kharbanda S, Kufe D (October 1998). «Regulation of Bcr-Abl-induced SAP kinase activity and transformation by the SHPTP1 protein tyrosine phosphatase». Oncogene 17 (15): 1889-92. PMID 9788431. doi:10.1038/sj.onc.1202117. 
  5. ↑ a b Kozlowski M, Larose L, Lee F, Le DM, Rottapel R, Siminovitch KA (April 1998). «SHP-1 binds and negatively modulates the c-Kit receptor by interaction with tyrosine 569 in the c-Kit juxtamembrane domain». Mol. Cell. Biol. 18 (4): 2089-99. PMC 121439. PMID 9528781. 
  6. ↑ a b Yi T, Ihle JN (June 1993). «Association of hematopoietic cell phosphatase with c-Kit after stimulation with c-Kit ligand». Mol. Cell. Biol. 13 (6): 3350-8. PMC 359793. PMID 7684496. 
  7. ↑ a b Blasioli J, Paust S, Thomas ML (January 1999). «Definition of the sites of interaction between the protein tyrosine phosphatase SHP-1 and CD22». J. Biol. Chem. 274 (4): 2303-7. PMID 9890995. doi:10.1074/jbc.274.4.2303. 
  8. ↑ a b Otipoby KL, Draves KE, Clark EA (November 2001). «CD22 regulates B cell receptor-mediated signals via two domains that independently recruit Grb2 and SHP-1». J. Biol. Chem. 276 (47): 44315-22. PMID 11551923. doi:10.1074/jbc.M105446200. 
  9. ↑ a b Greer SF, Justement LB (May 1999). «CD45 regulates tyrosine phosphorylation of CD22 and its association with the protein tyrosine phosphatase SHP-1». J. Immunol. 162 (9): 5278-86. PMID 10228003. 
  10. ↑ a b Law CL, Sidorenko SP, Chandran KA, Zhao Z, Shen SH, Fischer EH, Clark EA (February 1996). «CD22 associates with protein tyrosine phosphatase 1C, Syk, and phospholipase C-gamma(1) upon B cell activation». J. Exp. Med. 183 (2): 547-60. PMC 2192439. PMID 8627166. doi:10.1084/jem.183.2.547. 
  11. ↑ a b Adachi T, Wienands J, Wakabayashi C, Yakura H, Reth M, Tsubata T (July 2001). «SHP-1 requires inhibitory co-receptors to down-modulate B cell antigen receptor-mediated phosphorylation of cellular substrates». J. Biol. Chem. 276 (28): 26648-55. PMID 11356834. doi:10.1074/jbc.M100997200. 
  12. ↑ a b Pumphrey NJ, Taylor V, Freeman S, Douglas MR, Bradfield PF, Young SP, Lord JM, Wakelam MJ, Bird IN, Salmon M, Buckley CD (April 1999). «Differential association of cytoplasmic signalling molecules SHP-1, SHP-2, SHIP and phospholipase C-gamma1 with PECAM-1/CD31». FEBS Lett. 450 (1–2): 77-83. PMID 10350061. doi:10.1016/s0014-5793(99)00446-9. 
  13. ↑ a b Hua CT, Gamble JR, Vadas MA, Jackson DE (October 1998). «Recruitment and activation of SHP-1 protein-tyrosine phosphatase by human platelet endothelial cell adhesion molecule-1 (PECAM-1). Identification of immunoreceptor tyrosine-based inhibitory motif-like binding motifs and substrates». J. Biol. Chem. 273 (43): 28332-40. PMID 9774457. doi:10.1074/jbc.273.43.28332. 
  14. ↑ a b Keilhack H, Hellman U, van Hengel J, van Roy F, Godovac-Zimmermann J, Böhmer FD (August 2000). «The protein-tyrosine phosphatase SHP-1 binds to and dephosphorylates p120 catenin». J. Biol. Chem. 275 (34): 26376-84. PMID 10835420. doi:10.1074/jbc.M001315200. 
  15. ↑ a b Tomic S, Greiser U, Lammers R, Kharitonenkov A, Imyanitov E, Ullrich A, Böhmer FD (September 1995). «Association of SH2 domain protein tyrosine phosphatases with the epidermal growth factor receptor in human tumor cells. Phosphatidic acid activates receptor dephosphorylation by PTP1C». J. Biol. Chem. 270 (36): 21277-84. PMID 7673163. doi:10.1074/jbc.270.36.21277. 
  16. ↑ a b Keilhack H, Tenev T, Nyakatura E, Godovac-Zimmermann J, Nielsen L, Seedorf K, Böhmer FD (September 1998). «Phosphotyrosine 1173 mediates binding of the protein-tyrosine phosphatase SHP-1 to the epidermal growth factor receptor and attenuation of receptor signaling». J. Biol. Chem. 273 (38): 24839-46. PMID 9733788. doi:10.1074/jbc.273.38.24839. 
  17. ↑ a b Klingmüller U, Lorenz U, Cantley LC, Neel BG, Lodish HF (March 1995). «Specific recruitment of SH-PTP1 to the erythropoietin receptor causes inactivation of JAK2 and termination of proliferative signals». Cell 80 (5): 729-38. PMID 7889566. doi:10.1016/0092-8674(95)90351-8. 
  18. ↑ a b Xu MJ, Zhao R, Cao H, Zhao ZJ (May 2002). «SPAP2, an Ig family receptor containing both ITIMs and ITAMs». Biochem. Biophys. Res. Commun. 293 (3): 1037-46. PMID 12051764. doi:10.1016/S0006-291X(02)00332-7. 
  19. ↑ a b c d e f Ganju RK, Brubaker SA, Chernock RD, Avraham S, Groopman JE (June 2000). «Beta-chemokine receptor CCR5 signals through SHP1, SHP2, and Syk». J. Biol. Chem. 275 (23): 17263-8. PMID 10747947. doi:10.1074/jbc.M000689200. 
  20. ↑ a b Kon-Kozlowski M, Pani G, Pawson T, Siminovitch KA (February 1996). «The tyrosine phosphatase PTP1C associates with Vav, Grb2, and mSos1 in hematopoietic cells». J. Biol. Chem. 271 (7): 3856-62. PMID 8632004. doi:10.1074/jbc.271.7.3856. 
  21. ↑ a b Saci A, Liu WQ, Vidal M, Garbay C, Rendu F, Bachelot-Loza C (May 2002). «Differential effect of the inhibition of Grb2-SH3 interactions in platelet activation induced by thrombin and by Fc receptor engagement». Biochem. J. 363 (Pt 3): 717-25. PMC 1222524. PMID 11964172. doi:10.1042/0264-6021:3630717. 
  22. ↑ a b Eklund EA, Goldenberg I, Lu Y, Andrejic J, Kakar R (September 2002). «SHP1 protein-tyrosine phosphatase regulates HoxA10 DNA binding and transcriptional repression activity in undifferentiated myeloid cells». J. Biol. Chem. 277 (39): 36878-88. PMID 12145285. doi:10.1074/jbc.M203917200. 
  23. ↑ a b Jiao H, Berrada K, Yang W, Tabrizi M, Platanias LC, Yi T (December 1996). «Direct association with and dephosphorylation of Jak2 kinase by the SH2-domain-containing protein tyrosine phosphatase SHP-1». Mol. Cell. Biol. 16 (12): 6985-92. PMC 231702. PMID 8943354. doi:10.1128/mcb.16.12.6985. 
  24. ↑ a b Wu DW, Stark KC, Dunnington D, Dillon SB, Yi T, Jones C, Pelus LM (February 2000). «SH2-Containing protein tyrosine phosphatase-1 (SHP-1) association with Jak2 in UT-7/Epo cells». Blood Cells Mol. Dis. 26 (1): 15-24. PMID 10772872. doi:10.1006/bcmd.2000.0273. 
  25. ↑ a b c d Mousseau DD, Banville D, L'Abbé D, Bouchard P, Shen SH (February 2000). «PILRalpha, a novel immunoreceptor tyrosine-based inhibitory motif-bearing protein, recruits SHP-1 upon tyrosine phosphorylation and is paired with the truncated counterpart PILRbeta». J. Biol. Chem. 275 (6): 4467-74. PMID 10660620. doi:10.1074/jbc.275.6.4467. 
  26. ↑ a b Sathish JG, Johnson KG, Fuller KJ, LeRoy FG, Meyaard L, Sims MJ, Matthews RJ (February 2001). «Constitutive association of SHP-1 with leukocyte-associated Ig-like receptor-1 in human T cells». J. Immunol. 166 (3): 1763-70. PMID 11160222. doi:10.4049/jimmunol.166.3.1763. 
  27. ↑ a b Fournier N, Chalus L, Durand I, Garcia E, Pin JJ, Churakova T, Patel S, Zlot C, Gorman D, Zurawski S, Abrams J, Bates EE, Garrone P (August 2000). «FDF03, a novel inhibitory receptor of the immunoglobulin superfamily, is expressed by human dendritic and myeloid cells». J. Immunol. 165 (3): 1197-209. PMID 10903717. doi:10.4049/jimmunol.165.3.1197. 
  28. ↑ a b Meyaard L, Adema GJ, Chang C, Woollatt E, Sutherland GR, Lanier LL, Phillips JH (August 1997). «LAIR-1, a novel inhibitory receptor expressed on human mononuclear leukocytes». Immunity 7 (2): 283-90. PMID 9285412. doi:10.1016/s1074-7613(00)80530-0. 
  29. ↑ a b ((Xu Mj)), Zhao R, Zhao ZJ (June 2000). «Identification and characterization of leukocyte-associated Ig-like receptor-1 as a major anchor protein of tyrosine phosphatase SHP-1 in hematopoietic cells». J. Biol. Chem. 275 (23): 17440-6. PMID 10764762. doi:10.1074/jbc.M001313200. 
  30. ↑ a b Fanger NA, Cosman D, Peterson L, Braddy SC, Maliszewski CR, Borges L (November 1998). «The MHC class I binding proteins LIR-1 and LIR-2 inhibit Fc receptor-mediated signaling in monocytes». Eur. J. Immunol. 28 (11): 3423-34. PMID 9842885. doi:10.1002/(SICI)1521-4141(199811)28:11<3423::AID-IMMU3423>3.0.CO;2-2. 
  31. ↑ a b Colonna M, Samaridis J, Cella M, Angman L, Allen RL, O'Callaghan CA, Dunbar R, Ogg GS, Cerundolo V, Rolink A (April 1998). «Human myelomonocytic cells express an inhibitory receptor for classical and nonclassical MHC class I molecules». J. Immunol. 160 (7): 3096-100. PMID 9531263. 
  32. ↑ a b Wang LL, Blasioli J, Plas DR, Thomas ML, Yokoyama WM (February 1999). «Specificity of the SH2 domains of SHP-1 in the interaction with the immunoreceptor tyrosine-based inhibitory motif-bearing receptor gp49B». J. Immunol. 162 (3): 1318-23. PMID 9973385. 
  33. ↑ a b Yu CL, Jin YJ, Burakoff SJ (January 2000). «Cytosolic tyrosine dephosphorylation of STAT5. Potential role of SHP-2 in STAT5 regulation». J. Biol. Chem. 275 (1): 599-604. PMID 10617656. doi:10.1074/jbc.275.1.599. 
  34. ↑ a b Chiang GG, Sefton BM (June 2001). «Specific dephosphorylation of the Lck tyrosine protein kinase at Tyr-394 by the SHP-1 protein-tyrosine phosphatase». J. Biol. Chem. 276 (25): 23173-8. PMID 11294838. doi:10.1074/jbc.M101219200. 
  35. ↑ a b Lorenz U, Ravichandran KS, Pei D, Walsh CT, Burakoff SJ, Neel BG (March 1994). «Lck-dependent tyrosyl phosphorylation of the phosphotyrosine phosphatase SH-PTP1 in murine T cells». Mol. Cell. Biol. 14 (3): 1824-34. PMC 358540. PMID 8114715. doi:10.1128/mcb.14.3.1824. 
  36. ↑ a b Binstadt BA, Billadeau DD, Jevremović D, Williams BL, Fang N, Yi T, Koretzky GA, Abraham RT, Leibson PJ (October 1998). «SLP-76 is a direct substrate of SHP-1 recruited to killer cell inhibitory receptors». J. Biol. Chem. 273 (42): 27518-23. PMID 9765283. doi:10.1074/jbc.273.42.27518. 
  37. ↑ a b Mizuno K, Katagiri T, Hasegawa K, Ogimoto M, Yakura H (August 1996). «Hematopoietic cell phosphatase, SHP-1, is constitutively associated with the SH2 domain-containing leukocyte protein, SLP-76, in B cells». J. Exp. Med. 184 (2): 457-63. PMC 2192711. PMID 8760799. doi:10.1084/jem.184.2.457. 
  38. ↑ a b Yoshida K, Kufe D (December 2001). «Negative regulation of the SHPTP1 protein tyrosine phosphatase by protein kinase C delta in response to DNA damage». Mol. Pharmacol. 60 (6): 1431-8. PMID 11723252. 
  39. ↑ a b Kumar S, Avraham S, Bharti A, Goyal J, Pandey P, Kharbanda S (October 1999). «Negative regulation of PYK2/related adhesion focal tyrosine kinase signal transduction by hematopoietic tyrosine phosphatase SHPTP1». J. Biol. Chem. 274 (43): 30657-63. PMID 10521452. doi:10.1074/jbc.274.43.30657. 
  40. ↑ a b Keilhack H, Müller M, Böhmer SA, Frank C, Weidner KM, Birchmeier W, Ligensa T, Berndt A, Kosmehl H, Günther B, Müller T, Birchmeier C, Böhmer FD (January 2001). «Negative regulation of Ros receptor tyrosine kinase signaling. An epithelial function of the SH2 domain protein tyrosine phosphatase SHP-1». J. Cell Biol. 152 (2): 325-34. PMC 2199605. PMID 11266449. doi:10.1083/jcb.152.2.325. 
  41. ↑ a b Yang J, Cheng Z, Niu T, Liang X, Zhao ZJ, Zhou GW (February 2000). «Structural basis for substrate specificity of protein-tyrosine phosphatase SHP-1». J. Biol. Chem. 275 (6): 4066-71. PMID 10660565. doi:10.1074/jbc.275.6.4066. 
  42. ↑ a b Dustin LB, Plas DR, Wong J, Hu YT, Soto C, Chan AC, Thomas ML (March 1999). «Expression of dominant-negative src-homology domain 2-containing protein tyrosine phosphatase-1 results in increased Syk tyrosine kinase activity and B cell activation». J. Immunol. 162 (5): 2717-24. PMID 10072516. 
  43. ↑ a b Yetter A, Uddin S, Krolewski JJ, Jiao H, Yi T, Platanias LC (August 1995). «Association of the interferon-dependent tyrosine kinase Tyk-2 with the hematopoietic cell phosphatase». J. Biol. Chem. 270 (31): 18179-82. PMID 7629131. doi:10.1074/jbc.270.31.18179.