Protein Tyrosine Phosphatase 1B: A Novel Molecular Target for Retinal Degenerative Diseases

  • Devaraj K. Basavarajappa
  • Vivek K. Gupta
  • Raju V. S. RajalaEmail author
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 723)


Protein tyrosine phosphatase 1B (PTP1B) is considered as a major negative regulator of insulin receptor (IR) signaling. IR signaling in retina has been demonstrated to be neuroprotective. Photoreceptor-specific deletion of PTP1B results in enhanced retinal IR-mediated neuroprotection indicating the importance of PTP1B as a negative regulator in the retina. Elevated levels of retinal PTP1B activity have been observed in mice lacking retinal pigment epithelium (Rpe65−/−), a mouse model of leber congenital amaurosis (LCA-type 2), retinitis pigmentosa and diabetic retinopathy animal models. This enhanced PTP1B activity could downregulate the IR signaling which may contribute to the death of photoreceptor neurons and ultimately lead to retinal degenerations. The potential therapeutic agents that specifically reduce or inhibit the PTP1B activity could be beneficial in protecting or delaying the photoreceptor cell death in the retinal degenerative diseases.


Insulin receptor Protein tyrosine phosphatase-1B Retinal degeneration Rhodopsin Neuroprotection 



This work was supported by grants from the NIH (EY016507-05; EY00871).


  1. Ahmad F, Li PM, Meyerovitch J et al (1995) Osmotic loading of neutralizing antibodies demonstrates a role for protein-tyrosine phosphatase 1B in negative regulation of the insulin action pathway. J Biol Chem 270:20503–20508PubMedCrossRefGoogle Scholar
  2. Barber AJ, Lieth E, Khin SA et al (1998) Neural apoptosis in the retina during experimental and human diabetes: early onset and effect of insulin. J Clin Invest 102:783–791PubMedCrossRefGoogle Scholar
  3. Barber AJ, Nakamura M, Wolpert EB et al (2001) Insulin rescues retinal neurons from apoptosis by a phosphatidylinositol 3-kinase/Akt-mediated mechanism that reduces the activation of caspase-3. J Biol Chem 276:32814–32821PubMedCrossRefGoogle Scholar
  4. Barford D, Flint AJ, Tonks NK (1994) Crystal structure of human protein tyrosine phosphatase 1B. Science 263:1397–1404PubMedCrossRefGoogle Scholar
  5. Bence KK, Delibegovic M, Xue B et al (2006) Neuronal PTP1B regulates body weight, adiposity and leptin action. Nat Med 12:917–924PubMedCrossRefGoogle Scholar
  6. Buckley DA, Cheng A, Kiely PA et al (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 22:1998–2010PubMedCrossRefGoogle Scholar
  7. Byon JC, Kusari AB, Kusari J (1998) Protein-tyrosine phosphatase-1B acts as a negative regulator of insulin signal transduction. Mol Cell Biochem 182:101–108PubMedCrossRefGoogle Scholar
  8. Calera, M.R, Vallega G, Pilch PF (2000) Dynamics of protein-tyrosine phosphatases in rat adipocytes. J Biol Chem 275:6308–6312PubMedCrossRefGoogle Scholar
  9. Combs AP (2010) Recent advances in the discovery of competitive protein tyrosine phosphatase 1B inhibitors for the treatment of diabetes, obesity, and cancer. J Med Chem 53:2333–2344PubMedCrossRefGoogle Scholar
  10. Cook WS and Unger RH (2002) Protein tyrosine phosphatase 1B: a potential leptin resistance factor of obesity. Dev Cell 2:385–387PubMedCrossRefGoogle Scholar
  11. Dadke S, Kusari J, Chernoff J (2000) Down-regulation of insulin signalling by protein-tyrosine phosphatase 1B is mediated by an N-terminal binding region. J Biol Chem 275:23642–23647PubMedCrossRefGoogle Scholar
  12. Datta SR, Brunet A, Greenberg ME (1999) Cellular survival: a play in three Akts. Genes Dev 13:2905–2927PubMedCrossRefGoogle Scholar
  13. Delibegovic M, Zimmer D, Kauffman C et al (2009) Liver-specific deletion of protein-tyrosine phosphatase 1B (PTP1B) improves metabolic syndrome and attenuates diet-induced endoplasmic reticulum stress. Diabetes 58:590–599PubMedCrossRefGoogle Scholar
  14. Dudek H, Datta SR, Franke TF, et al (1997) Regulation of neuronal survival by the serine-threonine protein kinase Akt. Science 275:661–665PubMedCrossRefGoogle Scholar
  15. Elchebly M, Payette P, Michaliszyn E et al (1999) Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. Science 283:1544–1548PubMedCrossRefGoogle Scholar
  16. Flint AJ, Tiganis T, Barford D, Tonks NK (1997) Development of “substrate-trapping” mutants to identify physiological substrates of protein tyrosine phosphatases. Proc Natl Acad Sci USA 94:1680–1685PubMedCrossRefGoogle Scholar
  17. Frangioni JV, Beahm PH, Shifrin V et al (1992) The nontransmembrane tyrosine phosphatase PTP-1B localizes to the endoplasmic reticulum via its 35 amino acid C-terminal sequence. Cell 68:545–560PubMedCrossRefGoogle Scholar
  18. Goldstein BJ, Ahmad F, Ding W et al (1998) Regulation of the insulin signalling pathway by cellular protein-tyrosine phosphatases. Mol Cell Biochem 182:91–99PubMedCrossRefGoogle Scholar
  19. Gu F, Dube N, Kim JW et al (2003) Protein tyrosine phosphatase 1B attenuates growth-hormone-mediated JAk2-STAT signaling. Mol Cell Biol 23:3753–3762PubMedCrossRefGoogle Scholar
  20. Haj FG, Markova B, Klaman LD et al (2003) Regulation of receptor tyrosine kinase signaling by protein tyrosine phosphatase-1B. J Biol Chem 278:739–744PubMedCrossRefGoogle Scholar
  21. Haj FG, Verveer PJ, Squire A et al (2002) Imaging sites of receptor dephosphorylation by PTP1B on the surface of the endoplasmic reticulum. Science 295:1708–1711PubMedCrossRefGoogle Scholar
  22. Ivanovic I, Le YZ, Anderson RE, Rajala RV (2009) Deletion of the p85 regulatory subunit of phosphoinositide 3-kinase in cone photoreceptor cells results in cone photoreceptor degeneration. ARVO abstract A389Google Scholar
  23. Jia Z, Barford D, Flint AJ et al (2001) Structural basis for phosphotyrosine peptide recognition by protein tyrosine phosphatase-1B. Science 268:1754–1758CrossRefGoogle Scholar
  24. Klaman LD, Boss O, Peroni OD et al (2000) Increased energy expenditure, decreased adiposity, and tissue-specific insulin sensitivity in protein-tyrosine phosphatase1B-deficientmice. Mol Cell Biol 20:5479–5489PubMedCrossRefGoogle Scholar
  25. Myers MP, Anderson NJ, Cheng A et al (2001) TYK2 and JAK2 are substrates of protein tyrosine phosphatase 1B. J Biol Chem 276:47771–47774PubMedCrossRefGoogle Scholar
  26. Ostman A and Böhmer FD (2001) Regulation of receptor tyrosine kinase signaling by protein tyrosine phosphatases. Trends Cell Biol 11:258–266PubMedCrossRefGoogle Scholar
  27. Punzo C, Kornacker K, Cepko CL (2009) Stimulation of the insulin/mTOR pathway delays cone death in a mouse model of retinitis pigmentosa. Nat Neurosci 12:44–52PubMedCrossRefGoogle Scholar
  28. Rajala A, Tanito M, Le YZ et al (2008) Loss of neuroprotective survival signal in mice lacking insulin receptor gene in rod photoreceptor cells. J Biol Chem 283:19781–19792PubMedCrossRefGoogle Scholar
  29. Rajala RV, McClellan ME, Ash JD, et al (2002) In vivo regulation of phosphoinositide 3-kinase in retina through light-induced tyrosine phosphorylation of the insulin receptor beta-subunit. J Biol Chem 277:43319–43326PubMedCrossRefGoogle Scholar
  30. Rajala RV, Tanito M, Neel BG et al (2010) Enhanced retinal insulin receptor-activated neuroprotective survival signal in mice lacking the protein-tyrosine phosphatase-1B gene. J Biol Chem 285:8894–8904PubMedCrossRefGoogle Scholar
  31. Rajala RV, Wiskur B, Tanito M (2009) Diabetes reduces autophosphorylation of retinal insulin receptor and increases protein-tyrosine phosphatase-1B activity. Invest Ophthalmol Vis Sci 50:1033–1040PubMedCrossRefGoogle Scholar
  32. Reiter CE, Sandirasegarane L, Wolpert EB et al (2003) Characterization of insulin signaling in rat retina in vivo and ex vivo. Am J Physiol 285:E763-E774Google Scholar
  33. Reiter CE, Wu X, Sandirasegarane L (2006) Diabetes reduces basal retinal insulin receptor signaling: reversal with systemic and local insulin. Diabetes 55:1148–1156PubMedCrossRefGoogle Scholar
  34. Salmeen A, Andersen JN, Myers MP et al (2000) Molecular basis for recognition and dephosphorylation of the activation segment of the insulin receptor by protein tyrosine phosphatase 1B. Mol Cell 6:1401–1412PubMedCrossRefGoogle Scholar
  35. Salmeen A, Andersen JN, Myers MP, Tonks NK, Barford D (2001) Molecular basis for the dephosphorylation of the activation segment of the insulin receptor by protein tyrosine phosphatase 1B. Mol Cell 6:1401–1412PubMedCrossRefGoogle Scholar
  36. Samardzija M, Wenzel A, Aufenberg S, et al (2006) Differential role of Jak-STAT signaling in retinal degenerations. FASEB J 20:E1790–E1801CrossRefGoogle Scholar
  37. Song J, Wu L, Chen Z (2003) Axons guided by insulin receptor in Drosophila visual system. Science 300:502–505PubMedCrossRefGoogle Scholar
  38. Stuible M and Tremblay ML (2010) In control at the ER: PTP1B and the down-regulation of RTKs by dephosphorylation and endocytosis. Trends Cell Biol 20: 672–679Google Scholar
  39. Tonks NK (2003) PTP1B:from the sidelines to the front lines! FEBS Lett 546:140–148PubMedCrossRefGoogle Scholar
  40. Ueki Y, Le YZ, Chollangi S et al (2009) Preconditioning-induced protection of photoreceptors requires activation of the signal-transducing receptor gp130 in photoreceptors. Proc Natl Acad Sci USA 106:21389–21394PubMedCrossRefGoogle Scholar
  41. Yu X, Rajala RV, McGinnis JF et al (2004) Involvement of insulin/phosphoinositide 3-kinase/Akt signal pathway in 17 beta-estradiol-mediated neuroprotection. J Biol Chem 279:13086–13094PubMedCrossRefGoogle Scholar
  42. Zhang S and Zhang ZY (2007) PTP1B as a drug target: recent developments in PTP1B inhibitor discovery. Drug Discov Today 12:373–81PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Devaraj K. Basavarajappa
    • 1
  • Vivek K. Gupta
    • 1
  • Raju V. S. Rajala
    • 2
    Email author
  1. 1.Department of Ophthalmology, Dean A. McGee Eye InstituteUniversity of Oklahoma Health Sciences CenterOklahoma CityUSA
  2. 2.Departments of Ophthalmology and Cell Biology, Dean A. McGee Eye InstituteUniversity of Oklahoma Health Sciences CenterOklahoma CityUSA

Personalised recommendations