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. 1996 Sep 1;184(3):839–852. doi: 10.1084/jem.184.3.839

Signaling capacity of the T cell antigen receptor is negatively regulated by the PTP1C tyrosine phosphatase

PMCID: PMC2192780  PMID: 9064344

Abstract

The association of PTP1C deficiency with the multiplicity of lymphoid cell abnormalities manifested by motheaten (me) and viable motheaten (me(v)) mice suggests a pivotal role for this tyrosine phosphatase in the regulation of lymphocyte differentiation and function. To delineate the relevance of PTP1C to T cell physiology, we have examined me and me(v) T cells with regards to their capacity to transduce activating signals through the T cell antigen receptor (TCR). Although thymocyte maturation appeared normal in the mutant mice, both thymocytes and peripheral T cells from these animals exhibited proliferative response to TCR stimulation that were markedly increased relative to those elicited in normal cells. Compared to normal thymocytes, PTP1C- deficient thymocytes also showed increased constitutive tyrosine phosphorylation of the TCR complex and enhanced and prolonged TCR- induced tyrosine phosphorylation of the TCR-zeta and CD3-epsilon, as well as a number of cytosolic proteins, most notably a 38-kD phosphoprotein found to associate with the Grb2 adaptor SH2 domain in activated thymocytes. These latter phosphoproteins also associated with the Vav guanine nucleotide exchange factor upon TCR ligation, and were dephosphorylated by recombinant PTP1C in vitro. In conjunction with the finding of PTP1C-TCR association in unstimulated normal thymocytes, these results reveal the capacity of PTP1C to interact with and likely dephosphorylate resting and activated TCR complex components, as well as more distal signaling effectors that are normally recruited to the Vav and Grb2 SH2 domains after TCR stimulation. These data therefore strongly implicate PTP1C in the downregulation of TCR signaling capacity and, taken together with the aberrant prolongation of TCR- induced, mitogen-associated kinase (MAPK) activation observed in PTP1C- deficient thymocytes, these findings suggest that the inhibitory influence of PTP1C on TCR signal relay is realized through its effects on both the TCR complex and downstream signaling elements that couple the activated antigen receptor to the Ras/MAPK response pathway.

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Selected References

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  1. Alberola-Ila J., Forbush K. A., Seger R., Krebs E. G., Perlmutter R. M. Selective requirement for MAP kinase activation in thymocyte differentiation. Nature. 1995 Feb 16;373(6515):620–623. doi: 10.1038/373620a0. [DOI] [PubMed] [Google Scholar]
  2. Bignon J. S., Siminovitch K. A. Identification of PTP1C mutation as the genetic defect in motheaten and viable motheaten mice: a step toward defining the roles of protein tyrosine phosphatases in the regulation of hemopoietic cell differentiation and function. Clin Immunol Immunopathol. 1994 Nov;73(2):168–179. doi: 10.1006/clin.1994.1185. [DOI] [PubMed] [Google Scholar]
  3. Buday L., Egan S. E., Rodriguez Viciana P., Cantrell D. A., Downward J. A complex of Grb2 adaptor protein, Sos exchange factor, and a 36-kDa membrane-bound tyrosine phosphoprotein is implicated in ras activation in T cells. J Biol Chem. 1994 Mar 25;269(12):9019–9023. [PubMed] [Google Scholar]
  4. Buday L., Warne P. H., Downward J. Downregulation of the Ras activation pathway by MAP kinase phosphorylation of Sos. Oncogene. 1995 Oct 5;11(7):1327–1331. [PubMed] [Google Scholar]
  5. Cahir McFarland E. D., Hurley T. R., Pingel J. T., Sefton B. M., Shaw A., Thomas M. L. Correlation between Src family member regulation by the protein-tyrosine-phosphatase CD45 and transmembrane signaling through the T-cell receptor. Proc Natl Acad Sci U S A. 1993 Feb 15;90(4):1402–1406. doi: 10.1073/pnas.90.4.1402. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Chan A. C., van Oers N. S., Tran A., Turka L., Law C. L., Ryan J. C., Clark E. A., Weiss A. Differential expression of ZAP-70 and Syk protein tyrosine kinases, and the role of this family of protein tyrosine kinases in TCR signaling. J Immunol. 1994 May 15;152(10):4758–4766. [PubMed] [Google Scholar]
  7. Cyster J. G., Goodnow C. C. Protein tyrosine phosphatase 1C negatively regulates antigen receptor signaling in B lymphocytes and determines thresholds for negative selection. Immunity. 1995 Jan;2(1):13–24. doi: 10.1016/1074-7613(95)90075-6. [DOI] [PubMed] [Google Scholar]
  8. D'Ambrosio D., Hippen K. L., Minskoff S. A., Mellman I., Pani G., Siminovitch K. A., Cambier J. C. Recruitment and activation of PTP1C in negative regulation of antigen receptor signaling by Fc gamma RIIB1. Science. 1995 Apr 14;268(5208):293–297. doi: 10.1126/science.7716523. [DOI] [PubMed] [Google Scholar]
  9. Davies A. A., Ley S. C., Crumpton M. J. CD5 is phosphorylated on tyrosine after stimulation of the T-cell antigen receptor complex. Proc Natl Acad Sci U S A. 1992 Jul 15;89(14):6368–6372. doi: 10.1073/pnas.89.14.6368. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Doody G. M., Justement L. B., Delibrias C. C., Matthews R. J., Lin J., Thomas M. L., Fearon D. T. A role in B cell activation for CD22 and the protein tyrosine phosphatase SHP. Science. 1995 Jul 14;269(5221):242–244. doi: 10.1126/science.7618087. [DOI] [PubMed] [Google Scholar]
  11. Egan S. E., Giddings B. W., Brooks M. W., Buday L., Sizeland A. M., Weinberg R. A. Association of Sos Ras exchange protein with Grb2 is implicated in tyrosine kinase signal transduction and transformation. Nature. 1993 May 6;363(6424):45–51. doi: 10.1038/363045a0. [DOI] [PubMed] [Google Scholar]
  12. Fischer K. D., Zmuldzinas A., Gardner S., Barbacid M., Bernstein A., Guidos C. Defective T-cell receptor signalling and positive selection of Vav-deficient CD4+ CD8+ thymocytes. Nature. 1995 Mar 30;374(6521):474–477. doi: 10.1038/374474a0. [DOI] [PubMed] [Google Scholar]
  13. Gale N. W., Kaplan S., Lowenstein E. J., Schlessinger J., Bar-Sagi D. Grb2 mediates the EGF-dependent activation of guanine nucleotide exchange on Ras. Nature. 1993 May 6;363(6424):88–92. doi: 10.1038/363088a0. [DOI] [PubMed] [Google Scholar]
  14. Gulbins E., Coggeshall K. M., Baier G., Katzav S., Burn P., Altman A. Tyrosine kinase-stimulated guanine nucleotide exchange activity of Vav in T cell activation. Science. 1993 May 7;260(5109):822–825. doi: 10.1126/science.8484124. [DOI] [PubMed] [Google Scholar]
  15. Hayashi S., Witte P. L., Shultz L. D., Kincade P. W. Lymphohemopoiesis in culture is prevented by interaction with adherent bone marrow cells from mutant viable motheaten mice. J Immunol. 1988 Apr 1;140(7):2139–2147. [PubMed] [Google Scholar]
  16. Howe L. R., Weiss A. Multiple kinases mediate T-cell-receptor signaling. Trends Biochem Sci. 1995 Feb;20(2):59–64. doi: 10.1016/s0968-0004(00)88958-6. [DOI] [PubMed] [Google Scholar]
  17. Huang X., Li Y., Tanaka K., Moore K. G., Hayashi J. I. Cloning and characterization of Lnk, a signal transduction protein that links T-cell receptor activation signal to phospholipase C gamma 1, Grb2, and phosphatidylinositol 3-kinase. Proc Natl Acad Sci U S A. 1995 Dec 5;92(25):11618–11622. doi: 10.1073/pnas.92.25.11618. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Irving B. A., Weiss A. The cytoplasmic domain of the T cell receptor zeta chain is sufficient to couple to receptor-associated signal transduction pathways. Cell. 1991 Mar 8;64(5):891–901. doi: 10.1016/0092-8674(91)90314-o. [DOI] [PubMed] [Google Scholar]
  19. Katzav S., Sutherland M., Packham G., Yi T., Weiss A. The protein tyrosine kinase ZAP-70 can associate with the SH2 domain of proto-Vav. J Biol Chem. 1994 Dec 23;269(51):32579–32585. [PubMed] [Google Scholar]
  20. Kishihara K., Penninger J., Wallace V. A., Kündig T. M., Kawai K., Wakeham A., Timms E., Pfeffer K., Ohashi P. S., Thomas M. L. Normal B lymphocyte development but impaired T cell maturation in CD45-exon6 protein tyrosine phosphatase-deficient mice. Cell. 1993 Jul 16;74(1):143–156. doi: 10.1016/0092-8674(93)90302-7. [DOI] [PubMed] [Google Scholar]
  21. Klingmüller U., Lorenz U., Cantley L. C., Neel B. G., Lodish H. F. Specific recruitment of SH-PTP1 to the erythropoietin receptor causes inactivation of JAK2 and termination of proliferative signals. Cell. 1995 Mar 10;80(5):729–738. doi: 10.1016/0092-8674(95)90351-8. [DOI] [PubMed] [Google Scholar]
  22. Kon-Kozlowski M., Pani G., Pawson T., Siminovitch K. A. The tyrosine phosphatase PTP1C associates with Vav, Grb2, and mSos1 in hematopoietic cells. J Biol Chem. 1996 Feb 16;271(7):3856–3862. doi: 10.1074/jbc.271.7.3856. [DOI] [PubMed] [Google Scholar]
  23. Koo G. C., Rosen H., Sirotina A., Ma X. D., Shultz L. D. Anti-CD11b antibody prevents immunopathologic changes in viable moth-eaten bone marrow chimeric mice. J Immunol. 1993 Dec 15;151(12):6733–6741. [PubMed] [Google Scholar]
  24. Koretzky G. A., Picus J., Thomas M. L., Weiss A. Tyrosine phosphatase CD45 is essential for coupling T-cell antigen receptor to the phosphatidyl inositol pathway. Nature. 1990 Jul 5;346(6279):66–68. doi: 10.1038/346066a0. [DOI] [PubMed] [Google Scholar]
  25. Kozlowski M., Mlinaric-Rascan I., Feng G. S., Shen R., Pawson T., Siminovitch K. A. Expression and catalytic activity of the tyrosine phosphatase PTP1C is severely impaired in motheaten and viable motheaten mice. J Exp Med. 1993 Dec 1;178(6):2157–2163. doi: 10.1084/jem.178.6.2157. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Li W., Nishimura R., Kashishian A., Batzer A. G., Kim W. J., Cooper J. A., Schlessinger J. A new function for a phosphotyrosine phosphatase: linking GRB2-Sos to a receptor tyrosine kinase. Mol Cell Biol. 1994 Jan;14(1):509–517. doi: 10.1128/mcb.14.1.509. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Medlock E. S., Goldschneider I., Greiner D. L., Shultz L. Defective lymphopoiesis in the bone marrow of motheaten (me/me) and viable motheaten (mev/mev) mutant mice. II. Description of a microenvironmental defect for the generation of terminal deoxynucleotidyltransferase-positive bone marrow cells in vitro. J Immunol. 1987 Jun 1;138(11):3590–3597. [PubMed] [Google Scholar]
  28. Nel A. E., Gupta S., Lee L., Ledbetter J. A., Kanner S. B. Ligation of the T-cell antigen receptor (TCR) induces association of hSos1, ZAP-70, phospholipase C-gamma 1, and other phosphoproteins with Grb2 and the zeta-chain of the TCR. J Biol Chem. 1995 Aug 4;270(31):18428–18436. doi: 10.1074/jbc.270.31.18428. [DOI] [PubMed] [Google Scholar]
  29. Neumeister E. N., Zhu Y., Richard S., Terhorst C., Chan A. C., Shaw A. S. Binding of ZAP-70 to phosphorylated T-cell receptor zeta and eta enhances its autophosphorylation and generates specific binding sites for SH2 domain-containing proteins. Mol Cell Biol. 1995 Jun;15(6):3171–3178. doi: 10.1128/mcb.15.6.3171. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Nishibe S., Wahl M. I., Hernández-Sotomayor S. M., Tonks N. K., Rhee S. G., Carpenter G. Increase of the catalytic activity of phospholipase C-gamma 1 by tyrosine phosphorylation. Science. 1990 Nov 30;250(4985):1253–1256. doi: 10.1126/science.1700866. [DOI] [PubMed] [Google Scholar]
  31. Osman N., Lazarovits A. I., Crumpton M. J. Physical association of CD5 and the T cell receptor/CD3 antigen complex on the surface of human T lymphocytes. Eur J Immunol. 1993 May;23(5):1173–1176. doi: 10.1002/eji.1830230530. [DOI] [PubMed] [Google Scholar]
  32. Pani G., Kozlowski M., Cambier J. C., Mills G. B., Siminovitch K. A. Identification of the tyrosine phosphatase PTP1C as a B cell antigen receptor-associated protein involved in the regulation of B cell signaling. J Exp Med. 1995 Jun 1;181(6):2077–2084. doi: 10.1084/jem.181.6.2077. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Pelicci G., Lanfrancone L., Grignani F., McGlade J., Cavallo F., Forni G., Nicoletti I., Grignani F., Pawson T., Pelicci P. G. A novel transforming protein (SHC) with an SH2 domain is implicated in mitogenic signal transduction. Cell. 1992 Jul 10;70(1):93–104. doi: 10.1016/0092-8674(92)90536-l. [DOI] [PubMed] [Google Scholar]
  34. Plas D. R., Johnson R., Pingel J. T., Matthews R. J., Dalton M., Roy G., Chan A. C., Thomas M. L. Direct regulation of ZAP-70 by SHP-1 in T cell antigen receptor signaling. Science. 1996 May 24;272(5265):1173–1176. doi: 10.1126/science.272.5265.1173. [DOI] [PubMed] [Google Scholar]
  35. Raab M., Yamamoto M., Rudd C. E. The T-cell antigen CD5 acts as a receptor and substrate for the protein-tyrosine kinase p56lck. Mol Cell Biol. 1994 May;14(5):2862–2870. doi: 10.1128/mcb.14.5.2862. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Reif K., Buday L., Downward J., Cantrell D. A. SH3 domains of the adapter molecule Grb2 complex with two proteins in T cells: the guanine nucleotide exchange protein Sos and a 75-kDa protein that is a substrate for T cell antigen receptor-activated tyrosine kinases. J Biol Chem. 1994 May 13;269(19):14081–14087. [PubMed] [Google Scholar]
  37. Ria F., Chan B. M., Scherer M. T., Smith J. A., Gefter M. L. Immunological activity of covalently linked T-cell epitopes. Nature. 1990 Jan 25;343(6256):381–383. doi: 10.1038/343381a0. [DOI] [PubMed] [Google Scholar]
  38. Rozakis-Adcock M., McGlade J., Mbamalu G., Pelicci G., Daly R., Li W., Batzer A., Thomas S., Brugge J., Pelicci P. G. Association of the Shc and Grb2/Sem5 SH2-containing proteins is implicated in activation of the Ras pathway by tyrosine kinases. Nature. 1992 Dec 17;360(6405):689–692. doi: 10.1038/360689a0. [DOI] [PubMed] [Google Scholar]
  39. Sancho J., Franco R., Chatila T., Hall C., Terhorst C. The T cell receptor associated CD3-epsilon protein is phosphorylated upon T cell activation in the two tyrosine residues of a conserved signal transduction motif. Eur J Immunol. 1993 Jul;23(7):1636–1642. doi: 10.1002/eji.1830230736. [DOI] [PubMed] [Google Scholar]
  40. Secrist J. P., Burns L. A., Karnitz L., Koretzky G. A., Abraham R. T. Stimulatory effects of the protein tyrosine phosphatase inhibitor, pervanadate, on T-cell activation events. J Biol Chem. 1993 Mar 15;268(8):5886–5893. [PubMed] [Google Scholar]
  41. Seger R., Krebs E. G. The MAPK signaling cascade. FASEB J. 1995 Jun;9(9):726–735. [PubMed] [Google Scholar]
  42. Shultz L. D., Schweitzer P. A., Rajan T. V., Yi T., Ihle J. N., Matthews R. J., Thomas M. L., Beier D. R. Mutations at the murine motheaten locus are within the hematopoietic cell protein-tyrosine phosphatase (Hcph) gene. Cell. 1993 Jul 2;73(7):1445–1454. doi: 10.1016/0092-8674(93)90369-2. [DOI] [PubMed] [Google Scholar]
  43. Sieh M., Batzer A., Schlessinger J., Weiss A. GRB2 and phospholipase C-gamma 1 associate with a 36- to 38-kilodalton phosphotyrosine protein after T-cell receptor stimulation. Mol Cell Biol. 1994 Jul;14(7):4435–4442. doi: 10.1128/mcb.14.7.4435. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Swan K. A., Alberola-Ila J., Gross J. A., Appleby M. W., Forbush K. A., Thomas J. F., Perlmutter R. M. Involvement of p21ras distinguishes positive and negative selection in thymocytes. EMBO J. 1995 Jan 16;14(2):276–285. doi: 10.1002/j.1460-2075.1995.tb07001.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Tarakhovsky A., Kanner S. B., Hombach J., Ledbetter J. A., Müller W., Killeen N., Rajewsky K. A role for CD5 in TCR-mediated signal transduction and thymocyte selection. Science. 1995 Jul 28;269(5223):535–537. doi: 10.1126/science.7542801. [DOI] [PubMed] [Google Scholar]
  46. Tarakhovsky A., Turner M., Schaal S., Mee P. J., Duddy L. P., Rajewsky K., Tybulewicz V. L. Defective antigen receptor-mediated proliferation of B and T cells in the absence of Vav. Nature. 1995 Mar 30;374(6521):467–470. doi: 10.1038/374467a0. [DOI] [PubMed] [Google Scholar]
  47. Wange R. L., Malek S. N., Desiderio S., Samelson L. E. Tandem SH2 domains of ZAP-70 bind to T cell antigen receptor zeta and CD3 epsilon from activated Jurkat T cells. J Biol Chem. 1993 Sep 15;268(26):19797–19801. [PubMed] [Google Scholar]
  48. Weiss A., Littman D. R. Signal transduction by lymphocyte antigen receptors. Cell. 1994 Jan 28;76(2):263–274. doi: 10.1016/0092-8674(94)90334-4. [DOI] [PubMed] [Google Scholar]
  49. Wu Y., Pani G., Siminovitch K., Hozumi N. Antigen receptor-triggered apoptosis in immature B cell lines is associated with the binding of a 44-kDa phosphoprotein to the PTP1C tyrosine phosphatase. Eur J Immunol. 1995 Aug;25(8):2279–2284. doi: 10.1002/eji.1830250825. [DOI] [PubMed] [Google Scholar]
  50. Ye Z. S., Baltimore D. Binding of Vav to Grb2 through dimerization of Src homology 3 domains. Proc Natl Acad Sci U S A. 1994 Dec 20;91(26):12629–12633. doi: 10.1073/pnas.91.26.12629. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Yi T., Mui A. L., Krystal G., Ihle J. N. Hematopoietic cell phosphatase associates with the interleukin-3 (IL-3) receptor beta chain and down-regulates IL-3-induced tyrosine phosphorylation and mitogenesis. Mol Cell Biol. 1993 Dec;13(12):7577–7586. doi: 10.1128/mcb.13.12.7577. [DOI] [PMC free article] [PubMed] [Google Scholar]

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