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PAG: A POTENTIAL TUMOUR SUPPRESSOR AND HOW IT ALL STARTED. FROM IMMUNE SIGNALLING TO NEOPLASTIC TRANSFORMATION


Authors: A. Švec
Authors‘ workplace: Department of Cellular Pathology, James Cook University Hospital, Middlesbrough, United Kingdom
Published in: Čes.-slov. Patol., 45, 2009, No. 2, p. 35-39
Category: Reviews Article

Overview

Phosphoprotein associated with glycosphingolipid-enriched microdomains (PAG) also known as Csk-binding protein was first fully

characterized in 2000. It was initially recognized as a ubiquitously expressed adaptor protein recruiting cytoplasmic C-terminal Src-kinase

to the close proximity of plasma membrane-anchored Src-kinases thereby allowing Csk to impose its inhibitory potential on these kinases.

A role of PAG was initially seen in negative regulation of immune reactions. Since the year 2000 other Csk-dependent and independent

interactions have been discovered and some of them showed anti-oncogenic effects in experiment. According to current opinions, these

findings place PAG in a position of tumour suppressor candidate.

Key words:

PAG – Cbp – immune signalling – oncogenesis


Sources

1. Alberts, B., Johnson, A., Lewis, J., et al.: Biology of the Cell. 5th ed., New York: Garland Science, 2008, s. 879-964.

2. Alvarez., R.H., Kantarjian, H.M., Cortes, J.E.: The role of Src in solid and hematologic malignancies: development of new-generation Src inhibitors. Cancer, 107, 2006, s.918-29.

3. Baumgartner, M., Angelisova, P., Setterbladl, N., et al: Constitutive exclusion of Csk from Hck-positive membrane microdomains permits Src-kinase-dependent proliferation of Theileria-transformed B lymphocytes. Blood, 101, 2003, s.1874-81.

4. Besson, A., Hwang, H.C., Cicero, S., et al.: Discovery of an oncogenic activity in p27Kip1 that causes stem cell expansion and a multiple tumor phenotype. Genes Dev., 21, 2007, s.1731-46.

5. Brdicka, T., Imrich, M., Angelisova, P. et al.: Non-T Cell Activation Linker (NTAL): a transmembrane adaptor protein involved in immunoreceptor signaling. J. Exp. Med., 196, 2002, s.1617–1626.

6. Brdicka, T., Pavlistova, D., Leo, A. et al.: Phosphoprotein associated with glycosphingolipid-enriched microdomains (PAG), a novel ubiquitously expressed transmembrane adaptor protein, binds the protein tyrosine kinase csk and is involved in regulation of T cell activation. J. Exp. Med., 191, 2000, s.1591-604.

7. Brdickova, T., Brdicka, P., Angelisova, O., et al.: LIME: a new membrane Raft-associated adaptor protein involved in CD4 and CD8 coreceptor signaling. J. Exp. Med., 198, 2003, s.1453–1462

8. Brdicková, N., Brdicka, T., Andera, L., et al.: Interaction between two adapter proteins, PAG and EBP50: a possible link between membrane rafts and actin cytoskeleton. FEBS Lett., 507, 2001, s. 133-6.

9. Brown, M.T., Cooper, J.A.: Regulation, substrates and functions of src. Biochim Biophys Acta., 1287, 1996 s.121-49.

10. Davidson, D., Bakinowski, M.,Thomas, M.L., et al: Phosphorylation-dependent regulation of T-cell activation by PAG/Cbp, a lipid raft-associated transmembrane adaptor. Mol. Cell Biol., 23, 2003, s.2017-28..

11. Davidson, D., Schraven, B., Veillette, A., et al.: PAG-associated FynT regulates calcium signaling and promotes anergy in T lymphocytes. Mol. Cell Biol. 27, 2007, s.1960-73.

12. Dobbelaere, D.A., Küenzi, P.: The strategies of the Theileria parasite: a new twist in host-pathogen interactions. Curr. Opin. Immunol., 16, 2004, s.524-30.

13. Dobenecker, M.W., Schmedt, C., Okada, M. et al.: The ubiquitously expressed Csk adaptor protein Cbp is dispensable for embryogenesis and T-cell development and function. Mol. Cell Biol., 25, 2005, s.10533-42.

14. Engelberg, D.: Stress-activated protein kinases-tumor suppressors or tumor initiators? Semin. Cancer Biol., 14, 2004, s.271-82.

15. Esteller, M.: Epigenetics provides a new generation of oncogenes and tumour-suppressor genes. Br. J. Cancer., 96, 2007, Suppl:R26-30.

16. Horejsi, V., Zhang , W., Schraven, B.: Transmembrane adaptor proteins: organizers of immunoreceptor signalling. Nat. Rev. Immunol., 4, 2004, s.603-16.

17. Ingley, E.: Csk-binding protein can regulate Lyn signals controlling cell morphology. Int. J. Biochem. Cell. Biol., 2008, DOI 10.1016/j.biocel.2008.12.001

18. Ingley, E.: Src family kinases: Regulation of their activities, levels and identification of new pathways. Biochim. Biophys. Acta, 1784, 2008, s.56-65.

19. Ingley, E., Schneider, J.R. , Payne, C.J., et al: Csk-binding protein mediates sequential enzymatic down-regulation and degradation of Lyn in erythropoietin-stimulated cells. J. Biol. Chem., 281, 2006, s.31920-9.

20. Itoh, K., Sakakibara, M., Yamasaki, S., et al.: Cutting edge: negative regulation of immune synapse formation by anchoring lipid raft to cytoskeleton through Cbp-EBP50-ERM assembly. J. Immunol., 168, 2002, s. 541-4.

21. Jiang, L.Q., Feng, X., Zhou, W., et al.: Csk-binding protein (Cbp) negatively regulates epidermal growth factor-induced cell transformation by controlling Src activation. Oncogene, 25, 2006, s.5495-506.

22. Kawabuchi, M., Satomi, Y.,Takao, T. et al.: Transmembrane phosphoprotein Cbp regulates the activities of Src-family tyrosine kinases. Nature, 404, 2000, s.999-1003.

23. Kent, O.A., Mendell, J.T.: A small piece in the cancer puzzle: microRNAs as tumor suppressors and oncogenes. Oncogene, 25, 2006, s.6188-96.

24. Knudson, A.G.: Two genetic hits (more or less) to cancer. Nat. Rev. Cancer, 1, 2001 s.157-62.

25. Lindquist, J.A., Simeoni, L., Schraven, B.: Transmembrane adapters: attractants for cytoplasmic effectors. Immunol. Rev., 191, 2003, s.165-82.

26. Lowe, S.W., Cepero, E., Evan, G.: Intrinsic tumour suppression. Nature, 7015, 2004, s.307-15.

27. Matsuoka, H., Nada, S., Okada, M. Et al: Mechanism of Csk-mediated down-regulation of Src family tyrosine kinases in epidermal growth factor signaling. J. Biol. Chem., 279, 2004, s.5975-83.

28. McKeever, D.J.: Theileria parva and the bovine CTL response: down but not out? Parasite Immunol., 28, 2006, s.339–345.

29. Ohtake, H. N., Ichikawa, M., Okada, T. Et al.: Cutting Edge: Transmembrane phosphoprotein Csk-binding protein/phosphoprotein associated with glycosphingolipid-enriched microdomains as a negative feedback regulator of mast cell signaling through the FcepsilonRI. J. Immunol. 168, 2002, s.2087-90.

30. Okada, M., Nada, S., Yamanashi, Y., et al: CSK: a protein-tyrosine kinase involved in regulation of Src family kinases. J. Biol. Chem., 25, 1991, s.24249-52.

31. Okada, M., Nakagawa, H.: Identification of a novel protein tyrosine kinase that phosphorylates pp60c-src and regulates its activity in neonatal rat brain. Biochem. Biophys. Res. Commun., 154, 1988, s.796-802.

32. Oneyama, C., Hikita, T., Enya, K. Et al: The lipid raft-anchored adaptor protein Cbp controls the oncogenic potential of c-Src. Mol. Cell, 30, 2008, s.426-36.

33. Pelengaris, S., Khan, M.: Oncogenes. Introduction. In: Pelengaris, S., Khan, M., eds. The Molecular Biology of Cancer. Oxford, UK: Blackwell Publishing Ltd., 2006, s.158-171.

34. Pollard, T.D., Earnshaw, W.C.: Integration of signals, In: Pollard, T.D., Earnshaw, W.C., Cell Biology, 1st ed., Philadelphia, Saunders, 2002, s.445-447.

35. Resh, M.D.: The ups and downs of SRC regulation: tumor suppression by Cbp. Cancer Cell, 13, 2008, s.469-71.

36. Shima, T., Nada, S., Okada, M. et al: Transmembrane phosphoprotein Cbp senses cell adhesion signaling mediated by Src family kinase in lipid rafts. Proc. Natl. Acad. Sci. U. S. A., 100, 2003, s.14897-902.

37. Smida, M., Posevitz-Fejfar, A., Horejsi, V. et al.: A novel negative regulatory function of the phosphoprotein associated with glycosphingolipid-enriched microdomains: blocking Ras activation. Blood, 2007, 110, s.596-615.

38. Solheim, S.A., Torgersen, K.M., Taskén, K. et al.: Regulation of FynT function by dual domain docking on PAG/Cbp. J. Biol. Chem., 2008, 283, s.2773-83.

39. Svec, A.: Phosphoprotein associated with glycosphingolipid-enriched microdomains/Csk-binding protein: a protein that matters. Pathol. Res. Pract., 204, 2008, s. 785-92.

40. Svec, A., Velenska, Z., Horejsi, V.: Expression pattern of adaptor protein PAG: Correlation between secondary lymphatic follicle and histogenetically related malignant lymphomas. Immunol. Lett., 100, 2005, s.94-7.

41. Svojgr, K., Burjanivova, T., Vaskova, M., et al.: Adaptor molecules expression in normallymphopoiesis and in childhood leukemia. Immunol. Lett., 2009, DOI : 10.1016/j.imlet.2008.12.008

42. Takeuchi S., Takayama, Y., Ogawa, A. et al.: Transmembrane phosphoprotein Cbp positively regulates the activity of the carboxyl-terminal Src-kinase, Csk. J. Biol. Chem., 2000, 275 s.29183-6.

43. Tauzin, S., Ding, H., Khatib, K. et al.: Oncogenic association of the Cbp/PAG adaptor protein with the Lyn tyrosine kinase in human B-NHL rafts. Blood, 111, 2008, s.2310-20.

44. Tedoldi, S., Paterson, J.C., Hansmann, M.L. et al.: Transmembrane adaptor molecules: a new category of lymphoid-cell markers. Blood, 107, 2006, s.213-21.

45. Tice, D.A., Biscardi, J.S., Nickles, A.L. et al.: Mechanism of biological synergy between cellular Src and epidermal growth factor receptor. Proc. Natl. Acad. Sci. U. S. A., 96, 1999, s.1415-20.

46. Torgersen, K.M., Vang, T., Abrahamsen, H. et al.: Release from tonic inhibition of T cell activation through transient displacement of C-terminal Src kinase (Csk) from lipid rafts. J. Biol. Chem., 276, 2001, s.29313-8.

47. Veracini, L., Simon, V., Richard, V. et al: The Csk-binding protein PAG regulates PDGF-induced Src mitogenic signaling via GM1. J Cell Biol. 182, 2008, s. 603-14.

48. Xu, S., Huo, J., Tan, J.E. et al.: Cbp deficiency alters Csk localization in lipid rafts but does not affect T-cell development. Mol. Cell Biol., 19, 2005, s.8486-95.

49. Yasuda, K., M. Nagafuku, T. Shima, M. Et al.: Cutting edge: Fyn is essential for tyrosine phosphorylation of Csk-binding protein/phosphoprotein associated with glycolipid-enriched microdomains in lipid rafts in resting T cells. J. Immunol., 169, 2002, s.2813–2817.

50. Yilmaz, M., Christofori, G.: EMT, the cytoskeleton, and cancer cell invasion. Cancer Metastasis Rev., 2009, DOI : 10.1007/s10555-008-9169-0.

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