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Gene Review

PAG1  -  phosphoprotein membrane anchor with...

Homo sapiens

Synonyms: CBP, Csk-binding protein, PAG, Phosphoprotein associated with glycosphingolipid-enriched microdomains 1, Transmembrane adapter protein PAG, ...
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Disease relevance of PAG1


High impact information on PAG1

  • Expression of PAG in COS cells results in recruitment of endogenous Csk, altered Src kinase activity, and impaired phosphorylation of Src-specific substrates [6].
  • Moreover, overexpression of PAG in Jurkat cells downregulates T cell receptor-mediated activation of the transcription factor nuclear factor of activated T cells [6].
  • PAG comprises a short extracellular domain of 16 amino acids and a 397-amino acid cytoplasmic tail containing ten tyrosine residues that are likely phosphorylated by Src family kinases [6].
  • In lymphoid cell lines and in resting peripheral blood alpha/beta T cells, PAG is expressed as a constitutively tyrosine-phosphorylated protein and binds the major negative regulator of Src kinases, the tyrosine kinase Csk [6].
  • 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 [6].

Chemical compound and disease context of PAG1

  • However, the role of CBP has been controversial and the relationship between polyglutamine-induced toxicity and CBP depletion has not been examined on an individual cell basis [3].
  • CAS was found to bind the SRC1 interaction domain (SID) of CBP via a leucine-rich motif in the N-terminus of the protein, that is conserved in other SID-binding proteins [7].
  • Transmembrane adaptor protein PAG, also known as Csk-binding protein (Cbp), which binds and activates the cytoplasmic tyrosine kinase Csk, the major negative regulator of Src-family kinases, was found to be expressed in germinal centers of lymphoid follicles as well as in follicular, but not mantle cell lymphomas [8].
  • Several CBP were shown to have a high genetic barrier since multiple (>/=5) glycan deletions in the HIV envelope are necessary to provoke a moderate level of drug resistance [9].

Biological context of PAG1


Anatomical context of PAG1

  • Centriole overduplication was significantly reduced by siRNA-mediated knock down of CREB-binding protein (CBP), a transcriptional co-activator [14].
  • Phosphoprotein associated with GEMs (PAG), also known as Csk-binding protein (Cbp), is a broadly expressed palmitoylated transmembrane adapter protein found in membrane rafts, also called GEMs (glycosphingolipid-enriched membrane microdomains) [15].
  • After activation of peripheral blood alpha/beta T cells, PAG becomes rapidly dephosphorylated and dissociates from Csk [6].
  • We demonstrate, using both immunoaffinity purification and conventional chromatography, that a subset of the N-CoR-HDAC3 complex copurifies with CBP in HeLa cells [16].
  • Coexpression of Etsl and CBP induced a synergistic activation of the P3 promoter only in the tumorigenic cell line [17].

Associations of PAG1 with chemical compounds

  • Furthermore, we find that CBP has a significantly higher probability of being close to its known in vivo substrate histone H4 lysine 5 compared with the closely related H4 lysine 12 [18].
  • Heme-binding protein 23 kDa (HBP23), a rat isoform of human proliferation-associated gene product (PAG), is a member of the peroxiredoxin family of peroxidases, having two conserved cysteine residues [19].
  • In these mice, the CREB-CBP interaction is enhanced in both the absence and presence of cAMP stimulation [20].
  • In these beta cells, however, glucose-stimulated insulin secretion was diminished, resulting from concomitant CREB-CBP-mediated pgc1a gene activation [20].
  • CBP, but not p300, is phosphorylated at serine 436 in response to insulin action [20].

Physical interactions of PAG1

  • We show the high PAG-binding ability with CSK in vitro as well as the human PAG structure characterized by 11 alpha-helix structures including a 3 kDa transmembrane domain [10].

Other interactions of PAG1

  • The interaction involves the C-terminal sequence (TRL) of PAG and N-terminal PDZ domain(s) of EBP50 [15].
  • PAG is known to bind and activate the essential regulator of Src-family kinases, cytoplasmic protein tyrosine kinase Csk [15].
  • We have identified the abundant cytoplasmic adapter protein EBP50 (ezrin/radixin/moesin (ERM)-binding phosphoprotein of 50 kDa), also known as NHERF (Na(+)/H(+) exchanger regulatory factor), as a specific PAG-binding partner [15].
  • In this paper, we report an immunohistologic study of 6 of these molecules in normal and neoplastic human tissue sections and show that they are restricted to subpopulations of lymphoid cells, being present in either T cells (LAT, LIME, and TRIM), B cells (NTAL), or subsets of both cell types (PAG and SIT) [1].
  • Paxillin, a multidomain adaptor protein, has been shown to act as a Csk-binding protein and to inhibit Src activity during growth factor signalling [21].

Analytical, diagnostic and therapeutic context of PAG1


  1. Transmembrane adaptor molecules: a new category of lymphoid-cell markers. Tedoldi, S., Paterson, J.C., Hansmann, M.L., Natkunam, Y., Rüdiger, T., Angelisova, P., Du, M.Q., Roberton, H., Roncador, G., Sanchez, L., Pozzobon, M., Masir, N., Barry, R., Pileri, S., Mason, D.Y., Marafioti, T., Horejsí, V. Blood (2006) [Pubmed]
  2. Versatile reporter systems show that transactivation by human T-cell leukemia virus type 1 Tax occurs independently of chromatin remodeling factor BRG1. Zhang, L., Liu, M., Merling, R., Giam, C.Z. J. Virol. (2006) [Pubmed]
  3. Depletion of CBP is directly linked with cellular toxicity caused by mutant huntingtin. Jiang, H., Poirier, M.A., Liang, Y., Pei, Z., Weiskittel, C.E., Smith, W.W., DeFranco, D.B., Ross, C.A. Neurobiol. Dis. (2006) [Pubmed]
  4. Nuclear receptor coactivators function in estrogen receptor- and progestin receptor-dependent aspects of sexual behavior in female rats. Molenda-Figueira, H.A., Williams, C.A., Griffin, A.L., Rutledge, E.M., Blaustein, J.D., Tetel, M.J. Hormones and behavior. (2006) [Pubmed]
  5. Oncogenic association of the Cbp/PAG adaptor protein with the Lyn tyrosine kinase in human B-NHL rafts. Tauzin, S., Ding, H., Khatib, K., Ahmad, I., Burdevet, D., van Echten-Deckert, G., Lindquist, J.A., Schraven, B., Din, N.U., Borisch, B., Hoessli, D.C. Blood (2008) [Pubmed]
  6. 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. Brdicka, T., Pavlistová, D., Leo, A., Bruyns, E., Korínek, V., Angelisová, P., Scherer, J., Shevchenko, A., Hilgert, I., Cerný, J., Drbal, K., Kuramitsu, Y., Kornacker, B., Horejsí, V., Schraven, B. J. Exp. Med. (2000) [Pubmed]
  7. Functional interaction of CREB binding protein (CBP) with nuclear transport proteins and modulation by HDAC inhibitors. Ryan, C.M., Harries, J.C., Kindle, K.B., Collins, H.M., Heery, D.M. Cell Cycle (2006) [Pubmed]
  8. Expression pattern of adaptor protein PAG: correlation between secondary lymphatic follicle and histogenetically related malignant lymphomas. Svec, A., Velenská, Z., Horejsí, V. Immunol. Lett. (2005) [Pubmed]
  9. Inhibition of HIV entry by carbohydrate-binding proteins. Balzarini, J. Antiviral Res. (2006) [Pubmed]
  10. Expression and Purification of Human PAG, a Transmembrane Adapter Protein Using an Insect Cell Expression System and its Structure Basis. Takeuchi, S. Protein J. (2006) [Pubmed]
  11. PEG1 expression in maternal uniparental disomy 7. Cuisset, L., Le Stunff, C., Dupont, J.M., Vasseur, C., Cartigny, M., Despert, F., Delpech, M., Bougnere, P., Jeanpierre, M. Ann. Genet. (1997) [Pubmed]
  12. p300/CREB-binding Protein Interacts with ATR and Is Required for the DNA Replication Checkpoint. Stauffer, D., Chang, B., Huang, J., Dunn, A., Thayer, M. J. Biol. Chem. (2007) [Pubmed]
  13. Role of plant CBP/p300-like genes in the regulation of flowering time. Han, S.K., Song, J.D., Noh, Y.S., Noh, B. Plant J. (2007) [Pubmed]
  14. RNA polymerase II transcription is required for human papillomavirus type 16 E7- and hydroxyurea-induced centriole overduplication. Duensing, A., Liu, Y., Spardy, N., Bartoli, K., Tseng, M., Kwon, J.A., Teng, X., Duensing, S. Oncogene (2007) [Pubmed]
  15. Interaction between two adapter proteins, PAG and EBP50: a possible link between membrane rafts and actin cytoskeleton. Brdicková, N., Brdicka, T., Andera, L., Spicka, J., Angelisová, P., Milgram, S.L., Horejsí, V. FEBS Lett. (2001) [Pubmed]
  16. Direct Association between the CREB-Binding Protein (CBP) and Nuclear Receptor Corepressor (N-CoR). Cowger, J.J., Torchia, J. Biochemistry (2006) [Pubmed]
  17. PTHrP P3 promoter activity in breast cancer cell lines: Role of Ets1 and CBP (CREB binding protein). Hamzaoui, H., Rizk-Rabin, M., Gordon, J., Offutt, C., Bertherat, J., Bouizar, Z. Mol. Cell. Endocrinol. (2007) [Pubmed]
  18. The Transcriptional Regulator CBP Has Defined Spatial Associations within Interphase Nuclei. McManus, K.J., Stephens, D.A., Adams, N.M., Islam, S.A., Freemont, P.S., Hendzel, M.J. PLoS Comput. Biol. (2006) [Pubmed]
  19. Crystal structure of a multifunctional 2-Cys peroxiredoxin heme-binding protein 23 kDa/proliferation-associated gene product. Hirotsu, S., Abe, Y., Okada, K., Nagahara, N., Hori, H., Nishino, T., Hakoshima, T. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  20. Increased Pancreatic {beta}-Cell Proliferation Mediated by CREB Binding Protein Gene Activation. Hussain, M.A., Porras, D.L., Rowe, M.H., West, J.R., Song, W.J., Schreiber, W.E., Wondisford, F.E. Mol. Cell. Biol. (2006) [Pubmed]
  21. Paxillin family members function as Csk-binding proteins that regulate Lyn activity in human and murine platelets. Rathore, V.B., Okada, M., Newman, P.J., Newman, D.K. Biochem. J. (2007) [Pubmed]
  22. Melanomas and melanoma cell lines do not express HLA-G, and the expression cannot be induced by gammaIFN treatment. Frumento, G., Franchello, S., Palmisano, G.L., Nicotra, M.R., Giacomini, P., Loke, Y.W., Geraghty, D.E., Maio, M., Manzo, C., Natali, P.G., Ferrara, G.B. Tissue Antigens (2000) [Pubmed]
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