Disease relevance of PAG1

• For example, lymphocytic lymphoma and mantle-cell lymphoma showed similar profiles but differed clearly from follicle-center lymphoma, whereas PAG tended to be selectively expressed in germinal center-derived subsets of diffuse large B-cell lymphoma [1].
• Their expression in neoplastic lymphoid cells broadly reflects that of normal lymphoid tissue, including the positivity of plasma cells and myeloma/plasmacytoma for LIME, NTAL, PAG, and SIT [1].
• These results suggest that the assembly of stable multiprotein complexes containing Tax, CREB/ATF-1, and CBP/p300 on the 21-bp repeats is the principal mechanism employed by Tax to preclude nucleosome formation at the HTLV-1 enhancer/promoter [2].
• CBP overexpression rescued both acetylated histone levels and cell toxicity [3].
• In Exp. 1, infusion of antisense oligodeoxynucleotides to SRC-1 and CBP mRNA into the VMN decreased lordosis intensity in rats treated with E alone, suggesting that these coactivators modulate ER-mediated female sexual behavior [4].
• Cell death followed decreases in Lyn or Cbp/PAG expression levels in one mantle cell lymphoma line, but not in a Hodgkin-derived one [5].

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

• Consequently, although human PAG sequence shares well-known sites for modifications such as myristoylation, palmitoylation, and tyrosine phosphorylation sites, perhaps the difference suggests the existence of unknown modification sites [10].
• PAG1/MEST is an imprinted gene mapping to human chromosome 7q32 [11].
• The highly related acetyltransferases, p300 and CREB-binding protein (CBP) are coactivators of signal-responsive transcriptional activation [12].
• In addition, recent evidence suggests that p300/CBP also interacts directly with complexes that mediate DNA replication and repair [12].
• This CBP/p300-mediated FLC repression may involve reversible protein acetylation independent of histone modification within FLC chromatin [13].

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

• The final purity of gel-purified PAG was evaluated by SDS-PAGE and mass spectrometry [10].
• The PAG was purified by metal affinity, ion exchange, and gel filtration chromatographies [10].
• Analysis was performed by immunofluorescence and flow cytometry, using the anti-HLA-G MoAbs 87G and G233, by Western blot, using the anti-HLA-G MEM/G1 MoAb and PAG1 antiserum, and by RT-PCR analysis [22].
• The CREB-binding protein (CBP) is one such transcriptional regulator that, when visualised by confocal microscopy, reveals a highly punctate staining pattern comprising several hundred individual foci distributed within the nuclear volume [18].
• In addition, indirect immunofluorescence also indicates an association between N-CoR and CBP in intact MCF-7 cells [16].

References