Affinage

PAG1

Phosphoprotein associated with glycosphingolipid-enriched microdomains 1 · UniProt Q9NWQ8

Length
432 aa
Mass
47.0 kDa
Annotated
2026-06-10
100 papers in source corpus 22 papers cited in narrative 21 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PAG1 (PAG/Cbp) is a palmitoylated transmembrane adaptor that resides constitutively in glycosphingolipid-enriched lipid rafts and functions as a central negative regulator of Src-family kinase signaling by recruiting the inhibitory kinase Csk to the membrane (PMID:10790433, PMID:12612075). In resting T cells PAG1 is tyrosine-phosphorylated by raft-associated FynT, which docks through a dual SH2/SH3 mechanism—its SH3 domain engaging a PAG1 proline-rich region to initiate phosphorylation and its SH2 domain binding PAG1 phosphotyrosines to render FynT resistant to Csk—and this phosphorylation creates the binding site that anchors Csk to inactivate raft SFKs including Lck (PMID:17210649, PMID:18056706). TCR engagement triggers CD45-mediated dephosphorylation of PAG1 and Csk release, relieving the brake and permitting T cell activation (PMID:12612075). Localization within rafts, which depends on the palmitoylation (CxxC) motif, is strictly required for the inhibitory function: a non-palmitoylated mutant still binds Fyn and Csk but fails to suppress TCR signaling and instead depletes Csk from rafts (PMID:18085663). Genetic loss of PAG1 selectively augments effector T cell activation and autoimmunity, with Csk redistributing to alternative scaffolds PTPN22 and Dok in epistatic cooperation (PMID:27926878, PMID:26512138). PAG1 nucleates additional raft signalosomes, linking rafts to the actin cytoskeleton via an EBP50/Ezrin module and to cAMP control via a PKA-I/Ezrin/EBP50/PAG/Csk complex (PMID:11684085, PMID:20420835), and it transmits PD-1 inhibitory signaling in human T cells (PMID:34083754). Beyond lymphocytes, PAG1 acts as a tumor suppressor by recruiting c-Src and Csk to rafts in lung cancer (PMID:21156787), is epigenetically silenced through HDAC-dependent histone modifications in Src-transformed cells (PMID:21388951), and is transcriptionally induced under hypoxia through a HIF-1-bound distal enhancer that loops to the promoter (PMID:26007655). Its regulatory output is context-dependent, acting as a positive regulator of FcεRI but a negative regulator of Kit signaling in mast cells (PMID:25246632).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 2000 High

    Established PAG1 as the membrane anchor that recruits Csk to lipid rafts, answering how the cytosolic inhibitory kinase reaches raft-resident Src kinases.

    Evidence Co-IP, COS-cell overexpression, and Jurkat NFAT reporter assays in T cells

    PMID:10790433

    Open questions at the time
    • Did not resolve which kinase phosphorylates PAG1 or which phosphatase reverses it
    • Specific Src substrates affected not enumerated
  2. 2003 High

    Demonstrated that PAG1 inhibition of TCR signaling requires its phosphorylation and Csk association, and identified CD45 as the phosphatase driving post-TCR PAG1 dephosphorylation.

    Evidence Phosphorylation-defective PAG mutants and constitutively active Src rescue in primary mouse T cells, plus CD45-, PEP-, SHP-1-deficient mice

    PMID:12612075

    Open questions at the time
    • Mechanism of CD45 access/specificity to PAG1 not defined
    • Kinase responsible for PAG1 phosphorylation not yet identified here
  3. 2001 Medium

    Connected PAG1 rafts to the actin cytoskeleton by mapping a C-terminal PDZ-binding motif that engages EBP50/NHERF.

    Evidence Yeast two-hybrid screen with PAG C-terminal truncation domain mapping

    PMID:11684085

    Open questions at the time
    • Not confirmed by reciprocal Co-IP in mammalian cells in this study
    • Functional consequence of raft-actin linkage not tested
  4. 2005 Medium

    Placed PAG1 phosphorylation downstream of raft Fyn activity by showing PTPalpha loss hyperactivates Fyn and hyperphosphorylates PAG1, while excluding PTPalpha as the TCR-responsive PAG1 phosphatase.

    Evidence PTPalpha-knockout thymocytes with kinase assays and raft fractionation

    PMID:16339530

    Open questions at the time
    • Identity of the TCR-stimulation phosphatase still open in this study
    • Single lab
  5. 2007 High

    Defined the dual SH2/SH3 docking mechanism by which FynT binds and phosphorylates PAG1 and showed PAG1-FynT interactions can drive T-cell anergy independently of Csk binding.

    Evidence SPR binding kinetics, SH2/SH3 mutants, FynT-KO mice, Co-IP, and calcium/anergy assays

    PMID:17210649 PMID:18056706

    Open questions at the time
    • Trigger for PAG1-FynT dissociation after TCR engagement not fully resolved
    • Structural basis of the dual-domain docking not solved
  6. 2007 Medium

    Extended PAG1 signalosome function to malignancy, showing a constitutive raft PAG-Lyn-STAT3 complex sustains B-NHL survival.

    Evidence Biochemical fractionation, phosphosite antibodies, Lyn inhibitor treatment, viability assays

    PMID:18070987

    Open questions at the time
    • Single lab
    • Direct contribution of PAG1 versus Lyn to survival not genetically separated
  7. 2008 Medium

    Proved that raft compartmentalization, conferred by palmitoylation, is essential for PAG1's inhibitory function, separating membrane localization from Csk/Fyn binding.

    Evidence Palmitoylation-deficient (CxxC) mutant with raft fractionation, Co-IP, TCR/migration assays, RNAi

    PMID:18085663

    Open questions at the time
    • Single lab
    • Quantitative raft-versus-non-raft Csk pool dynamics not measured in vivo
  8. 2008 Medium

    Revealed a Csk-independent PAG1 mechanism: an N-terminal segment raises surface GM1 via Neu-3 to displace PDGFR from caveolae and modulate mitogenic SFK signaling.

    Evidence PAG truncation mutants, GM1 quantification, caveolae fractionation, Csk-deficient reconstitution, Neu-3 siRNA

    PMID:18695048

    Open questions at the time
    • Molecular link between PAG1 N-terminus and Neu-3 activity unresolved
    • Single lab
  9. 2010 Medium

    Defined PAG1 as a tumor suppressor in c-Src-driven lung cancer by recruiting c-Src and Csk to rafts and suppressing anchorage-independent growth and metastasis.

    Evidence PAG1 ectopic re-expression in NSCLC lines, c-Src kinase assay, raft fractionation, xenograft and invasion assays

    PMID:21156787

    Open questions at the time
    • Cause of PAG1 downregulation in NSCLC not yet established here
    • Single lab
  10. 2010 Medium

    Identified a higher-order raft scaffold (PKA-I/Ezrin/EBP50/PAG/Csk) coupling cAMP signaling to the Csk inhibitory pathway in effector T cells.

    Evidence Co-IP and lipid raft fractionation defining complex composition

    PMID:20420835

    Open questions at the time
    • Direct versus indirect connectivity among complex members not dissected
    • Single lab
  11. 2011 Medium

    Explained PAG1 loss in transformed cells as epigenetic silencing through MAPK/PI3K-driven HDAC-dependent histone modifications rather than DNA methylation.

    Evidence MEK/PI3K and HDAC inhibitors, HDAC1/2 siRNA, ChIP for histone marks, promoter reporter assays

    PMID:21388951

    Open questions at the time
    • Direct HDAC1/2 recruitment mechanism to the promoter not shown
    • Single lab
  12. 2013 Medium

    Extended PAG1/Lyn raft signaling to neural development, showing ganglioside crosslinking activates Lyn to phosphorylate Cbp/PAG at Y314 in cerebellar growth cones.

    Evidence Anti-ganglioside Co-IP, density gradient fractionation, Lyn/Cbp ectopic expression and crosslinking assays

    PMID:23035659

    Open questions at the time
    • Functional consequence for axon/growth-cone behavior not established
    • Single lab
  13. 2013 Medium

    Uncovered a CTLA-4-dependent fail-safe downstream of PAG loss, where Fyn-driven CTLA-4 hyperphosphorylation recruits Shp-1 and enforces T cell unresponsiveness despite elevated Src activity.

    Evidence PAG and CTLA-4 siRNA co-knockdown in primary human T cells, kinase and phosphorylation assays, proliferation readouts

    PMID:23601194

    Open questions at the time
    • Whether this fail-safe operates in vivo not tested here
    • Single lab
  14. 2014 High

    Showed PAG1 has receptor-context-dependent polarity in mast cells—positive for FcεRI, negative for Kit—rather than a uniform inhibitory role.

    Evidence PAG-knockout/knockdown BMMCs, degranulation, calcium flux, phospho-flow, cytokine ELISA, in vivo anaphylaxis

    PMID:25246632

    Open questions at the time
    • Molecular basis distinguishing FcεRI versus Kit outcomes not resolved
    • Single lab
  15. 2015 High

    Identified a HIF-1-bound distal HRE that loops constitutively to the PAG1 promoter to drive hypoxic induction, defining transcriptional control of PAG1.

    Evidence ChIP, 3C chromosome conformation capture, TALEN editing, luciferase reporters, RT-qPCR across cell lines and tissues

    PMID:26007655

    Open questions at the time
    • Physiological role of hypoxic PAG1 induction not connected to signaling output
    • Loop-forming factors not identified
  16. 2015 Medium

    Quantitative endogenous-tag proteomics challenged the constitutive-phosphorylation model, showing low resting PAG1 phosphorylation that rises after stimulation and revealed dynamic recruitment of PTPN22 and SHIP-1.

    Evidence AP-MS with knock-in tagged PAG and quantitative phosphoproteomics in primary CD4+ T cells

    PMID:26512138

    Open questions at the time
    • Reconciliation with earlier constitutive-phosphorylation biochemistry incomplete
    • Functional role of SHIP-1 association not tested
  17. 2016 High

    Genetic epistasis defined PAG1 as a selective brake on effector T cells whose loss redistributes Csk to PTPN22 and Dok adaptors in cooperative inhibition.

    Evidence PAG, PTPN22, and Dok single and double knockout mice with autoimmunity and Co-IP readouts

    PMID:27926878

    Open questions at the time
    • Why effector but not naive T cells depend on PAG not mechanistically resolved
    • Stoichiometry of Csk redistribution not quantified
  18. 2018 Medium

    Linked PAG1 to therapy resistance, mapping two cytoplasmic binding sites that engage integrin β1 to activate STAT3 and confer radioresistance in laryngeal cancer.

    Evidence Proteomic Co-IP, peptide-array mapping, MβCD raft disruption, integrin β1 siRNA, STAT3 inhibitor, clonogenic assays

    PMID:29913153 PMID:30519312

    Open questions at the time
    • Mechanism coupling integrin β1 binding to STAT3 activation not detailed
    • Single lab
  19. 2019 Medium

    Demonstrated an in vivo role for PAG1 in restraining type 2 airway inflammation via both T-cell-intrinsic and -extrinsic control of TH2 differentiation.

    Evidence Pag1-knockout mice with HDM challenge, T cell depletion, OVA-specific adoptive transfer, flow cytometry

    PMID:31321783

    Open questions at the time
    • Molecular pathway linking PAG1 loss to epithelial HMGB1 release unresolved
    • Single lab
  20. 2021 Medium

    Placed PAG1 within PD-1 inhibitory signaling, showing it is phosphorylated upon PD-1 ligation and required for PD-1-mediated T cell suppression, with deletion sensitizing tumors to checkpoint blockade.

    Evidence PAG knockdown/overexpression in primary T cells, PD-1 ligation, phospho-assays, MC38/B16 in vivo tumor models

    PMID:34083754

    Open questions at the time
    • Direct biochemical link between PD-1 and PAG1 phosphorylation not defined
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How PAG1 integrates competing positive and negative inputs across receptor and tissue contexts—and the structural basis and recruitment logic that switch its output—remains unresolved.
  • No structural model of the PAG1 cytoplasmic scaffold bound to its partners
  • Mechanism determining positive versus negative regulatory polarity not defined
  • In vivo phosphatase-kinase dynamics governing PAG1 phosphorylation timing not fully reconciled

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 2 GO:0005829 cytosol 1
Pathway
R-HSA-168256 Immune System 5 R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 3 R-HSA-74160 Gene expression (Transcription) 2
Partners
CSKEBP50/NHERF1FYNITGB1LCKLYNPDCD1/PD-1PTPN22
Complex memberships
PAG-Lyn-STAT3 signalosome (B-NHL rafts)PAG/Csk raft complexPKA-I/Ezrin/EBP50/PAG/Csk complex

Evidence

Reading pass · 21 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 PAG (PAG1) is a transmembrane adaptor protein constitutively tyrosine-phosphorylated in resting T cells and lymphoid lines; it directly binds the tyrosine kinase Csk via its cytoplasmic tail, recruiting Csk to glycosphingolipid-enriched membrane microdomains (lipid rafts). Expression in COS cells recruits endogenous Csk, alters Src kinase activity, and impairs phosphorylation of Src-specific substrates. Overexpression in Jurkat cells downregulates TCR-mediated NFAT activation. Co-immunoprecipitation, COS-cell overexpression functional assay, Jurkat NFAT reporter assay, primary T cell biochemistry The Journal of experimental medicine High 10790433
2003 PAG-mediated inhibition of TCR signaling requires tyrosine phosphorylation of PAG and its association with Csk; the inhibitory effect is rescued by a constitutively activated Src-related kinase, confirming that PAG-associated Csk inactivates Src kinases. CD45 transmembrane phosphatase is implicated in PAG dephosphorylation following TCR stimulation, whereas PEP and SHP-1 are not required for this dephosphorylation. Wild-type and phosphorylation-defective PAG overexpression in primary mouse T cells, cell fractionation, analysis of CD45-, PEP-, and SHP-1-deficient mice Molecular and cellular biology High 12612075
2001 PAG interacts with EBP50 (NHERF) via a C-terminal PDZ-binding motif (TRL sequence of PAG) and the N-terminal PDZ domain(s) of EBP50; since EBP50 binds ERM-family proteins that connect to actin cytoskeleton, this interaction links membrane rafts to the actin cytoskeleton. Yeast two-hybrid screen, domain-mapping with PAG C-terminal truncations FEBS letters Medium 11684085
2007 PAG is constitutively associated with FynT in unstimulated T cells via tyrosines other than Y314; FynT is required for PAG tyrosine phosphorylation and consequent Csk binding. Dissociation of the PAG-FynT complex precedes PAG dephosphorylation after TCR engagement. In anergic T cells, PAG-FynT association is increased. A PAG variant that binds FynT but not Csk enhances TCR-triggered calcium flux and promotes T-cell anergy in a FynT-dependent manner. Co-immunoprecipitation, PAG mutant overexpression, FynT-knockout mice, calcium flux assays, T-cell anergy assays Molecular and cellular biology High 17210649
2007 In B-NHL rafts, PAG/Cbp is phosphorylated at Y317 and binds Lyn SH2 via pY299; together with auto-phosphorylated Lyn and phospho-STAT3 (linked via SH2 to Lyn C-terminal regulatory tyrosine), they form a constitutive raft-associated signalosome. Lyn inhibitors prevent Lyn and PAG phosphorylation, dissociate the signalosome, and induce cell death, implicating the PAG-Lyn complex in B-NHL survival. Biochemical fractionation, Co-IP, site-specific phospho-antibodies, Lyn kinase inhibitor treatment, cell viability assays Blood Medium 18070987
2007 FynT interacts with PAG via a dual-domain docking mechanism: FynT SH2 domain binds PAG phosphotyrosines and FynT SH3 domain binds the first proline-rich region of PAG. SH3 engagement is required for efficient PAG phosphorylation initiation, while SH2 engagement renders FynT insensitive to Csk negative regulation. This dual-domain binding modulates FynT kinase activity, PAG phosphorylation, and recruitment of FynT and Csk in Jurkat and primary T cells. SPR binding assays, kinase activity assays, SH3/SH2 domain mutant overexpression in Jurkat cells and primary T cells, Co-IP The Journal of biological chemistry High 18056706
2005 Protein tyrosine phosphatase alpha (PTPalpha) localizes in part to lipid rafts of thymocytes and regulates raft-associated Fyn activity; in PTPalpha-null thymocytes, Fyn is hyperactivated (increased phosphorylation of Y528 and Y417), which causes hyperphosphorylation of PAG/Cbp and enhanced association of PAG with Csk. PTPalpha is not the phosphatase responsible for PAG dephosphorylation after TCR stimulation. PTPalpha-knockout mouse thymocytes, kinase activity assays, phospho-specific antibodies, lipid raft fractionation Journal of immunology Medium 16339530
2008 PAG regulates PDGF receptor (PDGFR) partitioning in caveolae and SFK mitogenic signaling through a Csk-independent mechanism. The N-terminal 97 aa of PAG (including extracellular/transmembrane domains, palmitoylation sites, and short cytoplasmic sequence) increase ganglioside GM1 levels at the cell surface via the ganglioside-specific sialidase Neu-3, thereby displacing PDGFR from caveolae. PAG truncation mutants, ganglioside GM1 quantification, PDGFR caveolae fractionation, Csk-deficient cell reconstitution, Neu-3 siRNA knockdown The Journal of cell biology Medium 18695048
2010 PAG/Cbp (PAG1) suppresses anchorage-independent growth of c-Src-upregulated NSCLC cells by recruiting c-Src and Csk to lipid rafts, thereby reducing c-Src kinase activity. PAG1 re-expression attenuates tumor formation in nude mice, invasion in vitro, and metastasis in vivo; its expression is markedly downregulated in NSCLC cells. PAG1 ectopic expression in NSCLC cell lines, c-Src kinase assay, lipid raft fractionation, Co-IP, xenograft tumor model, in vitro invasion assay Molecular cancer research : MCR Medium 21156787
2011 PAG1/Cbp expression is downregulated in Src-transformed cells by epigenetic histone modifications (decreased H4 acetylation and increased H3K27 trimethylation at the cbp promoter) via the MAPK/PI3K pathway; HDAC inhibitors and HDAC1/2 siRNA knockdown restore PAG1 expression. DNA methylation of the cbp promoter CpG islands is not involved. MEK/PI3K inhibitors, HDAC inhibitor treatment, HDAC1/2 siRNA, ChIP for histone modifications, mRNA stability assay, promoter reporter assay The Journal of biological chemistry Medium 21388951
2013 Cbp/PAG is phosphorylated by Lyn at Y314 in developing cerebellar growth cones; ganglioside GD3 co-immunoprecipitates with Cbp/PAG and antibody crosslinking of GD3 or GD1b activates Lyn and induces Cbp/PAG tyrosine phosphorylation. Active Lyn and Y314-phosphorylated Cbp/PAG are concentrated in growth cone DRM raft fractions of developing cerebellum. Co-immunoprecipitation with anti-ganglioside antibody, sucrose density gradient fractionation, Lyn/Cbp overexpression in CHO cells, antibody-induced signaling assays Journal of neurochemistry Medium 23035659
2015 A distal hypoxia response element (HRE) 82 kb upstream of PAG1 physically interacts with the PAG1 promoter in a HIF-independent constitutive chromatin loop (shown by 3C); HIF-1 directly binds this HRE to drive hypoxia-induced PAG1 expression. Ablation of the consensus HRE motif by TALEN gene editing abolishes hypoxic PAG1 induction without affecting general oxygen signaling. ChIP, chromosome conformation capture (3C), TALEN gene editing, luciferase reporter assays, RT-qPCR in multiple cell lines and mouse tissues Nucleic acids research High 26007655
2016 Genetic deletion of PAG enhances effector (but not naive) T cell activation and augments T cell-dependent autoimmunity and resistance to anergy in vivo. In PAG-deficient mice, Csk redistributes to alternative partners PTPN22 and Dok adaptors; combined PAG + PTPN22 or PAG + Dok deficiency further amplifies effector T cell responses, establishing epistatic cooperation. PAG-knockout mice, PTPN22- and Dok-deficient mice, double knockout combinations, T cell activation and autoimmunity assays, Co-IP for Csk partners Cell reports High 27926878
2014 PAG-deficient bone marrow-derived mast cells exhibit impaired antigen-induced degranulation, calcium uptake, tyrosine phosphorylation of FcεRI subunits, Syk, and PLCγ, cytokine/chemokine production, and chemotaxis, indicating PAG acts as a positive regulator of FcεRI signaling. Conversely, PAG-deficient BMMCs show enhanced Kit receptor-induced degranulation, indicating PAG acts as a negative regulator of Kit signaling. LYN and FYN kinase activities are increased in non-activated PAG-KO cells, suggesting a negative regulatory loop. PAG-knockout and PAG-knockdown bone marrow-derived mast cells, degranulation assays, calcium flux, phospho-flow cytometry, cytokine ELISA, in vivo passive systemic anaphylaxis Molecular and cellular biology High 25246632
2021 PAG is phosphorylated following PD-1 ligation in human T cells and mediates PD-1 inhibitory signaling; PAG knockdown prevents PD-1-mediated inhibition of cytokine secretion, cell adhesion, CD69 expression, and ERK phosphorylation, and enhances SRC527 phosphorylation. PAG overexpression rescues these effects. In vivo, PAG deficiency limits T cell presence in tumors and sensitizes tumors to PD-1 blockade. PAG knockdown/overexpression in primary T cells, PD-1 ligation experiments, phospho-protein assays, in vivo murine tumor models (MC38 and B16) with PAG deletion Communications biology Medium 34083754
2010 PAG participates in a supramolecular signaling complex consisting of PKA type I, Ezrin, EBP50, PAG, and Csk in effector T cell lipid rafts. This Ezrin-EBP50-PAG scaffold spatiotemporally controls cAMP immunomodulation through the PKA-Csk inhibitory pathway. Co-immunoprecipitation, lipid raft fractionation, complex component identification FEBS letters Medium 20420835
2015 Quantitative proteomics of tagged-PAG complexes in primary mouse CD4+ T cells reveals PAG has low tyrosine phosphorylation in resting cells that increases after stimulation (peaking at 2 min), contrary to prior biochemical studies showing constitutive phosphorylation in resting cells. PTPN22 and SHIP-1 dynamically associate with PAG following T cell activation, suggesting they cooperate with Csk to terminate T cell activation. Affinity-purification mass spectrometry (AP-MS) with knock-in tagged PAG, quantitative phosphoproteomics, primary thymocytes and CD4+ T cells Journal of immunology Medium 26512138
2013 PAG knockdown in primary human T cells enhances Src kinase activity and TCR proximal signaling, but rather than causing hyperproliferation, leads to unresponsiveness mediated by Fyn-dependent hyperphosphorylation of CTLA-4, which recruits Shp-1 phosphatase to lipid rafts. Co-suppression of CTLA-4 restores proliferation, identifying a CTLA-4-dependent fail-safe downstream of PAG loss. PAG siRNA knockdown in primary human T cells, CTLA-4 co-knockdown, Src kinase activity assay, CTLA-4 phosphorylation assay, lipid raft fractionation, proliferation assays Cell communication and signaling : CCS Medium 23601194
2018 PAG1 interacts with integrin β1 in lipid rafts of radioresistant laryngeal cancer cells; this interaction can be disrupted by methyl-β-cyclodextrin (lipid raft disruptor). PAG1-integrin β1 complex activates STAT3, and STAT3 activation is required for PAG1-mediated radioresistance; STAT3 inhibition sensitizes cells to radiation. Two binding sites in the PAG1 cytoplasmic domain (Pro216-Arg232 and Asn356-Gly377) mediate interaction with integrin β1. Proteomic Co-IP screen, immunofluorescence co-localization, MβCD disruption, peptide array mapping, integrin β1 siRNA knockdown, STAT3 inhibitor treatment, clonogenic survival assay Journal of Cancer / Experimental cell research Medium 29913153 30519312
2019 PAG1 deficiency in mice leads to increased airway epithelial HMGB1 translocation/release, expanded ILC2s and monocyte-derived dendritic cells, and enhanced TH2-cell differentiation following allergen challenge, resulting in more severe type 2 airway inflammation. T cell adoptive transfer experiments show that the heightened TH2 differentiation is both T cell-intrinsic and T cell-extrinsic. Pag1-knockout mice, HDM allergen challenge, CD4+ T cell depletion, adoptive transfer of OVA-specific T cells, flow cytometry, cytokine measurements Allergy Medium 31321783
2008 A palmitoylation-deficient PAG mutant (lacking the CxxC palmitoylation motif) is expressed at the plasma membrane but outside GEM rafts; it still binds Fyn, EBP50, becomes tyrosine-phosphorylated, and recruits Csk, but unlike wild-type PAG does not block proximal TCR signaling. Instead, it depletes Csk from GEM fractions, enhancing CXCL12-induced T cell migration and Src kinase activity in rafts. This demonstrates that raft compartmentalization of PAG is essential for its inhibitory function on TCR signaling. PAG palmitoylation mutant overexpression, lipid raft fractionation, Co-IP, TCR signaling assays, PAG RNAi, migration assays European journal of immunology Medium 18085663

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 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. The Journal of experimental medicine 383 10790433
1997 The PAG gene product, a stress-induced protein with antioxidant properties, is an Abl SH3-binding protein and a physiological inhibitor of c-Abl tyrosine kinase activity. Genes & development 234 9334312
2003 Phosphorylation-dependent regulation of T-cell activation by PAG/Cbp, a lipid raft-associated transmembrane adaptor. Molecular and cellular biology 160 12612075
2011 The mu-opioid receptor and the NMDA receptor associate in PAG neurons: implications in pain control. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 142 21814188
2018 Altered Excitability and Local Connectivity of mPFC-PAG Neurons in a Mouse Model of Neuropathic Pain. The Journal of neuroscience : the official journal of the Society for Neuroscience 128 29695413
2014 PAG1, a cotton brassinosteroid catabolism gene, modulates fiber elongation. The New phytologist 126 24786710
2012 Motor cortex stimulation inhibits thalamic sensory neurons and enhances activity of PAG neurons: possible pathways for antinociception. Pain 118 23017297
2006 TRPV1 receptor mediates glutamatergic synaptic input to dorsolateral periaqueductal gray (dl-PAG) neurons. Journal of neurophysiology 113 17065246
2003 Predatory hunting and exposure to a live predator induce opposite patterns of Fos immunoreactivity in the PAG. Behavioural brain research 105 12493627
2003 Capsaicin infused into the PAG affects rat tail flick responses to noxious heat and alters neuronal firing in the RVM. Journal of neurophysiology 99 12815018
2001 Interaction between two adapter proteins, PAG and EBP50: a possible link between membrane rafts and actin cytoskeleton. FEBS letters 95 11684085
2001 Regulation of macrophage migration inhibitory factor and thiol-specific antioxidant protein PAG by direct interaction. The Journal of biological chemistry 89 11297517
1999 Behavioral sensitization to cocaine after a brief social defeat stress: c-fos expression in the PAG. Psychopharmacology 79 10027503
2000 Caprine pregnancy-associated glycoproteins (PAG): their cloning, expression, and evolutionary relationship to other PAG. Molecular reproduction and development 75 11066059
2007 PAG-associated FynT regulates calcium signaling and promotes anergy in T lymphocytes. Molecular and cellular biology 72 17210649
2009 Panic disorder: is the PAG involved? Neural plasticity 69 19283082
2006 PAG mu opioid receptor activation underlies sex differences in morphine antinociception. Behavioural brain research 61 17118467
1996 Effects of GABA and glycine receptor antagonists on the activity and PAG-induced inhibition of rat dorsal horn neurons. Brain research 55 8930324
2006 Identification of novel pregnancy-associated glycoproteins (PAG) expressed by the peri-implantation conceptus of domestic ruminants. Animal reproduction science 54 17204380
1989 Effects of serotonin receptor antagonists on PAG stimulation induced aversion: different contributions of 5HT1, 5HT2 and 5HT3 receptors. Psychopharmacology 52 2498946
2011 Metamizol, a non-opioid analgesic, acts via endocannabinoids in the PAG-RVM axis during inflammation in rats. European journal of pain (London, England) 48 22337336
2007 Oncogenic association of the Cbp/PAG adaptor protein with the Lyn tyrosine kinase in human B-NHL rafts. Blood 47 18070987
2007 Role of IL-1 beta and 5-HT2 receptors in midbrain periaqueductal gray (PAG) in potentiating defensive rage behavior in cat. Brain, behavior, and immunity 46 17890051
1999 Autogenous regulation of the Bacillus anthracis pag operon. Journal of bacteriology 46 10419943
1994 Putative role of medullary off- and on-cells in the antinociception produced by dipyrone (metamizol) administered systemically or microinjected into PAG. Pain 45 8090517
1995 Anti-nociception induced by systemic or PAG-microinjected lysine-acetylsalicylate in rats. Effects on tail-flick related activity of medullary off- and on-cells. The European journal of neuroscience 41 8528459
2002 Comparison of morphine and kainic acid microinjections into identical PAG sites on the activity of RVM neurons. Journal of neurophysiology 40 12364500
2013 Specific expression patterns and cell distribution of ancient and modern PAG in bovine placenta during pregnancy. Reproduction (Cambridge, England) 39 23858478
2005 Protein tyrosine phosphatase alpha regulates Fyn activity and Cbp/PAG phosphorylation in thymocyte lipid rafts. Journal of immunology (Baltimore, Md. : 1950) 39 16339530
2021 Sex differences in the expression of the endocannabinoid system within V1M cortex and PAG of Sprague Dawley rats. Biology of sex differences 38 34749819
2016 The Csk-Associated Adaptor PAG Inhibits Effector T Cell Activation in Cooperation with Phosphatase PTPN22 and Dok Adaptors. Cell reports 37 27926878
2013 PAG--a multipurpose transmembrane adaptor protein. Oncogene 37 24213579
1994 Organization and chromosomal assignment of two human PAG gene loci: PAGA encoding a functional gene and PAGB a processed pseudogene. Genomics 37 8188254
2003 Trigeminal antinociception induced by bicuculline in the periaqueductal gray (PAG) is not affected by PAG P/Q-type calcium channel blockade in rat. Neuroscience letters 36 12499053
2002 PAG-3, a Zn-finger transcription factor, determines neuroblast fate in C. elegans. Development (Cambridge, England) 36 11923211
2007 5-HT2 receptor activation in the midbrain periaqueductal grey (PAG) reduces anxiety-like behaviour in mice. Behavioural brain research 34 17935799
1999 Inhibition of interleukin-2 production and downregulation of IL-2 and transferrin receptors on rat splenic lymphocytes following PAG morphine administration: a role in natural killer and T cell suppression. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 34 10433363
1998 The pag gene product, a physiological inhibitor of c-abl tyrosine kinase, is overexpressed in cells entering S phase and by contact with agents inducing oxidative stress. FEBS letters 34 9506838
2014 β-Arrestin-2 knockout prevents development of cellular μ-opioid receptor tolerance but does not affect opioid-withdrawal-related adaptations in single PAG neurons. British journal of pharmacology 33 24597632
2009 Nociceptin/Orphanin FQ in PAG modulates the release of amino acids, serotonin and norepinephrine in the rostral ventromedial medulla and spinal cord in rats. Pain 32 20036056
2008 Antiepileptic drugs on calcium currents recorded from cortical and PAG neurons: therapeutic implications for migraine. Cephalalgia : an international journal of headache 32 18771493
2007 Regulation of FynT function by dual domain docking on PAG/Cbp. The Journal of biological chemistry 31 18056706
2006 Biodiversity of multiple Pregnancy-Associated Glycoprotein (PAG) family: gene cloning and chorionic protein purification in domestic and wild eutherians (Placentalia)--a review. Reproduction, nutrition, development 31 17107639
1997 The C. elegans gene pag-3 is homologous to the zinc finger proto-oncogene gfi-1. Development (Cambridge, England) 31 9169852
1980 Biological and clinical significance of pregnancy-associated alpha2-glycorprotein (alpha/-PAG)-a review. Investigative & cell pathology 31 7429885
2009 Inhibition of endogenous hydrogen sulfide synthesis by PAG protects against ethanol-induced gastric damage in the rat. European journal of pharmacology 30 20035745
2010 The transmembrane adaptor Cbp/PAG1 controls the malignant potential of human non-small cell lung cancers that have c-src upregulation. Molecular cancer research : MCR 29 21156787
2015 Destruction of a distal hypoxia response element abolishes trans-activation of the PAG1 gene mediated by HIF-independent chromatin looping. Nucleic acids research 28 26007655
2011 Down-regulation of the tumor suppressor C-terminal Src kinase (Csk)-binding protein (Cbp)/PAG1 is mediated by epigenetic histone modifications via the mitogen-activated protein kinase (MAPK)/phosphatidylinositol 3-kinase (PI3K) pathway. The Journal of biological chemistry 28 21388951
2008 The Csk-binding protein PAG regulates PDGF-induced Src mitogenic signaling via GM1. The Journal of cell biology 28 18695048
2006 Effects of intra-PAG infusion of ovine CRF on defensive behaviors in Swiss-Webster mice. Behavioural brain research 28 17095103
1999 Characterization of antigens from the human exocrine pancreatic tissue (Pag) relevant as target antigens for autoantibodies in Crohn's disease. European journal of clinical investigation 28 10092987
2002 Presenilin-1 protects against neuronal apoptosis caused by its interacting protein PAG. Neurobiology of disease 27 11895366
2005 Potentiating role of interleukin 2 (IL-2) receptors in the midbrain periaqueductal gray (PAG) upon defensive rage behavior in the cat: role of neurokinin NK(1) receptors. Behavioural brain research 26 16242788
1978 Relationship of pregnancy-associated alpha2-glycoprotein (alpha2-PAG) to peripheral blood leucocytes. Scandinavian journal of immunology 26 81516
1983 Detection of pregnancy associated alpha 2-glycoprotein (alpha 2-PAG), an immunosuppressive agent, in IgA producing plasma cells and in body secretions. Clinical and experimental immunology 25 6342887
2014 Transmembrane adaptor protein PAG/CBP is involved in both positive and negative regulation of mast cell signaling. Molecular and cellular biology 24 25246632
2013 Involvement of gangliosides in the process of Cbp/PAG phosphorylation by Lyn in developing cerebellar growth cones. Journal of neurochemistry 24 23035659
2012 Quantitative phosphoproteomics reveals SLP-76 dependent regulation of PAG and Src family kinases in T cells. PloS one 23 23071622
2004 N-glycodiversity of the Pregnancy-Associated Glycoprotein family (PAG) produced in vitro by trophoblast and trophectoderm explants during implantation, placentation and advanced pregnancy in the pig. Reproductive biology 23 15094796
2015 PAGER: constructing PAGs and new PAG-PAG relationships for network biology. Bioinformatics (Oxford, England) 22 26072489
2008 A displaced PAG enhances proximal signaling and SDF-1-induced T cell migration. European journal of immunology 22 18085663
2016 Transmembrane adaptor protein PAG1 is a novel tumor suppressor in neuroblastoma. Oncotarget 21 26993602
2015 Long-Range Modulation of PAG1 Expression by 8q21 Allergy Risk Variants. American journal of human genetics 20 26211970
2010 Spatiotemporal control of cyclic AMP immunomodulation through the PKA-Csk inhibitory pathway is achieved by anchoring to an Ezrin-EBP50-PAG scaffold in effector T cells. FEBS letters 20 20420835
2008 Novel form of phosphate activated glutaminase in cultured astrocytes and human neuroblastoma cells, PAG in brain pathology and localization in the mitochondria. Neurochemical research 20 18274897
2008 Interactions between the Fyn SH3-domain and adaptor protein Cbp/PAG derived ligands, effects on kinase activity and affinity. The FEBS journal 20 18721137
2007 Molecular interaction in the mouse PAG between NMDA and opioid receptors in morphine-induced acute thermal nociception. Journal of neurochemistry 20 17996026
2017 Upregulation of PAG1/Cbp contributes to adipose-derived mesenchymal stem cells promoted tumor progression and chemoresistance in breast cancer. Biochemical and biophysical research communications 19 29079189
2003 Chorionic expression of heterogeneous products of the PAG (Pregnancy-Associated Glycoprotein) gene family secreted in vitro throughout embryonic and foetal development in the pig. Reproduction, nutrition, development 19 15141435
1999 Highly delta selective antagonists in the RVM attenuate the antinociceptive effect of PAG DAMGO. Neuroreport 19 10574547
2023 ABHD6 and MAGL control 2-AG levels in the PAG and allodynia in a CSD-induced periorbital model of headache. Frontiers in pain research (Lausanne, Switzerland) 18 37287623
1986 Comparative studies on tree pollen allergens. XIII. Partial characterization of the alder (Alnus incana) pollen extract by two-dimensional IEF/SDS-PAG electrophoresis combined with electrophoretic transfer and immunoautoradiography. International archives of allergy and applied immunology 18 3514476
1979 Association between pregnancy-associated alpha2-glycoprotein (alpha2-PAG) and mixed leucocyte reaction determinants on the leucocyte surface. Experientia 17 87341
2021 Transmembrane adaptor protein PAG is a mediator of PD-1 inhibitory signaling in human T cells. Communications biology 16 34083754
2017 Activation of P2X3 receptors in the cerebrospinal fluid-contacting nucleus neurons reduces formalin-induced pain behavior via PAG in a rat model. Neuroscience 16 28673711
2008 Modulation of tonic immobility in guinea pig PAG by homocysteic acid, a glutamate agonist. Physiology & behavior 16 18378267
2006 Elevated pCREB in the PAG after exposure to the elevated plus maze in rats previously exposed to a cat. Behavioural brain research 16 16997391
2005 Specific protein interaction of human Pag with Omi/HtrA2 and the activation of the protease activity of Omi/HtrA2. Free radical biology & medicine 16 16413409
1979 Pregnancy-associated alpha 2-glycoprotein (alpha 2-PAG) and various acute phase reactants in rheumatoid arthritis and osteoarthritis. Biomedicine / [publiee pour l'A.A.I.C.I.G.] 16 476269
2004 Distinct regions of periaqueductal gray (PAG) are involved in freezing behavior in hooded PVG rats on the cat-freezing test apparatus. Neuroscience letters 15 14698458
2020 Positive allosteric modulation of the cannabinoid type-1 receptor (CB1R) in periaqueductal gray (PAG) antagonizes anti-nociceptive and cellular effects of a mu-opioid receptor agonist in morphine-withdrawn rats. Psychopharmacology 14 32857187
2017 CaMKIIα may modulate fentanyl-induced hyperalgesia via a CeLC-PAG-RVM-spinal cord descending facilitative pain pathway in rats. PloS one 14 28489932
2007 Prostaglandin E2 (PGE2) inhibits glutamatergic synaptic transmission in dorsolateral periaqueductal gray (dl-PAG). Brain research 14 17612511
2005 Chorionic mRNA expression and N-glycodiversity of pregnancy-associated glycoprotein family (PAG) of the European bison (Bison bonasus). Animal reproduction science 14 16143214
1990 Immunological reactivity and passive protective activity of monoclonal antibodies against protective antigen (PAg) of Leptospira interrogans serovar lai. Zentralblatt fur Bakteriologie : international journal of medical microbiology 14 2331299
2019 PAG1 limits allergen-induced type 2 inflammation in the murine lung. Allergy 13 31321783
2018 Positive and Negative Regulatory Roles of C-Terminal Src Kinase (CSK) in FcεRI-Mediated Mast Cell Activation, Independent of the Transmembrane Adaptor PAG/CSK-Binding Protein. Frontiers in immunology 13 30116247
2009 Role of homocysteic acid in the guinea pig (Cavia porcellus) anterior cingulate cortex in tonic immobility and the influence of NMDA receptors on the dorsal PAG. Behavioural brain research 13 19963012
2020 Chronic Fluoxetine Impairs the Effects of 5-HT1A and 5-HT2C Receptors Activation in the PAG and Amygdala on Antinociception Induced by Aversive Situation in Mice. Frontiers in pharmacology 12 32218734
2011 Heliothis zea nudivirus 1 gene hhi1 induces apoptosis which is blocked by the Hz-iap2 gene and a noncoding gene, pag1. Journal of virology 12 21543471
2010 Pregnancy-associated glycoprotein (PAG) family localized in chorionic cells within the epitheliochorial/diffuse placenta of the alpaca (Lama pacos). Acta histochemica 12 20656339
2001 Lamina I-periaqueductal gray (PAG) projections represent only a limited part of the total spinal and caudal medullary input to the PAG in the cat. Brain research bulletin 12 11275406
2023 PAG neuronal NMDARs activation mediated morphine-induced hyperalgesia by HMGB1-TLR4 dependent microglial inflammation. Journal of psychiatric research 11 37352811
2018 PAG1 promotes the inherent radioresistance of laryngeal cancer cells via activation of STAT3. Experimental cell research 11 29913153
2018 Identification of Integrin β1 as a Novel PAG1-Interacting Protein Involved in the Inherent Radioresistance of Human Laryngeal Carcinoma. Journal of Cancer 11 30519312
2015 Revisiting the Timing of Action of the PAG Adaptor Using Quantitative Proteomics Analysis of Primary T Cells. Journal of immunology (Baltimore, Md. : 1950) 11 26512138
2013 PAG/Cbp suppression reveals a contribution of CTLA-4 to setting the activation threshold in T cells. Cell communication and signaling : CCS 11 23601194
2009 Pregnancy-associated glycoprotein (PAG) family: transcripts and gene amplicons in camelids. Reproductive biology 11 19734952
2005 Expression pattern of adaptor protein PAG: correlation between secondary lymphatic follicle and histogenetically related malignant lymphomas. Immunology letters 10 15975665

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