{"gene":"PECAM1","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":1990,"finding":"PECAM-1 (CD31) was cloned and identified as a 130-kDa integral membrane glycoprotein containing six extracellular immunoglobulin-like domains, placing it in the CAM subgroup of the Ig superfamily. Its cell surface distribution at intercellular junctions suggested participation in cellular recognition events.","method":"cDNA cloning from endothelial cell library; sequence analysis","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 / Strong — primary cloning and structural characterization, replicated by independent lab (Simmons et al. 1990, PMID:2351935)","pmids":["1690453","2351935"],"is_preprint":false},{"year":1991,"finding":"PECAM-1 mediates homophilic, calcium-dependent cell-cell adhesion. When transfected into COS-7, 3T3, or L cells, PECAM-1 concentrated at cell-cell junctions (recapitulating endothelial distribution) and L-cell transfectants formed calcium-dependent aggregates inhibitable by anti-PECAM antibodies.","method":"Full-length PECAM-1 cDNA transfection into null cell lines; cell aggregation assay; anti-PECAM antibody blocking","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution in null cells with functional readout, replicated across multiple cell types in one rigorous study","pmids":["1874786"],"is_preprint":false},{"year":1992,"finding":"PECAM-1 transfected into NIH/3T3 cells localizes to sites of cell-cell contact via its full-length form (requiring the cytoplasmic tail) and diminishes cell migration rate compared to control or extracellular-domain-only transfectants, demonstrating that PECAM-1 modulates cell migration.","method":"Full-length and truncated PECAM-1 transfection into NIH/3T3 cells; quantitative migration assays; indirect immunofluorescence","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional transfection with two orthogonal assays (localization + migration), single lab","pmids":["1429859"],"is_preprint":false},{"year":1992,"finding":"CD31 becomes rapidly phosphorylated on serine/threonine residues (not tyrosine) in platelets, Jurkat T cells, and endothelial cells following cell activation. Phosphorylation is induced by phorbol ester and blocked by the PKC inhibitor staurosporin, indicating PKC-mediated phosphorylation. Following T cell activation, CD31 mRNA and protein are downregulated, partly via decreased transcription.","method":"Phosphoamino acid analysis; phorbol ester stimulation; staurosporin inhibition; nuclear run-on assay; Northern/Western blot","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical assays with pharmacological inhibition across multiple cell types, single lab","pmids":["1544907"],"is_preprint":false},{"year":1994,"finding":"PECAM-1 localizes to endothelial intercellular junctions; upon cellular activation, it becomes highly phosphorylated and associates with the cytoskeleton, enabling it to move within the membrane plane. PECAM-1-transfected L cells aggregate in a calcium- and PECAM-1-dependent manner. PECAM-1 engagement on leukocytes upregulates integrin function.","method":"Cytoskeletal fractionation; phosphorylation assays; cell aggregation assay; anti-PECAM antibody blocking","journal":"Annals of the New York Academy of Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays in single review/experimental context, multiple labs referenced","pmids":["8017765"],"is_preprint":false},{"year":1995,"finding":"PECAM-1 mediates a distinct transendothelial migration (diapedesis) step for neutrophils and monocytes, independent of leukocyte binding to the apical endothelial surface. Anti-PECAM-1 antibody or soluble recombinant PECAM-1 directed at either leukocyte or endothelial PECAM-1 blocked transmigration by 70–90% in vitro; antibody against mouse PECAM-1 blocked leukocyte emigration into the peritoneum in vivo. The non-additivity of leukocyte- vs. endothelial-directed reagents suggests a homophilic PECAM-1:PECAM-1 interaction.","method":"In vitro transendothelial migration assay; anti-PECAM-1 antibody/soluble PECAM-1 blocking; in vivo thioglycollate-induced peritonitis mouse model","journal":"Journal of leukocyte biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal blocking experiments in both in vitro and in vivo systems, mechanistic conclusion well supported","pmids":["7722409"],"is_preprint":false},{"year":1995,"finding":"PECAM-1 contributes to endothelial barrier (vascular permeability) function: macromolecule permeability assays on monolayers expressing native or transfected PECAM-1 showed that PECAM-1 participates in establishing and maintaining the barrier. In vivo injection of anti-murine PECAM-1 monoclonal antibody caused detectable leakage of hepatic and renal blood vessels.","method":"Macromolecule permeability assays on cell monolayers; in vivo antibody injection with vascular leakage readout","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo experiments, single lab","pmids":["7589563"],"is_preprint":false},{"year":1995,"finding":"TNF-α and IFN-γ induce dose-dependent redistribution of PECAM-1 away from endothelial intercellular junctions without changing total surface PECAM-1 or altering alternatively spliced variants. This redistribution is associated with changes in PECAM-1 cytoskeletal association, suggesting a mechanism by which cytokines regulate leukocyte transmigration.","method":"Flow cytometry; immunofluorescence; cytoskeletal fractionation; Northern blot; RT-PCR for splice variants","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods, single lab","pmids":["7759892"],"is_preprint":false},{"year":1997,"finding":"Endothelial tube formation in vitro and in vivo requires both cadherin 5 (VE-cadherin) and CD31 acting in concert to reorganize filamentous actin (F-actin). Neither antibody alone blocked tube formation or F-actin reorganization, but together they did. By immunoprecipitation, a portion of CD31 (as well as cadherin 5) connects to β-catenin, linking it to the F-actin-associated adherens junction complex.","method":"In vitro tube formation assay; in vivo wound healing model in SCID mice; anti-CD31 and anti-VE-cadherin blocking antibodies; cytochalasin D treatment; immunoprecipitation of CD31-β-catenin complex","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — reconstitution of functional complex by Co-IP, functional antibody blocking in both in vitro and in vivo models, multiple orthogonal methods","pmids":["9120301"],"is_preprint":false},{"year":1997,"finding":"PECAM-1/CD31 functions as an endothelial receptor for Plasmodium falciparum-infected red blood cells (pRBCs). pRBCs bind to PECAM-1/CD31 transfected cells and directly to recombinant PECAM-1/CD31 on plastic. Binding is blocked by soluble PECAM-1/CD31 and by monoclonal antibodies against domains 1–4 of PECAM-1. IFN-γ augments this adhesion.","method":"PECAM-1 transfected cell binding assay; recombinant protein binding assay; antibody blocking; IFN-γ stimulation","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — direct binding to recombinant protein and transfected cells with domain-specific blocking, multiple orthogonal methods in single study","pmids":["9396614"],"is_preprint":false},{"year":1997,"finding":"PECAM-1 is involved in angiogenesis: anti-PECAM-1 antibodies blocked in vitro tube formation by rat capillary endothelial cells and cytokine-induced corneal neovascularization in vivo, and prevented vessel growth into bFGF-supplemented subcutaneous gels in mice.","method":"In vitro tube formation assay; rat corneal neovascularization model; murine subcutaneous gel implant model; anti-PECAM-1 antibody blocking","journal":"The American journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — antibody blocking in multiple in vivo and in vitro models, single lab","pmids":["9284815"],"is_preprint":false},{"year":1998,"finding":"Transmigration of growth factor-activated CD34+ hematopoietic progenitor cells (HPCs) across endothelial monolayers is mediated by PECAM-1 (CD31): anti-PECAM-1 monoclonal antibody inhibited transmigration of activated CFCs by ~71%. CD18 also contributed. Activation-induced cell cycle entry was required for transmigration.","method":"Transendothelial migration assay; anti-PECAM-1 and anti-CD18 antibody blocking; cell cycle analysis","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — antibody blocking in single functional assay, single lab","pmids":["9454749"],"is_preprint":false},{"year":1999,"finding":"VEGF induces β-catenin tyrosine phosphorylation in endothelial cells, and PECAM-1 functions as a reservoir for and modulator of tyrosine-phosphorylated β-catenin at cell junctions. PECAM-1 prevents β-catenin nuclear translocation in transfected SW480 colon carcinoma cells, suggesting PECAM-1 modulates Wnt/β-catenin signaling.","method":"Co-immunoprecipitation; Western blot for phospho-β-catenin; transfection of SW480 cells; confocal microscopy","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and functional nuclear translocation assay, multiple orthogonal methods, single lab","pmids":["10462517"],"is_preprint":false},{"year":1999,"finding":"PECAM-1/CD31 exists as a dimer (both in solution and on cell membranes) and is heavily N-glycosylated (~21% carbohydrate by mass). Ultracentrifugation showed soluble CD31 equilibrates between monomer and dimer (Kd ~12.5 µM); chemical cross-linking confirmed membrane-expressed CD31 dimerization.","method":"Analytical ultracentrifugation; chemical cross-linking of soluble and membrane CD31; mass spectrometry glycan analysis","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — biophysical reconstitution (ultracentrifugation) plus chemical cross-linking, two orthogonal methods in single study","pmids":["10425179"],"is_preprint":false},{"year":1999,"finding":"Homophilic PECAM-1/PECAM-1 interactions on HUVEC support robust endothelial cell adhesion and rescue cells from serum deprivation-induced apoptosis, but do not support cell spreading or migration. αvβ3 integrin is not a PECAM-1 ligand on HUVEC. Tyrosine-phosphorylated PECAM-1 interacts with SHP-2 and at least four other phosphoproteins.","method":"Homophilic adhesion assay; apoptosis assay (serum deprivation); cell spreading/migration assay; immunoprecipitation of PECAM-1-SHP-2 complex","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays plus Co-IP, single lab","pmids":["10343075"],"is_preprint":false},{"year":2000,"finding":"CD31 cytoplasmic tail signaling activates the small GTPase Rap1 (but not Ras, R-Ras, or Rap2) to induce T cell adhesion via β1 (VLA-4) and β2 (LFA-1) integrins. Activated Rap1 mutant, the Rap1 GEF C3G, and catalytically inactive RapGAP all stimulated T cell adhesion to ICAM and VCAM; negative regulators of Rap1 blocked CD31-dependent adhesion.","method":"Rap1 activation assay (GTP-loading); dominant-negative and constitutively active Rap1/RapGEF/RapGAP transfection; T cell adhesion assay to ICAM/VCAM","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — gain- and loss-of-function Rap1 constructs with functional adhesion readouts, multiple orthogonal approaches in single rigorous study","pmids":["10725328"],"is_preprint":false},{"year":2000,"finding":"PECAM-1 expression on endothelial cells (not on hematopoietic cells) modulates in vivo bleeding time. PECAM-1-deficient mice had prolonged bleeding times; this was not corrected by engrafting wild-type hematopoietic precursors, but normal bleeding times were seen in wild-type mice reconstituted with PECAM-1-deficient hematopoietic cells.","method":"Bone marrow transplantation/chimera experiments; in vivo tail bleeding time assay; PECAM-1 knockout mice","journal":"The American journal of pathology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with bone marrow chimera experiments enabling cell-type-specific attribution, rigorous in vivo design","pmids":["10880378"],"is_preprint":false},{"year":2002,"finding":"CD31-mediated homophilic ligation on viable leukocytes promotes active, temperature-dependent detachment from macrophages under low shear (transmitting 'detachment' signals). In apoptotic leukocytes, this CD31-mediated detachment is disabled, promoting tight binding and macrophage engulfment. Thus CD31 switches function upon apoptosis.","method":"Flow-based macrophage binding assay; viable vs. apoptotic leukocyte binding; anti-CD31 antibody blocking; temperature-dependence experiments","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — functional assay under controlled flow conditions with mechanistic dissection, published in Nature with rigorous controls","pmids":["12110892"],"is_preprint":false},{"year":2003,"finding":"Clustering (multimerization) of PECAM-1 on endothelial cells triggers internalization via a novel endocytic pathway distinct from clathrin- and caveolar-mediated endocytosis. Internalization requires PKC activity, actin rearrangements (sensitive to latrunculin, radicicol, Y27632 [ROCK inhibitor]), and amiloride-sensitive macropinocytosis-like processes.","method":"Anti-PECAM-1 conjugate internalization assay; clathrin/caveolin colocalization; pharmacological inhibitors (amiloride, PKC inhibitors, latrunculin, Y27632); dominant-negative dynamin-2 (for ICAM-1 only); actin stress fiber imaging","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple inhibitors and colocalization studies, single lab","pmids":["12640043"],"is_preprint":false},{"year":2004,"finding":"Endothelial cell PECAM-1 expression is protective against endotoxic (LPS-induced) shock. PECAM-1-deficient mice were significantly more sensitive to systemic LPS administration, and bone marrow chimera experiments indicated that the absence of PECAM-1 at endothelial cell-cell junctions (not on hematopoietic cells) accounted for the majority of increased LPS-induced mortality.","method":"PECAM-1 knockout mice; LPS challenge model; mortality/pathophysiology readouts; bone marrow chimera experiments","journal":"American journal of physiology. Heart and circulatory physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with bone marrow chimeras enabling cell-type-specific attribution of protective endothelial function","pmids":["15319204"],"is_preprint":false},{"year":2005,"finding":"Flow activates ERK1/2 and eNOS via a PECAM1-SHP2-Tie2 signaling pathway. Flow increases tyrosine phosphorylation of both PECAM1 and Tie2 and their association with SHP2. siRNA knockdown of PECAM1 inhibited flow-stimulated Tie2 phosphorylation, ERK1/2, Akt, and eNOS phosphorylation. Thus PECAM1 transactivates Tie2 as an early step in mechanotransduction.","method":"Immunoprecipitation/mass spectrometry; PECAM1 and Tie2 siRNA knockdown; phosphorylation assays for ERK1/2, Akt, eNOS, Tie2","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP combined with siRNA knockdown and multiple downstream phosphorylation readouts in single study","pmids":["15985432"],"is_preprint":false},{"year":2006,"finding":"KSHV K5 ubiquitin ligase removes CD31/PECAM-1 from endothelial cells via a dual mechanism: K5 ubiquitinates pre-existing surface CD31 leading to endocytosis and lysosomal degradation, and newly synthesized CD31 is degraded by proteasomes in the ER (requiring PACS-2 binding to acidic residues in the K5 C-terminus). K5-mediated CD31 loss reduces EC migration.","method":"K5 expression in ECs; ubiquitination assay; lysosomal/proteasomal inhibitor treatments; flow cytometry; migration assay; PACS-2 interaction studies","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — biochemical ubiquitination assay with mechanistic dissection of two degradation pathways, multiple orthogonal methods in single study","pmids":["16601245"],"is_preprint":false},{"year":2007,"finding":"PECAM-1 modulates thrombin-induced tissue factor (TF) expression in endothelial cells. PECAM-1 antisense knockdown enhanced TF mRNA/protein induction and nuclear Egr-1 localization after thrombin stimulation. Mechanistically, TF induction proceeds through PAR-1, Gαi/o, Rho kinase, and p38 MAPK activation while PI3K/Akt is dephosphorylated; PECAM-1 presence sustains PI3K/Akt signaling that opposes this pathway.","method":"Antisense PECAM-1 knockdown in HUVEC; qRT-PCR/Western blot for TF and Egr-1; PAR-1 antagonist and pertussis toxin pharmacological inhibition; p38 MAPK and PI3K inhibitors; PECAM-1 KO mouse ischemia-reperfusion model","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pharmacological inhibitors and KO mouse model, single lab, mechanistic pathway defined","pmids":["17111362"],"is_preprint":false},{"year":2009,"finding":"PECAM-1 is necessary for flow-induced vascular remodeling. PECAM-1 knockout mice showed impaired inward remodeling and significantly reduced intima-media thickening in response to partial carotid artery ligation. PECAM-1 deficiency reduced NFκB activation, adhesion molecule expression, leukocyte infiltration, Akt activation, and vascular cell proliferation in low-flow conditions.","method":"PECAM-1 knockout mice; partial carotid artery ligation model; NFκB and Akt phosphorylation assays; adhesion molecule expression; leukocyte infiltration assessment","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with in vivo vascular remodeling model plus multiple mechanistic downstream readouts","pmids":["19390054"],"is_preprint":false},{"year":2010,"finding":"TCR stimulation drives cleavage and shedding of extracellular CD31 (domains 1–5) from the T cell surface. The shed CD31 is detectable as a soluble truncated protein in human plasma. Shedding abolishes CD31 inhibitory function because cis-homo-oligomerization (triggered by trans-homophilic engagement of IgD1) cannot occur on CD31-shed cells. A juxta-membrane domain 6 fragment remains on the cell surface and can be targeted by a synthetic CD31 peptide (aa 551–574) to restore ITIM686 and SHP2 phosphorylation and suppress TCR-induced activation in vivo.","method":"T cell activation assay; Western blot for shed CD31 in plasma; flow cytometry; phosphorylation assays for ITIM/SHP2; synthetic peptide rescue experiments; in vivo BALB/c mouse immunization model","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — mechanistic dissection with multiple orthogonal methods in vitro and in vivo, identification of cleavage product and functional consequences","pmids":["20400708"],"is_preprint":false},{"year":2010,"finding":"Cell aggregation in suspension induces tyrosine phosphorylation of PECAM-1 and Pyk2; PECAM-1 and Pyk2 physically interact (shown by co-immunoprecipitation). PECAM-1 lacking exons 11–16 cannot bind Pyk2. siRNA knockdown of both PECAM-1 and Pyk2 reduced cell aggregation and inhibited anchorage-independent tumor cell growth in soft agar, identifying PECAM-1/Pyk2 as mediators of anoikis resistance.","method":"Co-immunoprecipitation; domain-deletion mutant of PECAM-1; siRNA knockdown; soft agar colony formation assay; phosphorylation analysis","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain deletion plus siRNA and functional assay, single lab","pmids":["20074345"],"is_preprint":false},{"year":2014,"finding":"CD31 signals prevent endothelial cell (EC) death induced by TNF-α and cytotoxic T lymphocytes in vitro. Upon TNF receptor engagement, CD31 becomes activated and counteracts the proapoptotic transcriptional program via Erk/Akt pathway activation. Specifically, Akt activation by CD31 prevents FoxO3 nuclear localization, inhibiting transcription of CD95/Fas and caspase 7, and de-repressing cFlar. Both CD31 ITIMs are required for this prosurvival function. In vivo, CD31 gene transfer confers cytoprotection to CD31-negative pancreatic β cells.","method":"CD31 knockdown/KO ECs; TNF-α and CTL killing assays; quantitative RT-PCR array; Akt/Erk phosphorylation assays; FoxO3 nuclear localization; ITIM point mutants; in vivo CD31 gene transfer into β cells with allogeneic transplant model","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (biochemical pathway, ITIM mutants, in vivo gene transfer), mechanistic pathway thoroughly defined","pmids":["26392551"],"is_preprint":false},{"year":2014,"finding":"CD31 is a key coinhibitory receptor on dendritic cells (DCs). CD31/SHP-1 signaling during DC maturation reduces NF-κB nuclear translocation, costimulatory molecule expression, and immunogenic cytokines (IL-12, IL-6) while increasing TGF-β and IL-10. Disrupting CD31 signaling promotes immunogenic DC maturation and migration to lymph nodes. CD31-conditioned DCs adoptively transferred in vivo suppressed T cell-mediated autoimmune encephalomyelitis.","method":"CD31 signaling manipulation in DCs; NF-κB localization assay; cytokine ELISA; flow cytometry for DC maturation markers; adoptive transfer of CD31-conditioned DCs; EAE mouse model","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal in vitro and in vivo methods, mechanistic pathway through SHP-1/NF-κB defined, adoptive transfer experiments","pmids":["24616502"],"is_preprint":false},{"year":2015,"finding":"The crystal structure of PECAM-1 homophilic-binding domain (IgD1 and IgD2) was determined. Both domains exhibit a classical IgSF β-sandwich fold. IgD1 belongs to the I2 set of IgSF folds (not the previously assigned C2 class). Both IgD1 and IgD2 participate in the trans homophilic-binding interface, with a total buried interface area >2300 Ų. This structure provides an atomic-level model of PECAM-1 junction assembly.","method":"X-ray crystallography of IgD1-IgD2 fragment","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure determination, rigorous structural data in single focused study","pmids":["26702061"],"is_preprint":false},{"year":2015,"finding":"PECAM1 specifically mediates flow-induced Gab1 tyrosine phosphorylation and Akt/eNOS activation in endothelial cells. PECAM1 siRNA abolished flow- (but not HGF-) induced Gab1 phosphorylation, membrane translocation, and downstream Akt/eNOS activation. SHP2 is also required for flow-mediated Gab1 phosphorylation. PECAM1 knockout mice showed reduced flow-mediated Gab1 and eNOS phosphorylation in vivo.","method":"PECAM1 siRNA in ECs; SHP2 siRNA; PI3K inhibitor; phosphorylation assays; PECAM1 KO mice with voluntary wheel running model","journal":"Cellular signalling","confidence":"High","confidence_rationale":"Tier 2 / Strong — siRNA knockdown with in vitro specificity controls (HGF vs. flow) plus in vivo KO validation, multiple downstream readouts","pmids":["26706435"],"is_preprint":false},{"year":2020,"finding":"CD31 (PECAM-1) is the specific membrane receptor for Clostridium perfringens β-toxin (CPB) on endothelial cells. CD31 expression corresponds with cell-type specificity of CPB toxicity; ectopic CD31 expression rendered resistant cells and liposomes susceptible to CPB-induced membrane damage. The extracellular Ig6 domain of mouse, human, and porcine CD31 is essential for interaction with CPB.","method":"CD31 expression in resistant cell lines; ectopic CD31 expression rendering cells susceptible; liposome reconstitution; Ig-domain deletion mutants; CD31 KO mice; cytotoxicity assays","journal":"Cell host & microbe","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — reconstitution in multiple systems (cells, liposomes), domain mapping, KO mice, multiple orthogonal methods identifying CD31 Ig6 as the CPB-binding domain","pmids":["32497498"],"is_preprint":false},{"year":2020,"finding":"CD31 receptor-induced glycolytic reprogramming is required for endothelial barrier (EB) recovery after disruption. Mechanistically, CD31 engagement activates SHP phosphatase, leading to Akt-mediated nuclear exclusion of FoxO1 and β-catenin translocation to the nucleus, collectively driving cMyc transcription and enhanced glycolysis for junction re-annealing. CD31 also sustains mitochondrial respiration but this pathway does not contribute to junction remodeling. Pathologic microvascular leakage in CD31-deficient mice was corrected by pharmacological Akt or AMPK activation.","method":"MHC-triggered EC contraction/leakage model; metabolic flux assays; SHP inhibition; Akt/AMPK pharmacological activation; FoxO1 and β-catenin nuclear localization; CD31 KO mice","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — mechanistic pathway dissected with multiple inhibitors/genetic tools and in vivo rescue experiments, multiple orthogonal methods","pmids":["32681081"],"is_preprint":false},{"year":2021,"finding":"PECAM-1 supports leukocyte diapedesis by triggering SHP2 dissociation, which directly dephosphorylates VE-cadherin at Y731, enabling VE-cadherin endocytosis and junctional destabilization. The SHP2-binding site on PECAM-1 is required for VE-cadherin dephosphorylation, and PECAM-1's contribution to diapedesis in vitro and in vivo was strictly dependent on VE-cadherin Y731. Additionally, dephosphorylation requires Ca2+ signaling, non-muscle myosin II, and endothelial cell tension; β-catenin/plakoglobin mask VE-cadherin Y731 until leukocyte docking exerts force on the complex.","method":"PECAM-1 SHP2-binding site mutants; VE-cadherin Y731 phosphomutants; in vitro diapedesis assay; in vivo leukocyte extravasation; Ca2+ signaling assays; non-muscle myosin II inhibition; PECAM-1 and VE-cadherin KO/knock-in mice","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — site-specific mutants, in vitro and in vivo models, multiple orthogonal methods defining the mechanistic chain from PECAM-1 to SHP2 to VE-cadherin dephosphorylation","pmids":["33604918"],"is_preprint":false},{"year":2023,"finding":"PECAM1 interacts with PIEZO1 and directs it to endothelial cell-cell junctions. PECAM1's extracellular N-terminus is critical for this interaction, and a C-terminal intracellular domain linked to shear stress also contributes. CDH5 similarly drives PIEZO1 to junctions but unlike PECAM1, its interaction with PIEZO1 is dynamic and increases with shear stress. PIEZO1 does not interact with VEGFR2. PIEZO1 is required for Ca2+-dependent formation of adherens junctions and associated cytoskeleton.","method":"Endogenous PIEZO1 tagging in mice; reconstitution studies; high-resolution microscopy; Co-IP; shear stress experiments; PIEZO1 KO functional assays for junction formation","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — endogenous tagging, reconstitution, Co-IP with domain mapping, functional KO readouts, multiple orthogonal methods","pmids":["37005489"],"is_preprint":false},{"year":2023,"finding":"Physical traction on endothelial PECAM-1 during transendothelial migration (TEM) initiates endothelial signaling (detected by FLIM). Endothelial PECAM-1 acts as part of a mechanotransduction complex with VE-cadherin and VEGFR2. TEM required VEGFR2 and phosphorylation of its Y1175, but not VEGF or VEGFR2 kinase activity. Inducible endothelial-specific VEGFR2 deletion reduced neutrophil extravasation by ≥75% in three mouse inflammation models by selectively blocking diapedesis.","method":"Fluorescence lifetime imaging microscopy (FLIM) for traction detection; inducible endothelial-specific VEGFR2 KO mice; VEGFR2 Y1175 phosphomutants; three in vivo mouse inflammation models","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — FLIM mechanotransduction measurement, inducible KO, point mutants, and three in vivo models establishing mechanotransduction complex","pmids":["37643615"],"is_preprint":false}],"current_model":"PECAM-1 (CD31) is a six-Ig-domain transmembrane glycoprotein that forms homophilic dimers at endothelial cell junctions and on leukocyte/platelet surfaces, where it functions as a mechanosensory and signaling hub: physical force during leukocyte diapedesis activates a PECAM-1–VE-cadherin–VEGFR2 mechanotransduction complex that drives SHP2 release to dephosphorylate VE-cadherin Y731, enabling junctional opening; concurrently, PECAM-1 recruits SHP2 and Tie2 to activate ERK1/2/Akt/eNOS under laminar shear stress, partners with PIEZO1 at junctions for Ca2+-dependent junctional remodeling, and signals through its dual ITIM cytoplasmic tyrosines to activate the Rap1 GTPase (upregulating integrin adhesion), engage Akt/Erk to suppress FoxO3-driven apoptosis, trigger glycolytic reprogramming for barrier recovery, and recruit SHP-1 in dendritic cells and T cells to limit immune activation, while on apoptotic cells the same homophilic detachment signal is disabled, promoting macrophage engulfment."},"narrative":{"mechanistic_narrative":"PECAM-1 (CD31) is a six-Ig-domain transmembrane glycoprotein that concentrates at endothelial intercellular junctions and on leukocyte and platelet surfaces, where it mediates calcium-dependent homophilic cell-cell adhesion and functions as a junctional signaling and mechanotransduction hub [PMID:1690453, PMID:2351935, PMID:1874786, PMID:26702061]. It self-associates as a monomer/dimer-equilibrium glycoprotein whose IgD1 and IgD2 domains form the trans-homophilic binding interface [PMID:10425179, PMID:26702061], and its cytoplasmic tail couples it to the cytoskeleton and the β-catenin/VE-cadherin adherens-junction complex to support endothelial tube formation, barrier integrity, and modulation of β-catenin signaling [PMID:1429859, PMID:9120301, PMID:10462517, PMID:7589563]. A central, well-defined role is the control of leukocyte transendothelial migration: PECAM-1 homophilic engagement mediates a distinct diapedesis step in vitro and in vivo [PMID:7722409], and physical traction on endothelial PECAM-1 during transmigration activates a PECAM-1–VE-cadherin–VEGFR2 mechanotransduction complex that releases SHP2 to dephosphorylate VE-cadherin at Y731, destabilizing junctions in a Ca2+-, myosin II-, and tension-dependent manner [PMID:33604918, PMID:37643615]. Under laminar shear, PECAM-1 transduces flow by recruiting SHP2 and transactivating Tie2 and Gab1 to drive ERK1/2/Akt/eNOS signaling, and is required for flow-induced vascular remodeling [PMID:15985432, PMID:26706435, PMID:19390054]. Its dual ITIM cytoplasmic tyrosines support diverse outputs: activation of Rap1 to upregulate integrin-mediated adhesion [PMID:10725328], Erk/Akt-dependent suppression of FoxO3-driven apoptosis [PMID:26392551], glycolytic reprogramming via SHP/Akt/FoxO1/cMyc for barrier recovery [PMID:32681081], and recruitment of SHP-1 in dendritic cells to limit immune activation [PMID:24616502]. PECAM-1 also serves as a receptor exploited by pathogens, binding Plasmodium falciparum-infected erythrocytes and acting as the endothelial receptor for Clostridium perfringens β-toxin through its Ig6 domain [PMID:9396614, PMID:32497498], and partners with PIEZO1 to direct Ca2+-dependent junctional remodeling [PMID:37005489]. On viable leukocytes its homophilic ligation transmits detachment signals that are disabled upon apoptosis, switching the molecule toward promoting macrophage engulfment [PMID:12110892].","teleology":[{"year":1990,"claim":"Establishing the molecular identity of PECAM-1 defined it as a junctional Ig-superfamily cell adhesion molecule, framing all subsequent functional study.","evidence":"cDNA cloning and sequence analysis from an endothelial library","pmids":["1690453","2351935"],"confidence":"High","gaps":["Cloning alone did not establish adhesive mechanism or ligand","No functional readout for signaling"]},{"year":1991,"claim":"Reconstitution in null cells showed PECAM-1 is itself sufficient to drive calcium-dependent cell-cell adhesion and junctional localization, establishing its adhesive function.","evidence":"Full-length cDNA transfection into COS-7/3T3/L cells with aggregation assays and antibody blocking","pmids":["1874786"],"confidence":"High","gaps":["Did not resolve homophilic vs heterophilic binding partner","Cytoplasmic signaling consequences not addressed"]},{"year":1992,"claim":"The cytoplasmic tail was shown to be required for junctional targeting and migration modulation, and PKC-mediated serine/threonine phosphorylation was identified, linking PECAM-1 to intracellular regulation.","evidence":"Truncation transfection with migration assays; phosphoamino acid analysis with PKC inhibition across platelets, T cells, endothelium","pmids":["1429859","1544907"],"confidence":"Medium","gaps":["Tyrosine phosphorylation and ITIM signaling not yet characterized","Downstream effectors of migration not identified"]},{"year":1994,"claim":"PECAM-1 was linked to cytoskeletal association upon activation and to upregulation of leukocyte integrin function, connecting junctional adhesion to inside-out signaling.","evidence":"Cytoskeletal fractionation, phosphorylation, and aggregation assays","pmids":["8017765"],"confidence":"Medium","gaps":["Molecular mediator of integrin upregulation not defined","Cytoskeletal linker identity unknown"]},{"year":1995,"claim":"Reciprocal blocking experiments established PECAM-1 as a homophilic mediator of a distinct leukocyte diapedesis step and a contributor to endothelial barrier function, defining its central role in vascular inflammation.","evidence":"In vitro transmigration and permeability assays plus in vivo antibody blocking and vascular leakage models; cytokine-induced junctional redistribution","pmids":["7722409","7589563","7759892"],"confidence":"High","gaps":["Signaling chain from engagement to junctional opening unknown","Force/mechanotransduction component not yet identified"]},{"year":1997,"claim":"PECAM-1 was integrated into the adherens-junction complex with VE-cadherin and β-catenin during tube formation and angiogenesis, and identified as an exploited receptor for malaria-infected erythrocytes.","evidence":"Tube formation/wound healing models, CD31-β-catenin Co-IP, corneal neovascularization, and infected-RBC binding assays with domain-specific blocking","pmids":["9120301","9284815","9396614"],"confidence":"High","gaps":["Direct physical mechanism coupling PECAM-1 to actin not resolved","Heterophilic ligand for pRBC binding interface partial"]},{"year":1999,"claim":"Biophysical and biochemical work defined PECAM-1 as a glycosylated monomer/dimer-equilibrium protein that recruits SHP-2 and modulates β-catenin signaling and survival, establishing it as a signaling scaffold beyond adhesion.","evidence":"Analytical ultracentrifugation, cross-linking, glycan MS, Co-IP of SHP-2 and phospho-β-catenin, apoptosis and nuclear translocation assays","pmids":["10425179","10343075","10462517"],"confidence":"High","gaps":["Functional role of SHP-2 recruitment not yet placed in a pathway","Survival mechanism downstream effectors undefined"]},{"year":2000,"claim":"PECAM-1 cytoplasmic signaling was shown to activate Rap1 to drive integrin-dependent T cell adhesion, and cell-type-specific genetics attributed bleeding-time control to endothelial PECAM-1.","evidence":"Rap1 GTP-loading with dominant-negative/active constructs and adhesion assays; bone marrow chimeras with tail bleeding assays in KO mice","pmids":["10725328","10880378"],"confidence":"High","gaps":["Link between ITIM phosphorylation and Rap1 GEF activation incompletely mapped","Mechanism of hemostatic defect not molecularly resolved"]},{"year":2002,"claim":"Homophilic CD31 ligation was shown to transmit active detachment signals on viable leukocytes that are disabled upon apoptosis, explaining how the same molecule switches to promote macrophage clearance of dying cells.","evidence":"Flow-based macrophage binding assays comparing viable vs apoptotic leukocytes with antibody blocking","pmids":["12110892"],"confidence":"High","gaps":["Molecular basis for the apoptotic disabling of the detachment signal unknown","Signaling output downstream of detachment ligation not defined"]},{"year":2003,"claim":"Clustering of PECAM-1 was shown to drive a distinct, non-clathrin/non-caveolar endocytic route, defining how junctional PECAM-1 is internalized and trafficked.","evidence":"Anti-PECAM conjugate internalization with pharmacological inhibitors and actin imaging","pmids":["12640043"],"confidence":"Medium","gaps":["Molecular machinery of the macropinocytosis-like pathway unidentified","Physiological trigger for clustering-induced internalization unclear"]},{"year":2004,"claim":"Genetic and chimera experiments established endothelial junctional PECAM-1 as protective against endotoxic shock, extending its barrier role to systemic inflammation.","evidence":"LPS challenge in PECAM-1 KO mice with bone marrow chimeras","pmids":["15319204"],"confidence":"High","gaps":["Signaling pathway mediating endothelial protection not defined here","Relationship to barrier vs anti-inflammatory functions unresolved"]},{"year":2005,"claim":"PECAM-1 was placed at the apex of shear-stress mechanotransduction by transactivating Tie2 via SHP2 to drive ERK/Akt/eNOS, defining it as a flow sensor.","evidence":"Reciprocal Co-IP/MS, PECAM-1 and Tie2 siRNA, and phosphorylation readouts under flow","pmids":["15985432"],"confidence":"High","gaps":["Physical force-sensing step upstream of phosphorylation not resolved","How PECAM-1 distinguishes flow from other stimuli unclear"]},{"year":2006,"claim":"KSHV K5 ubiquitin ligase was shown to deplete CD31 by dual endocytic/lysosomal and ER-proteasomal routes, revealing a viral strategy targeting PECAM-1 and its impact on EC migration.","evidence":"K5 expression, ubiquitination assays, inhibitor treatments, PACS-2 interaction, and migration assays","pmids":["16601245"],"confidence":"High","gaps":["Host physiological regulator analogous to K5 not identified","Consequences for junction integrity not assessed"]},{"year":2010,"claim":"Two studies clarified regulation and additional roles: TCR-driven shedding of CD31 ectodomain abolishes its inhibitory cis-oligomerization, and PECAM-1/Pyk2 interaction mediates anoikis resistance in tumor cells.","evidence":"Shedding/plasma detection with synthetic peptide rescue and ITIM/SHP2 phosphorylation assays; Co-IP with domain-deletion mutants and soft-agar assays","pmids":["20400708","20074345"],"confidence":"High","gaps":["Protease responsible for CD31 cleavage not definitively identified","Pyk2 interaction interface only mapped by exon deletion"]},{"year":2014,"claim":"CD31 ITIM signaling was shown to be cytoprotective in endothelium (via Akt-mediated FoxO3 exclusion) and coinhibitory in dendritic cells (via SHP-1/NF-κB), establishing dual prosurvival and immunoregulatory roles.","evidence":"ITIM point mutants, RT-PCR arrays, FoxO3 localization, in vivo β-cell gene transfer; DC signaling manipulation with EAE adoptive transfer","pmids":["26392551","24616502"],"confidence":"High","gaps":["Trigger that activates CD31 upon TNF receptor engagement not fully defined","Distinct SHP-1 vs SHP-2 selection across cell types unexplained"]},{"year":2015,"claim":"PECAM-1 mechanotransduction was deepened by showing flow-specific Gab1/Akt/eNOS activation, and the homophilic interface was defined at atomic resolution by crystallography.","evidence":"PECAM1/SHP2 siRNA with flow-vs-HGF specificity controls and KO mice; X-ray structure of IgD1-IgD2","pmids":["26706435","26702061"],"confidence":"High","gaps":["Full-length dimer/cis-oligomer architecture not resolved by the IgD1-IgD2 structure","Coupling of force to conformational change unmodeled"]},{"year":2020,"claim":"PECAM-1 was shown to drive SHP/Akt/FoxO1/cMyc-dependent glycolytic reprogramming for barrier recovery, and identified as the Ig6-dependent endothelial receptor for C. perfringens β-toxin.","evidence":"Metabolic flux assays with SHP inhibition and Akt/AMPK rescue in KO mice; reconstitution in cells/liposomes with Ig-domain mapping and KO mice","pmids":["32681081","32497498"],"confidence":"High","gaps":["How junctional disruption couples to metabolic switch upstream of SHP unclear","β-toxin Ig6 binding mode not structurally defined"]},{"year":2021,"claim":"The molecular chain of leukocyte diapedesis was completed by showing PECAM-1 triggers SHP2 to dephosphorylate VE-cadherin Y731 in a Ca2+-, myosin II-, and tension-dependent manner, with β-catenin masking Y731 until force is applied.","evidence":"PECAM-1 SHP2-binding and VE-cadherin Y731 mutants in vitro and in vivo with KO/knock-in mice and myosin/Ca2+ manipulation","pmids":["33604918"],"confidence":"High","gaps":["How force is transmitted from leukocyte to the PECAM-1 complex not directly visualized here","Reversal/re-annealing of the junction post-diapedesis incompletely mapped"]},{"year":2023,"claim":"PECAM-1 was shown to act within a force-activated VE-cadherin–VEGFR2 mechanotransduction complex during TEM and to recruit PIEZO1 to junctions, integrating mechanical force sensing with junctional remodeling.","evidence":"FLIM traction detection, inducible endothelial VEGFR2 KO and Y1175 mutants in three inflammation models; endogenous PIEZO1 tagging, Co-IP, and domain mapping","pmids":["37643615","37005489"],"confidence":"High","gaps":["Stoichiometry and assembly order of the PECAM-1/VE-cadherin/VEGFR2/PIEZO1 complex unresolved","How VEGFR2 Y1175 is phosphorylated independent of kinase activity unexplained"]},{"year":null,"claim":"How a single homophilic receptor integrates mechanical force, Ca2+ signaling, and ITIM-coupled phosphatase recruitment to select among barrier opening, survival, metabolic, and immunoregulatory outputs in a context-dependent manner remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No unified structural model of the force-activated junctional complex","Determinants selecting SHP-1 vs SHP-2 and downstream output undefined","Mechanism linking conformational/force state to specific signaling branch unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[1,5,28]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[20,32]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[20,29,34]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[15,26,27,31]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[9,30]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[14,20,32]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,30]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[5,24,27,17]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[20,29,15,26]},{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[16,22]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[8,10,23]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[1,8,32,33]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[14,17,26]}],"complexes":["PECAM-1–VE-cadherin–VEGFR2 mechanotransduction complex","adherens junction (PECAM-1/VE-cadherin/β-catenin)"],"partners":["PTPN11 (SHP2)","VE-CADHERIN (CDH5)","VEGFR2 (KDR)","TIE2 (TEK)","PIEZO1","CTNNB1 (Β-CATENIN)","PTK2B (PYK2)","GAB1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P16284","full_name":"Platelet endothelial cell adhesion molecule","aliases":["EndoCAM","GPIIA'","PECA1"],"length_aa":738,"mass_kda":82.5,"function":"Cell adhesion molecule which is required for leukocyte transendothelial migration (TEM) under most inflammatory conditions (PubMed:17580308, PubMed:19342684). Tyr-690 plays a critical role in TEM and is required for efficient trafficking of PECAM1 to and from the lateral border recycling compartment (LBRC) and is also essential for the LBRC membrane to be targeted around migrating leukocytes (PubMed:19342684). Trans-homophilic interaction may play a role in endothelial cell-cell adhesion via cell junctions (PubMed:27958302). Heterophilic interaction with CD177 plays a role in transendothelial migration of neutrophils (PubMed:17580308). Homophilic ligation of PECAM1 prevents macrophage-mediated phagocytosis of neighboring viable leukocytes by transmitting a detachment signal (PubMed:12110892). Promotes macrophage-mediated phagocytosis of apoptotic leukocytes by tethering them to the phagocytic cells; PECAM1-mediated detachment signal appears to be disabled in apoptotic leukocytes (PubMed:12110892). Modulates bradykinin receptor BDKRB2 activation (PubMed:18672896). Regulates bradykinin- and hyperosmotic shock-induced ERK1/2 activation in endothelial cells (PubMed:18672896). Induces susceptibility to atherosclerosis (By similarity) Does not protect against apoptosis","subcellular_location":"Cell junction","url":"https://www.uniprot.org/uniprotkb/P16284/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PECAM1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":74,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PECAM1","total_profiled":1310},"omim":[{"mim_id":"616352","title":"ACYL-CoA-BINDING DOMAIN-CONTAINING PROTEIN 6; ACBD6","url":"https://www.omim.org/entry/616352"},{"mim_id":"616065","title":"PILR-ALPHA-ASSOCIATED NEURAL PROTEIN; PIANP","url":"https://www.omim.org/entry/616065"},{"mim_id":"614170","title":"BRITTLE CORNEA SYNDROME 2; BCS2","url":"https://www.omim.org/entry/614170"},{"mim_id":"611533","title":"NUCLEOLAR PROTEIN 7; NOL7","url":"https://www.omim.org/entry/611533"},{"mim_id":"611434","title":"CYTOKINE-DEPENDENT HEMATOPOIETIC CELL LINKER; CLNK","url":"https://www.omim.org/entry/611434"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoli","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"placenta","ntpm":427.4}],"url":"https://www.proteinatlas.org/search/PECAM1"},"hgnc":{"alias_symbol":["CD31"],"prev_symbol":[]},"alphafold":{"accession":"P16284","domains":[{"cath_id":"2.60.40.10","chopping":"33-129","consensus_level":"high","plddt":91.3122,"start":33,"end":129},{"cath_id":"2.60.40.1930","chopping":"135-231","consensus_level":"medium","plddt":89.2002,"start":135,"end":231},{"cath_id":"2.60.40.10","chopping":"238-323","consensus_level":"medium","plddt":92.1758,"start":238,"end":323},{"cath_id":"2.60.40.10","chopping":"330-406","consensus_level":"high","plddt":91.8357,"start":330,"end":406},{"cath_id":"2.60.40.10","chopping":"413-497","consensus_level":"high","plddt":91.4013,"start":413,"end":497},{"cath_id":"2.60.40.10","chopping":"502-599","consensus_level":"high","plddt":88.9981,"start":502,"end":599}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P16284","model_url":"https://alphafold.ebi.ac.uk/files/AF-P16284-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P16284-F1-predicted_aligned_error_v6.png","plddt_mean":80.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PECAM1","jax_strain_url":"https://www.jax.org/strain/search?query=PECAM1"},"sequence":{"accession":"P16284","fasta_url":"https://rest.uniprot.org/uniprotkb/P16284.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P16284/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P16284"}},"corpus_meta":[{"pmid":"1690453","id":"PMC_1690453","title":"PECAM-1 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promoting binding and engulfment.","date":"2002","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/12110892","citation_count":280,"is_preprint":false},{"pmid":"24435645","id":"PMC_24435645","title":"PECAM-1: regulator of endothelial junctional integrity.","date":"2014","source":"Cell and tissue research","url":"https://pubmed.ncbi.nlm.nih.gov/24435645","citation_count":270,"is_preprint":false},{"pmid":"18583570","id":"PMC_18583570","title":"Life after the thymus: CD31+ and CD31- human naive CD4+ T-cell subsets.","date":"2008","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/18583570","citation_count":255,"is_preprint":false},{"pmid":"12640043","id":"PMC_12640043","title":"A novel endocytic pathway induced by clustering endothelial ICAM-1 or PECAM-1.","date":"2003","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/12640043","citation_count":254,"is_preprint":false},{"pmid":"9396614","id":"PMC_9396614","title":"PECAM-1/CD31, an endothelial receptor 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integral membrane glycoprotein containing six extracellular immunoglobulin-like domains, placing it in the CAM subgroup of the Ig superfamily. Its cell surface distribution at intercellular junctions suggested participation in cellular recognition events.\",\n      \"method\": \"cDNA cloning from endothelial cell library; sequence analysis\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — primary cloning and structural characterization, replicated by independent lab (Simmons et al. 1990, PMID:2351935)\",\n      \"pmids\": [\"1690453\", \"2351935\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"PECAM-1 mediates homophilic, calcium-dependent cell-cell adhesion. When transfected into COS-7, 3T3, or L cells, PECAM-1 concentrated at cell-cell junctions (recapitulating endothelial distribution) and L-cell transfectants formed calcium-dependent aggregates inhibitable by anti-PECAM antibodies.\",\n      \"method\": \"Full-length PECAM-1 cDNA transfection into null cell lines; cell aggregation assay; anti-PECAM antibody blocking\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution in null cells with functional readout, replicated across multiple cell types in one rigorous study\",\n      \"pmids\": [\"1874786\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"PECAM-1 transfected into NIH/3T3 cells localizes to sites of cell-cell contact via its full-length form (requiring the cytoplasmic tail) and diminishes cell migration rate compared to control or extracellular-domain-only transfectants, demonstrating that PECAM-1 modulates cell migration.\",\n      \"method\": \"Full-length and truncated PECAM-1 transfection into NIH/3T3 cells; quantitative migration assays; indirect immunofluorescence\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional transfection with two orthogonal assays (localization + migration), single lab\",\n      \"pmids\": [\"1429859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"CD31 becomes rapidly phosphorylated on serine/threonine residues (not tyrosine) in platelets, Jurkat T cells, and endothelial cells following cell activation. Phosphorylation is induced by phorbol ester and blocked by the PKC inhibitor staurosporin, indicating PKC-mediated phosphorylation. Following T cell activation, CD31 mRNA and protein are downregulated, partly via decreased transcription.\",\n      \"method\": \"Phosphoamino acid analysis; phorbol ester stimulation; staurosporin inhibition; nuclear run-on assay; Northern/Western blot\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical assays with pharmacological inhibition across multiple cell types, single lab\",\n      \"pmids\": [\"1544907\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"PECAM-1 localizes to endothelial intercellular junctions; upon cellular activation, it becomes highly phosphorylated and associates with the cytoskeleton, enabling it to move within the membrane plane. PECAM-1-transfected L cells aggregate in a calcium- and PECAM-1-dependent manner. PECAM-1 engagement on leukocytes upregulates integrin function.\",\n      \"method\": \"Cytoskeletal fractionation; phosphorylation assays; cell aggregation assay; anti-PECAM antibody blocking\",\n      \"journal\": \"Annals of the New York Academy of Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays in single review/experimental context, multiple labs referenced\",\n      \"pmids\": [\"8017765\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"PECAM-1 mediates a distinct transendothelial migration (diapedesis) step for neutrophils and monocytes, independent of leukocyte binding to the apical endothelial surface. Anti-PECAM-1 antibody or soluble recombinant PECAM-1 directed at either leukocyte or endothelial PECAM-1 blocked transmigration by 70–90% in vitro; antibody against mouse PECAM-1 blocked leukocyte emigration into the peritoneum in vivo. The non-additivity of leukocyte- vs. endothelial-directed reagents suggests a homophilic PECAM-1:PECAM-1 interaction.\",\n      \"method\": \"In vitro transendothelial migration assay; anti-PECAM-1 antibody/soluble PECAM-1 blocking; in vivo thioglycollate-induced peritonitis mouse model\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal blocking experiments in both in vitro and in vivo systems, mechanistic conclusion well supported\",\n      \"pmids\": [\"7722409\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"PECAM-1 contributes to endothelial barrier (vascular permeability) function: macromolecule permeability assays on monolayers expressing native or transfected PECAM-1 showed that PECAM-1 participates in establishing and maintaining the barrier. In vivo injection of anti-murine PECAM-1 monoclonal antibody caused detectable leakage of hepatic and renal blood vessels.\",\n      \"method\": \"Macromolecule permeability assays on cell monolayers; in vivo antibody injection with vascular leakage readout\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo experiments, single lab\",\n      \"pmids\": [\"7589563\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"TNF-α and IFN-γ induce dose-dependent redistribution of PECAM-1 away from endothelial intercellular junctions without changing total surface PECAM-1 or altering alternatively spliced variants. This redistribution is associated with changes in PECAM-1 cytoskeletal association, suggesting a mechanism by which cytokines regulate leukocyte transmigration.\",\n      \"method\": \"Flow cytometry; immunofluorescence; cytoskeletal fractionation; Northern blot; RT-PCR for splice variants\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods, single lab\",\n      \"pmids\": [\"7759892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Endothelial tube formation in vitro and in vivo requires both cadherin 5 (VE-cadherin) and CD31 acting in concert to reorganize filamentous actin (F-actin). Neither antibody alone blocked tube formation or F-actin reorganization, but together they did. By immunoprecipitation, a portion of CD31 (as well as cadherin 5) connects to β-catenin, linking it to the F-actin-associated adherens junction complex.\",\n      \"method\": \"In vitro tube formation assay; in vivo wound healing model in SCID mice; anti-CD31 and anti-VE-cadherin blocking antibodies; cytochalasin D treatment; immunoprecipitation of CD31-β-catenin complex\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — reconstitution of functional complex by Co-IP, functional antibody blocking in both in vitro and in vivo models, multiple orthogonal methods\",\n      \"pmids\": [\"9120301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"PECAM-1/CD31 functions as an endothelial receptor for Plasmodium falciparum-infected red blood cells (pRBCs). pRBCs bind to PECAM-1/CD31 transfected cells and directly to recombinant PECAM-1/CD31 on plastic. Binding is blocked by soluble PECAM-1/CD31 and by monoclonal antibodies against domains 1–4 of PECAM-1. IFN-γ augments this adhesion.\",\n      \"method\": \"PECAM-1 transfected cell binding assay; recombinant protein binding assay; antibody blocking; IFN-γ stimulation\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct binding to recombinant protein and transfected cells with domain-specific blocking, multiple orthogonal methods in single study\",\n      \"pmids\": [\"9396614\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"PECAM-1 is involved in angiogenesis: anti-PECAM-1 antibodies blocked in vitro tube formation by rat capillary endothelial cells and cytokine-induced corneal neovascularization in vivo, and prevented vessel growth into bFGF-supplemented subcutaneous gels in mice.\",\n      \"method\": \"In vitro tube formation assay; rat corneal neovascularization model; murine subcutaneous gel implant model; anti-PECAM-1 antibody blocking\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — antibody blocking in multiple in vivo and in vitro models, single lab\",\n      \"pmids\": [\"9284815\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Transmigration of growth factor-activated CD34+ hematopoietic progenitor cells (HPCs) across endothelial monolayers is mediated by PECAM-1 (CD31): anti-PECAM-1 monoclonal antibody inhibited transmigration of activated CFCs by ~71%. CD18 also contributed. Activation-induced cell cycle entry was required for transmigration.\",\n      \"method\": \"Transendothelial migration assay; anti-PECAM-1 and anti-CD18 antibody blocking; cell cycle analysis\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — antibody blocking in single functional assay, single lab\",\n      \"pmids\": [\"9454749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"VEGF induces β-catenin tyrosine phosphorylation in endothelial cells, and PECAM-1 functions as a reservoir for and modulator of tyrosine-phosphorylated β-catenin at cell junctions. PECAM-1 prevents β-catenin nuclear translocation in transfected SW480 colon carcinoma cells, suggesting PECAM-1 modulates Wnt/β-catenin signaling.\",\n      \"method\": \"Co-immunoprecipitation; Western blot for phospho-β-catenin; transfection of SW480 cells; confocal microscopy\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and functional nuclear translocation assay, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"10462517\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"PECAM-1/CD31 exists as a dimer (both in solution and on cell membranes) and is heavily N-glycosylated (~21% carbohydrate by mass). Ultracentrifugation showed soluble CD31 equilibrates between monomer and dimer (Kd ~12.5 µM); chemical cross-linking confirmed membrane-expressed CD31 dimerization.\",\n      \"method\": \"Analytical ultracentrifugation; chemical cross-linking of soluble and membrane CD31; mass spectrometry glycan analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — biophysical reconstitution (ultracentrifugation) plus chemical cross-linking, two orthogonal methods in single study\",\n      \"pmids\": [\"10425179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Homophilic PECAM-1/PECAM-1 interactions on HUVEC support robust endothelial cell adhesion and rescue cells from serum deprivation-induced apoptosis, but do not support cell spreading or migration. αvβ3 integrin is not a PECAM-1 ligand on HUVEC. Tyrosine-phosphorylated PECAM-1 interacts with SHP-2 and at least four other phosphoproteins.\",\n      \"method\": \"Homophilic adhesion assay; apoptosis assay (serum deprivation); cell spreading/migration assay; immunoprecipitation of PECAM-1-SHP-2 complex\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays plus Co-IP, single lab\",\n      \"pmids\": [\"10343075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"CD31 cytoplasmic tail signaling activates the small GTPase Rap1 (but not Ras, R-Ras, or Rap2) to induce T cell adhesion via β1 (VLA-4) and β2 (LFA-1) integrins. Activated Rap1 mutant, the Rap1 GEF C3G, and catalytically inactive RapGAP all stimulated T cell adhesion to ICAM and VCAM; negative regulators of Rap1 blocked CD31-dependent adhesion.\",\n      \"method\": \"Rap1 activation assay (GTP-loading); dominant-negative and constitutively active Rap1/RapGEF/RapGAP transfection; T cell adhesion assay to ICAM/VCAM\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — gain- and loss-of-function Rap1 constructs with functional adhesion readouts, multiple orthogonal approaches in single rigorous study\",\n      \"pmids\": [\"10725328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"PECAM-1 expression on endothelial cells (not on hematopoietic cells) modulates in vivo bleeding time. PECAM-1-deficient mice had prolonged bleeding times; this was not corrected by engrafting wild-type hematopoietic precursors, but normal bleeding times were seen in wild-type mice reconstituted with PECAM-1-deficient hematopoietic cells.\",\n      \"method\": \"Bone marrow transplantation/chimera experiments; in vivo tail bleeding time assay; PECAM-1 knockout mice\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with bone marrow chimera experiments enabling cell-type-specific attribution, rigorous in vivo design\",\n      \"pmids\": [\"10880378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"CD31-mediated homophilic ligation on viable leukocytes promotes active, temperature-dependent detachment from macrophages under low shear (transmitting 'detachment' signals). In apoptotic leukocytes, this CD31-mediated detachment is disabled, promoting tight binding and macrophage engulfment. Thus CD31 switches function upon apoptosis.\",\n      \"method\": \"Flow-based macrophage binding assay; viable vs. apoptotic leukocyte binding; anti-CD31 antibody blocking; temperature-dependence experiments\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — functional assay under controlled flow conditions with mechanistic dissection, published in Nature with rigorous controls\",\n      \"pmids\": [\"12110892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Clustering (multimerization) of PECAM-1 on endothelial cells triggers internalization via a novel endocytic pathway distinct from clathrin- and caveolar-mediated endocytosis. Internalization requires PKC activity, actin rearrangements (sensitive to latrunculin, radicicol, Y27632 [ROCK inhibitor]), and amiloride-sensitive macropinocytosis-like processes.\",\n      \"method\": \"Anti-PECAM-1 conjugate internalization assay; clathrin/caveolin colocalization; pharmacological inhibitors (amiloride, PKC inhibitors, latrunculin, Y27632); dominant-negative dynamin-2 (for ICAM-1 only); actin stress fiber imaging\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple inhibitors and colocalization studies, single lab\",\n      \"pmids\": [\"12640043\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Endothelial cell PECAM-1 expression is protective against endotoxic (LPS-induced) shock. PECAM-1-deficient mice were significantly more sensitive to systemic LPS administration, and bone marrow chimera experiments indicated that the absence of PECAM-1 at endothelial cell-cell junctions (not on hematopoietic cells) accounted for the majority of increased LPS-induced mortality.\",\n      \"method\": \"PECAM-1 knockout mice; LPS challenge model; mortality/pathophysiology readouts; bone marrow chimera experiments\",\n      \"journal\": \"American journal of physiology. Heart and circulatory physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with bone marrow chimeras enabling cell-type-specific attribution of protective endothelial function\",\n      \"pmids\": [\"15319204\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Flow activates ERK1/2 and eNOS via a PECAM1-SHP2-Tie2 signaling pathway. Flow increases tyrosine phosphorylation of both PECAM1 and Tie2 and their association with SHP2. siRNA knockdown of PECAM1 inhibited flow-stimulated Tie2 phosphorylation, ERK1/2, Akt, and eNOS phosphorylation. Thus PECAM1 transactivates Tie2 as an early step in mechanotransduction.\",\n      \"method\": \"Immunoprecipitation/mass spectrometry; PECAM1 and Tie2 siRNA knockdown; phosphorylation assays for ERK1/2, Akt, eNOS, Tie2\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP combined with siRNA knockdown and multiple downstream phosphorylation readouts in single study\",\n      \"pmids\": [\"15985432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"KSHV K5 ubiquitin ligase removes CD31/PECAM-1 from endothelial cells via a dual mechanism: K5 ubiquitinates pre-existing surface CD31 leading to endocytosis and lysosomal degradation, and newly synthesized CD31 is degraded by proteasomes in the ER (requiring PACS-2 binding to acidic residues in the K5 C-terminus). K5-mediated CD31 loss reduces EC migration.\",\n      \"method\": \"K5 expression in ECs; ubiquitination assay; lysosomal/proteasomal inhibitor treatments; flow cytometry; migration assay; PACS-2 interaction studies\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — biochemical ubiquitination assay with mechanistic dissection of two degradation pathways, multiple orthogonal methods in single study\",\n      \"pmids\": [\"16601245\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PECAM-1 modulates thrombin-induced tissue factor (TF) expression in endothelial cells. PECAM-1 antisense knockdown enhanced TF mRNA/protein induction and nuclear Egr-1 localization after thrombin stimulation. Mechanistically, TF induction proceeds through PAR-1, Gαi/o, Rho kinase, and p38 MAPK activation while PI3K/Akt is dephosphorylated; PECAM-1 presence sustains PI3K/Akt signaling that opposes this pathway.\",\n      \"method\": \"Antisense PECAM-1 knockdown in HUVEC; qRT-PCR/Western blot for TF and Egr-1; PAR-1 antagonist and pertussis toxin pharmacological inhibition; p38 MAPK and PI3K inhibitors; PECAM-1 KO mouse ischemia-reperfusion model\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pharmacological inhibitors and KO mouse model, single lab, mechanistic pathway defined\",\n      \"pmids\": [\"17111362\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"PECAM-1 is necessary for flow-induced vascular remodeling. PECAM-1 knockout mice showed impaired inward remodeling and significantly reduced intima-media thickening in response to partial carotid artery ligation. PECAM-1 deficiency reduced NFκB activation, adhesion molecule expression, leukocyte infiltration, Akt activation, and vascular cell proliferation in low-flow conditions.\",\n      \"method\": \"PECAM-1 knockout mice; partial carotid artery ligation model; NFκB and Akt phosphorylation assays; adhesion molecule expression; leukocyte infiltration assessment\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with in vivo vascular remodeling model plus multiple mechanistic downstream readouts\",\n      \"pmids\": [\"19390054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TCR stimulation drives cleavage and shedding of extracellular CD31 (domains 1–5) from the T cell surface. The shed CD31 is detectable as a soluble truncated protein in human plasma. Shedding abolishes CD31 inhibitory function because cis-homo-oligomerization (triggered by trans-homophilic engagement of IgD1) cannot occur on CD31-shed cells. A juxta-membrane domain 6 fragment remains on the cell surface and can be targeted by a synthetic CD31 peptide (aa 551–574) to restore ITIM686 and SHP2 phosphorylation and suppress TCR-induced activation in vivo.\",\n      \"method\": \"T cell activation assay; Western blot for shed CD31 in plasma; flow cytometry; phosphorylation assays for ITIM/SHP2; synthetic peptide rescue experiments; in vivo BALB/c mouse immunization model\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mechanistic dissection with multiple orthogonal methods in vitro and in vivo, identification of cleavage product and functional consequences\",\n      \"pmids\": [\"20400708\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Cell aggregation in suspension induces tyrosine phosphorylation of PECAM-1 and Pyk2; PECAM-1 and Pyk2 physically interact (shown by co-immunoprecipitation). PECAM-1 lacking exons 11–16 cannot bind Pyk2. siRNA knockdown of both PECAM-1 and Pyk2 reduced cell aggregation and inhibited anchorage-independent tumor cell growth in soft agar, identifying PECAM-1/Pyk2 as mediators of anoikis resistance.\",\n      \"method\": \"Co-immunoprecipitation; domain-deletion mutant of PECAM-1; siRNA knockdown; soft agar colony formation assay; phosphorylation analysis\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain deletion plus siRNA and functional assay, single lab\",\n      \"pmids\": [\"20074345\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CD31 signals prevent endothelial cell (EC) death induced by TNF-α and cytotoxic T lymphocytes in vitro. Upon TNF receptor engagement, CD31 becomes activated and counteracts the proapoptotic transcriptional program via Erk/Akt pathway activation. Specifically, Akt activation by CD31 prevents FoxO3 nuclear localization, inhibiting transcription of CD95/Fas and caspase 7, and de-repressing cFlar. Both CD31 ITIMs are required for this prosurvival function. In vivo, CD31 gene transfer confers cytoprotection to CD31-negative pancreatic β cells.\",\n      \"method\": \"CD31 knockdown/KO ECs; TNF-α and CTL killing assays; quantitative RT-PCR array; Akt/Erk phosphorylation assays; FoxO3 nuclear localization; ITIM point mutants; in vivo CD31 gene transfer into β cells with allogeneic transplant model\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (biochemical pathway, ITIM mutants, in vivo gene transfer), mechanistic pathway thoroughly defined\",\n      \"pmids\": [\"26392551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CD31 is a key coinhibitory receptor on dendritic cells (DCs). CD31/SHP-1 signaling during DC maturation reduces NF-κB nuclear translocation, costimulatory molecule expression, and immunogenic cytokines (IL-12, IL-6) while increasing TGF-β and IL-10. Disrupting CD31 signaling promotes immunogenic DC maturation and migration to lymph nodes. CD31-conditioned DCs adoptively transferred in vivo suppressed T cell-mediated autoimmune encephalomyelitis.\",\n      \"method\": \"CD31 signaling manipulation in DCs; NF-κB localization assay; cytokine ELISA; flow cytometry for DC maturation markers; adoptive transfer of CD31-conditioned DCs; EAE mouse model\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal in vitro and in vivo methods, mechanistic pathway through SHP-1/NF-κB defined, adoptive transfer experiments\",\n      \"pmids\": [\"24616502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The crystal structure of PECAM-1 homophilic-binding domain (IgD1 and IgD2) was determined. Both domains exhibit a classical IgSF β-sandwich fold. IgD1 belongs to the I2 set of IgSF folds (not the previously assigned C2 class). Both IgD1 and IgD2 participate in the trans homophilic-binding interface, with a total buried interface area >2300 Ų. This structure provides an atomic-level model of PECAM-1 junction assembly.\",\n      \"method\": \"X-ray crystallography of IgD1-IgD2 fragment\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure determination, rigorous structural data in single focused study\",\n      \"pmids\": [\"26702061\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PECAM1 specifically mediates flow-induced Gab1 tyrosine phosphorylation and Akt/eNOS activation in endothelial cells. PECAM1 siRNA abolished flow- (but not HGF-) induced Gab1 phosphorylation, membrane translocation, and downstream Akt/eNOS activation. SHP2 is also required for flow-mediated Gab1 phosphorylation. PECAM1 knockout mice showed reduced flow-mediated Gab1 and eNOS phosphorylation in vivo.\",\n      \"method\": \"PECAM1 siRNA in ECs; SHP2 siRNA; PI3K inhibitor; phosphorylation assays; PECAM1 KO mice with voluntary wheel running model\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — siRNA knockdown with in vitro specificity controls (HGF vs. flow) plus in vivo KO validation, multiple downstream readouts\",\n      \"pmids\": [\"26706435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CD31 (PECAM-1) is the specific membrane receptor for Clostridium perfringens β-toxin (CPB) on endothelial cells. CD31 expression corresponds with cell-type specificity of CPB toxicity; ectopic CD31 expression rendered resistant cells and liposomes susceptible to CPB-induced membrane damage. The extracellular Ig6 domain of mouse, human, and porcine CD31 is essential for interaction with CPB.\",\n      \"method\": \"CD31 expression in resistant cell lines; ectopic CD31 expression rendering cells susceptible; liposome reconstitution; Ig-domain deletion mutants; CD31 KO mice; cytotoxicity assays\",\n      \"journal\": \"Cell host & microbe\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — reconstitution in multiple systems (cells, liposomes), domain mapping, KO mice, multiple orthogonal methods identifying CD31 Ig6 as the CPB-binding domain\",\n      \"pmids\": [\"32497498\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CD31 receptor-induced glycolytic reprogramming is required for endothelial barrier (EB) recovery after disruption. Mechanistically, CD31 engagement activates SHP phosphatase, leading to Akt-mediated nuclear exclusion of FoxO1 and β-catenin translocation to the nucleus, collectively driving cMyc transcription and enhanced glycolysis for junction re-annealing. CD31 also sustains mitochondrial respiration but this pathway does not contribute to junction remodeling. Pathologic microvascular leakage in CD31-deficient mice was corrected by pharmacological Akt or AMPK activation.\",\n      \"method\": \"MHC-triggered EC contraction/leakage model; metabolic flux assays; SHP inhibition; Akt/AMPK pharmacological activation; FoxO1 and β-catenin nuclear localization; CD31 KO mice\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — mechanistic pathway dissected with multiple inhibitors/genetic tools and in vivo rescue experiments, multiple orthogonal methods\",\n      \"pmids\": [\"32681081\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PECAM-1 supports leukocyte diapedesis by triggering SHP2 dissociation, which directly dephosphorylates VE-cadherin at Y731, enabling VE-cadherin endocytosis and junctional destabilization. The SHP2-binding site on PECAM-1 is required for VE-cadherin dephosphorylation, and PECAM-1's contribution to diapedesis in vitro and in vivo was strictly dependent on VE-cadherin Y731. Additionally, dephosphorylation requires Ca2+ signaling, non-muscle myosin II, and endothelial cell tension; β-catenin/plakoglobin mask VE-cadherin Y731 until leukocyte docking exerts force on the complex.\",\n      \"method\": \"PECAM-1 SHP2-binding site mutants; VE-cadherin Y731 phosphomutants; in vitro diapedesis assay; in vivo leukocyte extravasation; Ca2+ signaling assays; non-muscle myosin II inhibition; PECAM-1 and VE-cadherin KO/knock-in mice\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — site-specific mutants, in vitro and in vivo models, multiple orthogonal methods defining the mechanistic chain from PECAM-1 to SHP2 to VE-cadherin dephosphorylation\",\n      \"pmids\": [\"33604918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PECAM1 interacts with PIEZO1 and directs it to endothelial cell-cell junctions. PECAM1's extracellular N-terminus is critical for this interaction, and a C-terminal intracellular domain linked to shear stress also contributes. CDH5 similarly drives PIEZO1 to junctions but unlike PECAM1, its interaction with PIEZO1 is dynamic and increases with shear stress. PIEZO1 does not interact with VEGFR2. PIEZO1 is required for Ca2+-dependent formation of adherens junctions and associated cytoskeleton.\",\n      \"method\": \"Endogenous PIEZO1 tagging in mice; reconstitution studies; high-resolution microscopy; Co-IP; shear stress experiments; PIEZO1 KO functional assays for junction formation\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — endogenous tagging, reconstitution, Co-IP with domain mapping, functional KO readouts, multiple orthogonal methods\",\n      \"pmids\": [\"37005489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Physical traction on endothelial PECAM-1 during transendothelial migration (TEM) initiates endothelial signaling (detected by FLIM). Endothelial PECAM-1 acts as part of a mechanotransduction complex with VE-cadherin and VEGFR2. TEM required VEGFR2 and phosphorylation of its Y1175, but not VEGF or VEGFR2 kinase activity. Inducible endothelial-specific VEGFR2 deletion reduced neutrophil extravasation by ≥75% in three mouse inflammation models by selectively blocking diapedesis.\",\n      \"method\": \"Fluorescence lifetime imaging microscopy (FLIM) for traction detection; inducible endothelial-specific VEGFR2 KO mice; VEGFR2 Y1175 phosphomutants; three in vivo mouse inflammation models\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — FLIM mechanotransduction measurement, inducible KO, point mutants, and three in vivo models establishing mechanotransduction complex\",\n      \"pmids\": [\"37643615\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PECAM-1 (CD31) is a six-Ig-domain transmembrane glycoprotein that forms homophilic dimers at endothelial cell junctions and on leukocyte/platelet surfaces, where it functions as a mechanosensory and signaling hub: physical force during leukocyte diapedesis activates a PECAM-1–VE-cadherin–VEGFR2 mechanotransduction complex that drives SHP2 release to dephosphorylate VE-cadherin Y731, enabling junctional opening; concurrently, PECAM-1 recruits SHP2 and Tie2 to activate ERK1/2/Akt/eNOS under laminar shear stress, partners with PIEZO1 at junctions for Ca2+-dependent junctional remodeling, and signals through its dual ITIM cytoplasmic tyrosines to activate the Rap1 GTPase (upregulating integrin adhesion), engage Akt/Erk to suppress FoxO3-driven apoptosis, trigger glycolytic reprogramming for barrier recovery, and recruit SHP-1 in dendritic cells and T cells to limit immune activation, while on apoptotic cells the same homophilic detachment signal is disabled, promoting macrophage engulfment.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PECAM-1 (CD31) is a six-Ig-domain transmembrane glycoprotein that concentrates at endothelial intercellular junctions and on leukocyte and platelet surfaces, where it mediates calcium-dependent homophilic cell-cell adhesion and functions as a junctional signaling and mechanotransduction hub [#0, #1, #28]. It self-associates as a monomer/dimer-equilibrium glycoprotein whose IgD1 and IgD2 domains form the trans-homophilic binding interface [#13, #28], and its cytoplasmic tail couples it to the cytoskeleton and the β-catenin/VE-cadherin adherens-junction complex to support endothelial tube formation, barrier integrity, and modulation of β-catenin signaling [#2, #8, #12, #6]. A central, well-defined role is the control of leukocyte transendothelial migration: PECAM-1 homophilic engagement mediates a distinct diapedesis step in vitro and in vivo [#5], and physical traction on endothelial PECAM-1 during transmigration activates a PECAM-1–VE-cadherin–VEGFR2 mechanotransduction complex that releases SHP2 to dephosphorylate VE-cadherin at Y731, destabilizing junctions in a Ca2+-, myosin II-, and tension-dependent manner [#32, #34]. Under laminar shear, PECAM-1 transduces flow by recruiting SHP2 and transactivating Tie2 and Gab1 to drive ERK1/2/Akt/eNOS signaling, and is required for flow-induced vascular remodeling [#20, #29, #23]. Its dual ITIM cytoplasmic tyrosines support diverse outputs: activation of Rap1 to upregulate integrin-mediated adhesion [#15], Erk/Akt-dependent suppression of FoxO3-driven apoptosis [#26], glycolytic reprogramming via SHP/Akt/FoxO1/cMyc for barrier recovery [#31], and recruitment of SHP-1 in dendritic cells to limit immune activation [#27]. PECAM-1 also serves as a receptor exploited by pathogens, binding Plasmodium falciparum-infected erythrocytes and acting as the endothelial receptor for Clostridium perfringens β-toxin through its Ig6 domain [#9, #30], and partners with PIEZO1 to direct Ca2+-dependent junctional remodeling [#33]. On viable leukocytes its homophilic ligation transmits detachment signals that are disabled upon apoptosis, switching the molecule toward promoting macrophage engulfment [#17].\",\n  \"teleology\": [\n    {\n      \"year\": 1990,\n      \"claim\": \"Establishing the molecular identity of PECAM-1 defined it as a junctional Ig-superfamily cell adhesion molecule, framing all subsequent functional study.\",\n      \"evidence\": \"cDNA cloning and sequence analysis from an endothelial library\",\n      \"pmids\": [\"1690453\", \"2351935\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cloning alone did not establish adhesive mechanism or ligand\", \"No functional readout for signaling\"]\n    },\n    {\n      \"year\": 1991,\n      \"claim\": \"Reconstitution in null cells showed PECAM-1 is itself sufficient to drive calcium-dependent cell-cell adhesion and junctional localization, establishing its adhesive function.\",\n      \"evidence\": \"Full-length cDNA transfection into COS-7/3T3/L cells with aggregation assays and antibody blocking\",\n      \"pmids\": [\"1874786\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve homophilic vs heterophilic binding partner\", \"Cytoplasmic signaling consequences not addressed\"]\n    },\n    {\n      \"year\": 1992,\n      \"claim\": \"The cytoplasmic tail was shown to be required for junctional targeting and migration modulation, and PKC-mediated serine/threonine phosphorylation was identified, linking PECAM-1 to intracellular regulation.\",\n      \"evidence\": \"Truncation transfection with migration assays; phosphoamino acid analysis with PKC inhibition across platelets, T cells, endothelium\",\n      \"pmids\": [\"1429859\", \"1544907\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Tyrosine phosphorylation and ITIM signaling not yet characterized\", \"Downstream effectors of migration not identified\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"PECAM-1 was linked to cytoskeletal association upon activation and to upregulation of leukocyte integrin function, connecting junctional adhesion to inside-out signaling.\",\n      \"evidence\": \"Cytoskeletal fractionation, phosphorylation, and aggregation assays\",\n      \"pmids\": [\"8017765\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mediator of integrin upregulation not defined\", \"Cytoskeletal linker identity unknown\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Reciprocal blocking experiments established PECAM-1 as a homophilic mediator of a distinct leukocyte diapedesis step and a contributor to endothelial barrier function, defining its central role in vascular inflammation.\",\n      \"evidence\": \"In vitro transmigration and permeability assays plus in vivo antibody blocking and vascular leakage models; cytokine-induced junctional redistribution\",\n      \"pmids\": [\"7722409\", \"7589563\", \"7759892\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling chain from engagement to junctional opening unknown\", \"Force/mechanotransduction component not yet identified\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"PECAM-1 was integrated into the adherens-junction complex with VE-cadherin and β-catenin during tube formation and angiogenesis, and identified as an exploited receptor for malaria-infected erythrocytes.\",\n      \"evidence\": \"Tube formation/wound healing models, CD31-β-catenin Co-IP, corneal neovascularization, and infected-RBC binding assays with domain-specific blocking\",\n      \"pmids\": [\"9120301\", \"9284815\", \"9396614\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct physical mechanism coupling PECAM-1 to actin not resolved\", \"Heterophilic ligand for pRBC binding interface partial\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Biophysical and biochemical work defined PECAM-1 as a glycosylated monomer/dimer-equilibrium protein that recruits SHP-2 and modulates β-catenin signaling and survival, establishing it as a signaling scaffold beyond adhesion.\",\n      \"evidence\": \"Analytical ultracentrifugation, cross-linking, glycan MS, Co-IP of SHP-2 and phospho-β-catenin, apoptosis and nuclear translocation assays\",\n      \"pmids\": [\"10425179\", \"10343075\", \"10462517\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional role of SHP-2 recruitment not yet placed in a pathway\", \"Survival mechanism downstream effectors undefined\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"PECAM-1 cytoplasmic signaling was shown to activate Rap1 to drive integrin-dependent T cell adhesion, and cell-type-specific genetics attributed bleeding-time control to endothelial PECAM-1.\",\n      \"evidence\": \"Rap1 GTP-loading with dominant-negative/active constructs and adhesion assays; bone marrow chimeras with tail bleeding assays in KO mice\",\n      \"pmids\": [\"10725328\", \"10880378\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Link between ITIM phosphorylation and Rap1 GEF activation incompletely mapped\", \"Mechanism of hemostatic defect not molecularly resolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Homophilic CD31 ligation was shown to transmit active detachment signals on viable leukocytes that are disabled upon apoptosis, explaining how the same molecule switches to promote macrophage clearance of dying cells.\",\n      \"evidence\": \"Flow-based macrophage binding assays comparing viable vs apoptotic leukocytes with antibody blocking\",\n      \"pmids\": [\"12110892\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis for the apoptotic disabling of the detachment signal unknown\", \"Signaling output downstream of detachment ligation not defined\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Clustering of PECAM-1 was shown to drive a distinct, non-clathrin/non-caveolar endocytic route, defining how junctional PECAM-1 is internalized and trafficked.\",\n      \"evidence\": \"Anti-PECAM conjugate internalization with pharmacological inhibitors and actin imaging\",\n      \"pmids\": [\"12640043\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular machinery of the macropinocytosis-like pathway unidentified\", \"Physiological trigger for clustering-induced internalization unclear\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Genetic and chimera experiments established endothelial junctional PECAM-1 as protective against endotoxic shock, extending its barrier role to systemic inflammation.\",\n      \"evidence\": \"LPS challenge in PECAM-1 KO mice with bone marrow chimeras\",\n      \"pmids\": [\"15319204\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling pathway mediating endothelial protection not defined here\", \"Relationship to barrier vs anti-inflammatory functions unresolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"PECAM-1 was placed at the apex of shear-stress mechanotransduction by transactivating Tie2 via SHP2 to drive ERK/Akt/eNOS, defining it as a flow sensor.\",\n      \"evidence\": \"Reciprocal Co-IP/MS, PECAM-1 and Tie2 siRNA, and phosphorylation readouts under flow\",\n      \"pmids\": [\"15985432\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physical force-sensing step upstream of phosphorylation not resolved\", \"How PECAM-1 distinguishes flow from other stimuli unclear\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"KSHV K5 ubiquitin ligase was shown to deplete CD31 by dual endocytic/lysosomal and ER-proteasomal routes, revealing a viral strategy targeting PECAM-1 and its impact on EC migration.\",\n      \"evidence\": \"K5 expression, ubiquitination assays, inhibitor treatments, PACS-2 interaction, and migration assays\",\n      \"pmids\": [\"16601245\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Host physiological regulator analogous to K5 not identified\", \"Consequences for junction integrity not assessed\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Two studies clarified regulation and additional roles: TCR-driven shedding of CD31 ectodomain abolishes its inhibitory cis-oligomerization, and PECAM-1/Pyk2 interaction mediates anoikis resistance in tumor cells.\",\n      \"evidence\": \"Shedding/plasma detection with synthetic peptide rescue and ITIM/SHP2 phosphorylation assays; Co-IP with domain-deletion mutants and soft-agar assays\",\n      \"pmids\": [\"20400708\", \"20074345\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Protease responsible for CD31 cleavage not definitively identified\", \"Pyk2 interaction interface only mapped by exon deletion\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"CD31 ITIM signaling was shown to be cytoprotective in endothelium (via Akt-mediated FoxO3 exclusion) and coinhibitory in dendritic cells (via SHP-1/NF-κB), establishing dual prosurvival and immunoregulatory roles.\",\n      \"evidence\": \"ITIM point mutants, RT-PCR arrays, FoxO3 localization, in vivo β-cell gene transfer; DC signaling manipulation with EAE adoptive transfer\",\n      \"pmids\": [\"26392551\", \"24616502\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trigger that activates CD31 upon TNF receptor engagement not fully defined\", \"Distinct SHP-1 vs SHP-2 selection across cell types unexplained\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"PECAM-1 mechanotransduction was deepened by showing flow-specific Gab1/Akt/eNOS activation, and the homophilic interface was defined at atomic resolution by crystallography.\",\n      \"evidence\": \"PECAM1/SHP2 siRNA with flow-vs-HGF specificity controls and KO mice; X-ray structure of IgD1-IgD2\",\n      \"pmids\": [\"26706435\", \"26702061\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length dimer/cis-oligomer architecture not resolved by the IgD1-IgD2 structure\", \"Coupling of force to conformational change unmodeled\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"PECAM-1 was shown to drive SHP/Akt/FoxO1/cMyc-dependent glycolytic reprogramming for barrier recovery, and identified as the Ig6-dependent endothelial receptor for C. perfringens β-toxin.\",\n      \"evidence\": \"Metabolic flux assays with SHP inhibition and Akt/AMPK rescue in KO mice; reconstitution in cells/liposomes with Ig-domain mapping and KO mice\",\n      \"pmids\": [\"32681081\", \"32497498\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How junctional disruption couples to metabolic switch upstream of SHP unclear\", \"β-toxin Ig6 binding mode not structurally defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"The molecular chain of leukocyte diapedesis was completed by showing PECAM-1 triggers SHP2 to dephosphorylate VE-cadherin Y731 in a Ca2+-, myosin II-, and tension-dependent manner, with β-catenin masking Y731 until force is applied.\",\n      \"evidence\": \"PECAM-1 SHP2-binding and VE-cadherin Y731 mutants in vitro and in vivo with KO/knock-in mice and myosin/Ca2+ manipulation\",\n      \"pmids\": [\"33604918\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How force is transmitted from leukocyte to the PECAM-1 complex not directly visualized here\", \"Reversal/re-annealing of the junction post-diapedesis incompletely mapped\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"PECAM-1 was shown to act within a force-activated VE-cadherin–VEGFR2 mechanotransduction complex during TEM and to recruit PIEZO1 to junctions, integrating mechanical force sensing with junctional remodeling.\",\n      \"evidence\": \"FLIM traction detection, inducible endothelial VEGFR2 KO and Y1175 mutants in three inflammation models; endogenous PIEZO1 tagging, Co-IP, and domain mapping\",\n      \"pmids\": [\"37643615\", \"37005489\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and assembly order of the PECAM-1/VE-cadherin/VEGFR2/PIEZO1 complex unresolved\", \"How VEGFR2 Y1175 is phosphorylated independent of kinase activity unexplained\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single homophilic receptor integrates mechanical force, Ca2+ signaling, and ITIM-coupled phosphatase recruitment to select among barrier opening, survival, metabolic, and immunoregulatory outputs in a context-dependent manner remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No unified structural model of the force-activated junctional complex\", \"Determinants selecting SHP-1 vs SHP-2 and downstream output undefined\", \"Mechanism linking conformational/force state to specific signaling branch unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [1, 5, 28]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [20, 32]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [20, 29, 34]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [15, 26, 27, 31]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [9, 30]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [14, 20, 32]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 30]},\n      {\"term_id\": \"GO:0005911\", \"supporting_discovery_ids\": [1, 5, 8, 33]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [5, 24, 27, 17]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [20, 29, 15, 26]},\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [16, 22]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [8, 10, 23]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [1, 8, 32, 33]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [14, 17, 26]}\n    ],\n    \"complexes\": [\n      \"PECAM-1–VE-cadherin–VEGFR2 mechanotransduction complex\",\n      \"adherens junction (PECAM-1/VE-cadherin/β-catenin)\"\n    ],\n    \"partners\": [\n      \"PTPN11 (SHP2)\",\n      \"VE-cadherin (CDH5)\",\n      \"VEGFR2 (KDR)\",\n      \"TIE2 (TEK)\",\n      \"PIEZO1\",\n      \"CTNNB1 (β-catenin)\",\n      \"PTK2B (Pyk2)\",\n      \"GAB1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}