Affinage

ICAM2

Intercellular adhesion molecule 2 · UniProt P13598

Length
275 aa
Mass
30.7 kDa
Annotated
2026-04-28
87 papers in source corpus 35 papers cited in narrative 35 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ICAM-2 is a constitutively expressed two-immunoglobulin-domain transmembrane glycoprotein that serves as an adhesion ligand on endothelium and hematopoietic cells, mediating leukocyte trafficking, vascular integrity, and cell survival signaling. Its extracellular domain 1 binds the leukocyte integrins LFA-1 (CD11a/CD18) and Mac-1 (CD11b/CD18) via a flat ridge on the GFC β-sheet centered on Glu-37, which coordinates Mg²⁺ in the integrin I domain, and also engages DC-SIGN through Lewis Y glycans (PMID:9153399, PMID:10077629, PMID:7561061, PMID:18155766). Its short cytoplasmic tail links to the actin cytoskeleton through direct binding of ERM proteins (regulated by PtdIns(4,5)P₂) and α-actinin, and transduces signals activating PI3K/AKT to promote cell survival and Rac-1 to regulate angiogenesis and endothelial barrier function (PMID:9705328, PMID:8824270, PMID:11825565, PMID:15920013, PMID:24593809). On inflamed endothelium, ICAM-2 acts sequentially with ICAM-1, JAM-A, and PECAM-1 to mediate neutrophil and T cell crawling and diapedesis, with genetic deficiency impairing leukocyte extravasation and increasing vascular permeability in vivo (PMID:20861356, PMID:24259506, PMID:24317296, PMID:10023766).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1989 High

    The discovery of ICAM-2 as a second LFA-1 ligand resolved why LFA-1-dependent adhesion persisted in the presence of saturating ICAM-1 blockade, establishing a new immunoglobulin superfamily member with two Ig-like domains.

    Evidence Functional cloning from COS cells with cell adhesion assays

    PMID:2497351

    Open questions at the time
    • No structural information on binding interface
    • Expression pattern across tissues not fully characterized
  2. 1991 High

    Characterization of ICAM-2 protein and a blocking monoclonal antibody established that ICAM-2 is constitutively expressed on endothelium and accounts for LFA-1-dependent adhesion to both resting and activated endothelium alongside ICAM-1.

    Evidence Monoclonal antibody CBR-IC2/2 blocking, immunoprecipitation, N-glycanase treatment, cell binding assays

    PMID:1676048

    Open questions at the time
    • Mac-1 binding not yet tested
    • Cytoplasmic interactions unknown
  3. 1995 High

    Identification of Mac-1 (CD11b/CD18) as a second integrin receptor for ICAM-2, binding through the CD11b A domain, broadened ICAM-2's role beyond LFA-1 to include myeloid cell interactions.

    Evidence Cell binding assays with purified CD11b/CD18, A-domain blocking

    PMID:7561061

    Open questions at the time
    • Relative affinity of Mac-1 vs. LFA-1 for ICAM-2 not quantified
    • In vivo relevance of Mac-1–ICAM-2 not yet demonstrated
  4. 1997 High

    The crystal structure of the ICAM-2 extracellular domain revealed a flat LFA-1 recognition surface on the GFC β-sheet of domain 1 with Glu-37 as the critical Mg²⁺-coordinating residue, providing the first atomic-level view of an ICAM–integrin interface.

    Evidence X-ray crystallography of ICAM-2 ectodomain, validated by subsequent site-directed mutagenesis

    PMID:10077629 PMID:9153399

    Open questions at the time
    • No co-crystal with LFA-1 I domain
    • Domain 2 contribution to binding unclear
  5. 1996 High

    Discovery that the ICAM-2 cytoplasmic tail binds α-actinin and ERM proteins linked this adhesion molecule to the actin cytoskeleton and revealed that ezrin-driven redistribution of ICAM-2 to uropods confers NK cell sensitivity.

    Evidence Affinity pulldown with cytoplasmic peptide, colocalization, ezrin transfection into NK-resistant targets with cytotoxicity assays

    PMID:8717043 PMID:8824270

    Open questions at the time
    • Relative contributions of α-actinin vs. ERM binding to cellular function not separated
    • Structural basis of cytoplasmic tail–ERM interaction not resolved
  6. 1998 High

    Quantitative biochemistry established the ezrin–ICAM-2 interaction (KD ~330 nM) and showed PtdIns(4,5)P₂ enhances this binding, identifying ICAM-2 as the first adhesion molecule with a PIP₂-regulated cytoskeletal linkage; in parallel, ICAM-2 was shown to co-stimulate T cells via LFA-1 and to mediate T cell transendothelial migration on ICAM-1-deficient endothelium.

    Evidence SPR, affinity precipitation, PIP₂ binding assays; T cell proliferation assays with transfected APCs; transendothelial migration using ICAM-1-KO endothelioma

    PMID:9122613 PMID:9705328 PMID:9808177

    Open questions at the time
    • Full structure of ERM–ICAM-2 complex not yet solved
    • Whether PIP₂ regulation occurs in vivo on endothelium not tested
  7. 1998 High

    Mapping of the ICAM-2 promoter identified Sp1, GATA, and Ets (Erg) binding sites as critical for endothelial-specific expression, establishing the transcriptional basis for constitutive ICAM-2 expression on vascular endothelium.

    Evidence Reporter gene assays, site-directed mutagenesis of promoter, EMSA with endothelial nuclear extracts

    PMID:9565596

    Open questions at the time
    • Chromatin-level regulation (histone marks, accessibility) not addressed
    • Whether the same elements drive expression in non-endothelial lineages unknown
  8. 1999 High

    TNF-α and IL-1β were shown to transcriptionally down-regulate ICAM-2 via reduction of Erg binding to promoter Ets sites, explaining how inflammation reciprocally regulates ICAM-1 (up) and ICAM-2 (down) on endothelium; separately, ICAM-2-deficient mice revealed a non-redundant role in eosinophil transmigration and megakaryopoiesis.

    Evidence Promoter mutagenesis, EMSA, Erg protein levels by Western blot; ICAM-2-KO mice with allergic lung inflammation model and bone marrow chimeras

    PMID:10023766 PMID:10223354 PMID:10574717

    Open questions at the time
    • Mechanism of Erg downregulation by TNF-α not elucidated
    • Megakaryopoiesis phenotype not mechanistically dissected
  9. 2002 High

    ICAM-2 was found to activate the PI3K/AKT survival pathway through ezrin phosphorylation, protecting B cells from apoptosis and establishing ICAM-2 as a signaling receptor, not merely a passive ligand; notably, ICAM-2 does not activate RhoA, distinguishing its signaling from ICAM-1.

    Evidence ICAM-2 clustering, phosphorylation cascades (ezrin/AKT/BAD/GSK3/FKHR), apoptosis protection assays; RhoA activity assays comparing ICAM-1 and ICAM-2 cross-linking

    PMID:11825565 PMID:12097408

    Open questions at the time
    • Direct kinase linking ezrin phosphorylation to PI3K recruitment unknown
    • Whether AKT signaling is relevant in endothelial context not shown
  10. 2005 High

    Genetic deletion demonstrated that endothelial ICAM-2 promotes angiogenesis through Rac-1 activation, supporting tube formation, migration, and cell survival — establishing a vascular morphogenesis function beyond leukocyte adhesion.

    Evidence ICAM-2-deficient mice and endothelial cells, in vitro and in vivo angiogenesis models, Rac GTPase activity assays

    PMID:15920013

    Open questions at the time
    • Upstream activator of Rac-1 downstream of ICAM-2 not identified
    • Whether homophilic ICAM-2 interaction is direct or indirect unclear
  11. 2008 High

    DC-SIGN was identified as a glycan-dependent receptor for ICAM-2 via Lewis Y epitopes, establishing ICAM-2 as a scaffold for dendritic cell rolling on endothelium; separately, ICAM-2 expression was shown to suppress neuroblastoma metastasis through α-actinin-mediated actin reorganization.

    Evidence DC-SIGN binding assays with glycosylation mutants, FUT1 siRNA, rolling assays under flow; co-IP and competitive peptide assays with in vivo metastasis model

    PMID:18155766 PMID:18978946

    Open questions at the time
    • Whether Lewis Y glycosylation of ICAM-2 varies by vascular bed in vivo unknown
    • Metastasis suppression mechanism beyond actin reorganization not defined
  12. 2010 High

    Systematic genetic dissection using single and double ICAM-1/ICAM-2 knockouts under physiological flow revealed that ICAM-2 specifically mediates leukocyte crawling and diapedesis (but not arrest) at the blood-brain barrier, acting sequentially with ICAM-1, JAM-A, and PECAM-1.

    Evidence Live imaging under flow with WT, ICAM-1-KO, ICAM-2-KO, and double-KO primary brain endothelial cells; intravital imaging in KO mice

    PMID:19211506 PMID:20861356 PMID:24259506

    Open questions at the time
    • Whether ICAM-2 signals to endothelial cells during crawling or only serves as a passive track unknown
    • Contribution at non-CNS vascular beds less well dissected
  13. 2014 High

    ICAM-2 was shown to regulate vascular barrier function through its cytoplasmic ERM-binding domain, activating Rac-1 to maintain N-cadherin junctions; deficiency increased thrombin-induced permeability in vivo, unifying its Rac-1 signaling role across angiogenesis and barrier maintenance.

    Evidence ICAM-2 domain mutants (ΔERM, ΔTAIL), constitutively active Rac-1 rescue, transendothelial resistance, intravital albumin extravasation in ICAM-2-KO mice

    PMID:24593809

    Open questions at the time
    • GEF linking ICAM-2/ERM to Rac-1 activation not identified
    • Relationship between barrier and angiogenesis phenotypes not integrated
  14. 2022 Medium

    METTL3-mediated m6A methylation of ICAM2 mRNA was identified as an epitranscriptomic regulatory mechanism, with ICAM-2 promoting RA fibroblast-like synoviocyte pathology through PI3K/AKT/p300 in a positive feedback loop.

    Evidence MeRIP, ChIP for p300 at METTL3 promoter, siRNA and overexpression, CIA mouse model

    PMID:36536495

    Open questions at the time
    • m6A regulation of ICAM2 not confirmed in endothelial or immune cell contexts
    • Whether m6A modification affects ICAM-2 protein level versus translation efficiency not resolved
    • Single-lab finding

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include: the identity of the GEF linking ICAM-2/ERM to Rac-1; whether ICAM-2 homophilic interactions are direct; the structural basis of the full radixin FERM–ICAM-2 cytoplasmic tail complex; and the physiological significance of differential glycosylation of ICAM-2 across cell types.
  • No co-crystal structure of ICAM-2 with LFA-1 or radixin FERM domain
  • GEF for ICAM-2-dependent Rac-1 activation unknown
  • In vivo relevance of differential glycosylation across vascular beds not tested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098631 cell adhesion mediator activity 6 GO:0048018 receptor ligand activity 4 GO:0060090 molecular adaptor activity 4
Localization
GO:0005886 plasma membrane 5 GO:0005829 cytosol 2
Pathway
R-HSA-168256 Immune System 7 R-HSA-1500931 Cell-Cell communication 5 R-HSA-162582 Signal Transduction 4 R-HSA-5357801 Programmed Cell Death 2
Partners
ACTN1CD209EZRICAM1ITGALITGAMMSNRDX

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1989 ICAM-2 was identified as a second ligand for the leukocyte integrin LFA-1 (CD11a/CD18). ICAM-2 is an integral membrane protein with two immunoglobulin-like domains, most closely related to the two N-terminal domains of ICAM-1 (34% identity), and supports LFA-1-dependent cell adhesion. Functional cloning using a novel ligand identification method; transfection of COS cells with ICAM-2 cDNA and cell adhesion assays Nature High 2497351
1991 ICAM-2 binds LFA-1; monoclonal antibody CBR-IC2/2 totally inhibits ICAM-2+ cell binding to purified LFA-1. ICAM-2 accounts for LFA-1-dependent adhesion to both stimulated and unstimulated endothelium together with ICAM-1. ICAM-2 has a peptide backbone of ~31 kDa (Mr ~60,000 as a broad glycosylated band), and is constitutively expressed on endothelium and hematopoietic cells with little inflammatory induction. Monoclonal antibody generation, immunoprecipitation, N-glycanase treatment, cell binding assays to purified LFA-1 The Journal of experimental medicine High 1676048
1995 ICAM-2 (CD102) binds to the leukocyte integrin CD11b/CD18 (Mac-1) through the CD11b A domain, in addition to its known interaction with CD11a/CD18 (LFA-1). Cell binding assays with purified CD11b/CD18; domain-specific blocking experiments using A-domain constructs Journal of immunology High 7561061
1997 Crystal structure of ICAM-2 extracellular region was solved. Glu-37 is critical for LFA-1 binding and is proposed to coordinate Mg2+ in the LFA-1 I domain. The LFA-1 recognition surface is relatively flat, lying on the GFC beta-sheet of domain 1, contrasting with loop-presented acidic residues in non-I-domain integrin ligands. A bend between domains 1 and 2 and N-linked glycan tripod arrangement may orient the recognition surface. X-ray crystallography of ICAM-2 extracellular domain Nature High 9153399
1999 Mutagenesis of ICAM-2 based on its crystal structure mapped the LFA-1 binding site to a diagonal ridge across the GFC beta-sheet including the CD edge of domain 1. Glu-37 ligates the Mg2+ in the LFA-1 I domain. The site is oblong and confined to the upper part of domain 1, distinct from the VCAM-1 binding surface for alpha4 integrins. Site-directed mutagenesis of ICAM-2 combined with cell adhesion assays and structural interpretation Proceedings of the National Academy of Sciences of the United States of America High 10077629
1996 ICAM-2 binds alpha-actinin through its cytoplasmic domain (residues 231-254, with optimal binding at amino acids 241-248). Alpha-actinin colocalized with ICAM-2 in endothelial cells. Multiple regions of alpha-actinin can mediate this interaction. Affinity pulldown using ICAM-2 cytoplasmic peptide as matrix from placental lysates, immunoblotting, 125I-labeled alpha-actinin binding, confocal microscopy colocalization, overlapping octapeptide competition, bacterially expressed alpha-actinin domain fusion proteins The Journal of biological chemistry High 8824270
1998 ERM proteins (ezrin/radixin/moesin) bind directly to a positively charged amino acid cluster in the juxta-membrane cytoplasmic domain of ICAM-2 (28 amino acids). This binding concentrates ICAM-2 at microvilli. Site-directed mutagenesis of these clusters abolishes ERM binding. GST fusion protein pulldown (in vitro binding), immunoprecipitation, chimeric E-cadherin construct expression in L fibroblasts, site-directed mutagenesis, colocalization by microscopy The Journal of cell biology High 9472040
1998 Ezrin interacts directly with ICAM-2 cytoplasmic tail with a KD of 3.3×10^-7 M. ICAM-2 colocalizes with ezrin in microvillar projections in transfected cells. Phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) enhances the ezrin–ICAM-2 interaction and binds to the ICAM-2 cytoplasmic tail, identifying ICAM-2 as the first adhesion protein shown to interact with PtdIns(4,5)P2. Affinity precipitation, microtiter binding assay, co-immunoprecipitation, surface plasmon resonance, PtdIns(4,5)P2 binding assays, confocal colocalization in transfected cells The Journal of biological chemistry High 9705328
1996 ICAM-2 redistribution to uropods (bud-like projections) by ezrin confers NK cell sensitivity to target cells. Ezrin transfection into NK-resistant cells induces uropod formation, redistributes ICAM-2 from uniform surface distribution to concentrated uropods, and sensitizes targets to IL-2-activated NK killing. Transfection of ezrin into NK-resistant cells, fluorescence imaging of ICAM-2/ezrin localization, NK cytotoxicity assays Nature High 8717043
2002 ICAM-2 activates the PI3K/AKT pathway. ICAM-2 induces tyrosine phosphorylation of ezrin and PI3K membrane translocation, leading to PtdIns(3,4,5)P3 production, PDK-1 and AKT activation, and phosphorylation of AKT substrates BAD, GSK3, and FKHR. ICAM-2 clustering protects primary human CD19+ B cells from TNFα- and Fas-mediated apoptosis. ICAM-2 engagement by LFA-1 on CD4+ T cells induces AKT activity in CD19+ cells in the absence of MHC-peptide interaction. Genetic screen, reporter assays, biochemical signaling assays (phosphorylation of ezrin, AKT, BAD, GSK3, FKHR), single-cell analysis of apoptosis, ICAM-2 clustering experiments Immunity High 11825565
2002 ICAM-1 cross-linking activates RhoA and induces stress fiber formation in endothelial cells, and stimulates c-fos and rhoA transcription, while ICAM-2 cross-linking does not activate RhoA or alter actin organization, demonstrating distinct downstream signaling despite both colocalizing with moesin in microvilli. Antibody cross-linking of ICAM-1 and ICAM-2 in HUVECs, RhoA activity assay, confocal microscopy, reporter gene assays for c-fos and rhoA transcription Journal of immunology High 12097408
2005 Endothelial ICAM-2 mediates angiogenesis. ICAM-2-deficient mice and cells show impaired angiogenesis in vitro and in vivo. ICAM-2 supports homophilic interaction involved in tube formation. ICAM-2-deficient cells show defective migration and increased apoptosis. ICAM-2 activates the small GTPase Rac, required for tube formation and migration. ICAM-2-deficient mice and endothelial cells, in vitro tube formation and migration assays, in vivo angiogenesis models, Rac GTPase activity assays, apoptosis assays Blood High 15920013
1993 A synthetic peptide from ICAM-2 spanning residues 21-42 of the first immunoglobulin domain binds specifically to purified CD11a/CD18 (LFA-1), inhibits adhesion of endothelial cells to LFA-1, and inhibits B lymphoblastoid cell binding to endothelial cells. Leukocytes bind this peptide when coated on plastic. Synthetic peptide binding assay to purified CD11a/CD18, cell adhesion inhibition assays The Journal of biological chemistry High 8349630
1995 An ICAM-2 peptide (residues 21-42) activates NK cell migration by 215% via CD11a/CD18 (LFA-1) ligation, induces F-actin polymerization at the leading edge of migratory NK cells, and increases phosphorylation of 150-kDa and 35-kDa proteins. Ligation of LFA-1 via ICAM-2 peptide transmits signals distinct from antibody cross-linking, triggering locomotion without necessarily triggering cytotoxicity. Boyden chamber migration assay, anti-CD11a antibody blocking, F-actin staining, phosphotyrosine immunoblotting The Journal of biological chemistry Medium 7721764
1999 ICAM-2 (and a peptide from its LFA-1 binding domain) activates leukocyte adhesion by increasing integrin affinity (inside-out signaling): soluble ICAM-2Fc induces T lymphocyte adhesion to immobilized ICAMs more potently than ICAM-1Fc or ICAM-3Fc, and stimulates binding of soluble recombinant ICAMs to T lymphocytes. The effect requires energy, divalent cations, temperature, and an intact cytoskeleton. T lymphocyte adhesion assays to immobilized purified ICAMs, flow cytometry for soluble ICAM binding, inhibitor studies (cytoskeletal, kinase inhibitors) Journal of immunology Medium 10352278
1998 The ICAM-2 promoter is endothelial cell-specific in vitro and in vivo. Critical Sp1 motif at -194 and eight-base pair palindrome at -268 each contribute ~70% of promoter activity. GATA motifs at -145 and -53 each contribute ~61-78%. The Ets family member Erg constitutively binds the ICAM-2 promoter in endothelial cells and transactivates it. Reporter gene assays, site-directed mutagenesis of promoter elements, gel shift (EMSA) with endothelial nuclear proteins, GATA-2 overexpression transactivation assay The Journal of biological chemistry High 9565596
1999 TNF-α and IL-1β down-regulate ICAM-2 expression on endothelium at the transcriptional level by reducing ICAM-2 mRNA to ~40% of control and decreasing ICAM-2 promoter activity. This correlates with loss of ICAM-2 protein from endothelial cell junctions. Flow cytometry, Northern blotting, ICAM-2 promoter reporter assay in HUVECs, immunocytochemistry Cell adhesion and communication Medium 10223354
1999 TNF-α-mediated down-regulation of ICAM-2 transcription involves three Ets binding sites (EBS) in the promoter. TNF-α decreases binding of nuclear proteins to the -135/-127 EBS. The Ets factor Erg constitutively transactivates the ICAM-2 promoter and is down-regulated by TNF-α, linking Erg to ICAM-2 transcriptional regulation. Site-directed mutagenesis of promoter Ets sites, EMSA, Erg cDNA transactivation assays in HeLa and HUVEC, Western blot for Erg protein, ex vivo artery model Journal of cell science High 10574717
2004 DC-SIGN binds ICAM-2 via a carbohydrate-dependent interaction. DC-SIGN mediates adhesion and rolling of dendritic cells on primary endothelial cells through the Lewis Y (Le^Y) glycan epitope expressed on ICAM-2. ICAM-2 expressed on CHO cells only serves as a DC-SIGN ligand when properly glycosylated, demonstrating ICAM-2 acts as a scaffold. The Le^Y-presenting enzyme FUT1 directs this endothelial expression; FUT1 silencing reduces DC rolling and adhesion. Recombinant soluble DC-SIGN binding assays, alanine-scanning mutagenesis of DC-SIGN, CHO cell expression of ICAM-2, FUT1 siRNA knockdown, rolling/adhesion assays under shear flow, glycan chip analysis Molecular immunology High 18155766
2004 Physiologic sialylation of platelet ICAM-2 (more acidic pI due to N-linked glycosylation) renders it ~50% less able to support LFA-1-dependent T cell adhesion compared to endothelial ICAM-2, and unable to support DC-SIGN-mediated dendritic cell adhesion. Neuraminidase treatment abolishes these functional differences. Isoelectric focusing of ICAM-2 from platelets vs. HUVECs, N-glycanase and neuraminidase treatment, T cell adhesion assays, DC adhesion assays Inflammation Medium 15673159
2014 ICAM-2 regulates endothelial barrier function and vascular permeability through a pathway involving N-cadherin, ERM proteins, and Rac-1 activation. The ERM-binding domain and cytoplasmic tail of ICAM-2 are required for junction formation and contact inhibition. Constitutively active Rac-1 restores barrier function in ICAM-2-deficient cells. In vivo, ICAM-2-deficient mice show increased thrombin-induced vascular permeability. ICAM-2 siRNA knockdown, ICAM-2-deficient endothelioma lines, re-expression of full-length and mutant ICAM-2 constructs (ΔERM, ΔTAIL), transendothelial electrical resistance measurement, constitutively active Rac-1 rescue, in vivo intravital fluorescence microscopy for albumin extravasation in mouse cremaster Cell communication and signaling High 24593809
1999 ICAM-2 deficiency in mice causes prolonged eosinophil accumulation in the lung interstitium during allergic inflammation, delayed transfer to airway lumen, and prolonged airway hyperresponsiveness. This phenotype is caused by lack of ICAM-2 on non-hematopoietic (endothelial) cells, and ICAM-2 deficiency on endothelium directly reduces eosinophil transmigration in vitro. ICAM-2 is also required for normal megakaryocyte progenitor numbers. ICAM-2-deficient mice (genetic KO), allergic lung inflammation model, histological analysis, bone marrow chimeras to identify non-hematopoietic requirement, in vitro transmigration assays, airway hyperresponsiveness measurement Immunity High 10023766
1998 Endothelial ICAM-1 and ICAM-2 are both essential for transendothelial migration of T cells. In ICAM-1-deficient endothelium, only ICAM-2 mediates residual T cell transmigration; PECAM-1, VCAM-1, and E-selectin are not involved in this process. ICAM-1-deficient endothelioma cells from ICAM-1 mutant mice, retroviral rescue with ICAM-1, antibody blocking of ICAM-2 and other candidates, in vitro transendothelial migration assay European journal of immunology High 9808177
2009 Endothelial ICAM-2, JAM-A, and PECAM-1 mediate neutrophil transmigration sequentially. In a stimulus-dependent manner (IL-1β but not TNF-α), when neutrophils lack TNF-α receptor signaling, their transmigration becomes dependent on endothelial ICAM-2, JAM-A, and PECAM-1 acting in sequence, as demonstrated by localization of arrested neutrophils in single KO mice for each molecule. TNF-receptor-deficient leukocyte transfer into WT and single KO mice (ICAM-2-/-, JAM-A-/-, PECAM-1-/-), fluorescence intravital microscopy, site-of-arrest analysis Blood High 19211506
2010 Endothelial ICAM-1 and VCAM-1 mediate shear-resistant T cell arrest, while endothelial ICAM-1 and ICAM-2 (but not VCAM-1) mediate T cell polarization and crawling at the BBB, establishing distinct and sequential roles. Endothelial ICAM-2 specifically contributes to the crawling step required for diapedesis. Live cell imaging under physiological flow; primary brain microvascular endothelial cells from WT, ICAM-1-deficient, ICAM-2-deficient, and ICAM-1/ICAM-2 double-deficient mice; analysis of T cell arrest, polarization, crawling, and diapedesis Journal of immunology High 20861356
2013 Beta-2 integrin-mediated neutrophil crawling on endothelial ICAM-1 and ICAM-2 is a prerequisite for transcellular neutrophil diapedesis across the inflamed BBB. LFA-1 primarily mediates shear-resistant arrest via ICAM-1, while Mac-1 dominates polarization. Both LFA-1 and Mac-1 mediate crawling via ICAM-1 and ICAM-2. Stationary (non-crawling) neutrophils cross exclusively via paracellular route. Live-cell imaging under flow; WT, CD11a-/-, CD11b-/-, CD18null neutrophils; WT, JAM-A-/-, ICAM-1null, ICAM-2-/-, ICAM-1null/ICAM-2-/- primary mouse BBB endothelial cells Journal of immunology High 24259506
2013 ICAM-2 is expressed both at EC junctions and on the EC body. Functional or genetic blockade of ICAM-2 reduces neutrophil crawling velocity, increases disrupted stop-start crawling, prolongs neutrophil interaction with EC junctions prior to TEM, and reduces overall extravasation in vivo. Some ICAM-2-dependent functions are mediated through Mac-1. Real-time in vivo confocal microscopy, ICAM-2-/- mice, functional antibody blockade, Mac-1 pharmacological inhibition, quantitative analysis of crawling parameters Journal of cell science High 24317296
2008 ICAM-2 forms a membrane-actin linkage with alpha-actinin and actin in neuroblastoma cells, as demonstrated by co-immunoprecipitation and competitive peptide assays. ICAM-2 expression limits neuroblastoma cell motility, redistributes actin, and suppresses disseminated metastatic tumors in vivo without affecting subcutaneous tumor growth. Co-immunoprecipitation, competitive peptide assays, in vitro migration assays, in vivo tail vein injection metastasis model, actin redistribution imaging, immunohistochemistry of primary tumors PloS one Medium 18978946
2014 The interaction of ICAM-2 with alpha-actinin via its cytoplasmic domain is critical for ICAM-2-mediated suppression of the metastatic phenotype in neuroblastoma cells in vivo. ICAM-2 variants with mutated alpha-actinin-binding domains fail to completely suppress disseminated tumor development in vivo, despite retaining some inhibitory effects in vitro, indicating both alpha-actinin-dependent and -independent mechanisms. In silico domain modeling, expression of ICAM-2 alpha-actinin-binding domain mutants, co-precipitation assays, cell adhesion and migration assays, colony formation assays, in vivo tumor dissemination model Oncogene Medium 24704826
2013 N-glycosylation of ICAM-2 at its six N-linked glycosylation sites is required for complete suppression of neuroblastoma metastatic potential in vivo. Hypo- or non-glycosylated ICAM-2 variants attenuate but do not abolish metastasis suppression. Site-directed mutagenesis of glycosylation sites (Asn-to-Ala), in vitro motility and colony growth assays, in vivo metastasis model BMC cancer Medium 23714211
2001 Crystals of the complex between the radixin FERM domain and the full-length cytoplasmic tail of ICAM-2 (28-residue peptide) were obtained and characterized, with data to 2.60 Å, establishing structural compatibility of the ERM-ICAM-2 cytoplasmic tail interaction. X-ray crystallography of radixin FERM domain – ICAM-2 cytoplasmic tail complex (crystal characterization paper) Acta crystallographica. Section D, Biological crystallography Medium 11375520
2008 ICAM-2 silencing by siRNA in oral squamous cell carcinoma cells enhances radiosensitivity and increases apoptosis via phosphorylation of AKT (Ser473) and activation of caspase-3. Conversely, ICAM-2 overexpression increases radioresistance, indicating ICAM-2 promotes cell survival through the AKT/caspase-3 pathway. siRNA knockdown and overexpression of ICAM-2, clonogenic radiosensitivity assay, flow cytometry for apoptosis, Western blot for phospho-AKT and caspase-3 British journal of cancer Medium 18349842
1998 ICAM-2 provides LFA-1-dependent co-stimulation to T cells beyond merely enhancing adhesion: ICAM-1 or ICAM-2 expression on fibroblast antigen-presenting cells increases T cell proliferation and, critically, enables a secondary allogeneic T cell response, indicating ICAM-2 delivers a co-stimulatory signal that prevents T cell anergy. ICAM-1 or ICAM-2 transfected fibroblasts as APCs, T cell proliferation (thymidine incorporation), primary/secondary allogeneic stimulation design, LFA-1 blocking antibody Scandinavian journal of immunology Medium 9122613
2023 ICAM-2 on leptomeningeal metastatic TNBC cells promotes blood-CSF barrier (BCB) adhesion, trans-BCB migration, and stemness via direct interaction with ICAM-1 on choroid plexus epithelial cells. Pull-down and antibody neutralization assays demonstrated ICAM2-ICAM1 interaction determines leptomeningeal metastasis specificity. Proteomic analysis, pull-down assay, antibody neutralization, in vivo spinal cord colonization model, siRNA knockdown Oncogene Medium 37620448
2022 ATT (artemisitene) inhibits ICAM2 expression via suppression of METTL3-mediated N6-methyladenosine (m6A) methylation of ICAM2 mRNA in RA fibroblast-like synoviocytes. ICAM2 acts as a promoter of RA-FLS proliferation, migration, and invasion through the PI3K/AKT/p300 pathway. p300 directly facilitates METTL3 transcription, forming a METTL3/ICAM2/PI3K/AKT/p300 feedback loop. RNA-seq, methylated RNA immunoprecipitation (MeRIP), chromatin immunoprecipitation (ChIP), plasmid/lentivirus overexpression, siRNA knockdown, Western blot, CIA mouse model Clinical and translational medicine Medium 36536495

Source papers

Stage 0 corpus · 87 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1989 Functional cloning of ICAM-2, a cell adhesion ligand for LFA-1 homologous to ICAM-1. Nature 855 2497351
1998 Ezrin/radixin/moesin (ERM) proteins bind to a positively charged amino acid cluster in the juxta-membrane cytoplasmic domain of CD44, CD43, and ICAM-2. The Journal of cell biology 519 9472040
1991 Characterization of ICAM-2 and evidence for a third counter-receptor for LFA-1. The Journal of experimental medicine 499 1676048
1998 Association of ezrin with intercellular adhesion molecule-1 and -2 (ICAM-1 and ICAM-2). Regulation by phosphatidylinositol 4, 5-bisphosphate. The Journal of biological chemistry 271 9705328
2010 Differential roles for endothelial ICAM-1, ICAM-2, and VCAM-1 in shear-resistant T cell arrest, polarization, and directed crawling on blood-brain barrier endothelium. Journal of immunology (Baltimore, Md. : 1950) 208 20861356
1996 ICAM-2 redistributed by ezrin as a target for killer cells. Nature 200 8717043
1993 Expression patterns of leukocyte adhesion ligand molecules on human liver endothelia. Lack of ELAM-1 and CD62 inducibility on sinusoidal endothelia and distinct distribution of VCAM-1, ICAM-1, ICAM-2, and LFA-3. The American journal of pathology 194 8434643
1994 Characterization of the function of intercellular adhesion molecule (ICAM)-3 and comparison with ICAM-1 and ICAM-2 in immune responses. The Journal of experimental medicine 155 7905020
2009 Endothelial cell activation leads to neutrophil transmigration as supported by the sequential roles of ICAM-2, JAM-A, and PECAM-1. Blood 153 19211506
1998 LFA-1 interaction with ICAM-1 and ICAM-2 regulates Th2 cytokine production. Journal of immunology (Baltimore, Md. : 1950) 148 9820482
2013 β2 integrin-mediated crawling on endothelial ICAM-1 and ICAM-2 is a prerequisite for transcellular neutrophil diapedesis across the inflamed blood-brain barrier. Journal of immunology (Baltimore, Md. : 1950) 147 24259506
2010 CXCL17 and ICAM2 are associated with a potential anti-tumor immune response in early intraepithelial stages of human pancreatic carcinogenesis. Gastroenterology 143 20955708
1994 Differential distribution of intercellular adhesion molecules (ICAM-1, ICAM-2, and ICAM-3) and the MS-1 antigen in normal and diseased human synovia. Their possible pathogenetic and clinical significance in rheumatoid arthritis. Arthritis and rheumatism 133 8129777
1998 T cell interaction with ICAM-1-deficient endothelium in vitro: essential role for ICAM-1 and ICAM-2 in transendothelial migration of T cells. European journal of immunology 132 9808177
2002 Intercellular adhesion molecule (ICAM)-1, but not ICAM-2, activates RhoA and stimulates c-fos and rhoA transcription in endothelial cells. Journal of immunology (Baltimore, Md. : 1950) 114 12097408
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2010 Comprehensive analysis of lymph node stroma-expressed Ig superfamily members reveals redundant and nonredundant roles for ICAM-1, ICAM-2, and VCAM-1 in lymphocyte homing. Blood 76 20395417
2000 Changed colonic profile of P-selectin, platelet-endothelial cell adhesion molecule-1 (PECAM-1), intercellular adhesion molecule-1 (ICAM-1), ICAM-2, and ICAM-3 in inflammatory bowel disease. Clinical and experimental immunology 75 10931137
2005 Endothelial intercellular adhesion molecule (ICAM)-2 regulates angiogenesis. Blood 74 15920013
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1997 Retinoic acid induces aggregation of the acute promyelocytic leukemia cell line NB-4 by utilization of LFA-1 and ICAM-2. Blood 73 9326242
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2020 Intercellular Adhesion Molecule-1 (ICAM-1) and ICAM-2 Differentially Contribute to Peripheral Activation and CNS Entry of Autoaggressive Th1 and Th17 Cells in Experimental Autoimmune Encephalomyelitis. Frontiers in immunology 50 31993059
2004 DC-SIGN binds to HIV-1 glycoprotein 120 in a distinct but overlapping fashion compared with ICAM-2 and ICAM-3. The Journal of biological chemistry 50 14970226
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