Affinage

CD99L2

CD99 antigen-like protein 2 · UniProt Q8TCZ2

Length
262 aa
Mass
28.0 kDa
Annotated
2026-04-28
17 papers in source corpus 14 papers cited in narrative 14 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CD99L2 is an X-linked type I transmembrane glycoprotein that functions as an adhesion and signaling molecule with cell-type-specific roles in leukocyte transendothelial migration, erythrocyte de-adhesion, and neuronal synapse development. In endothelial cells, CD99L2 mediates a discrete sequential step between PECAM-1 and CD99 during leukocyte diapedesis by recruiting the lateral border recycling compartment to transmigration sites, and its endothelial expression—rather than leukocyte expression—is required for neutrophil, monocyte, and T cell passage through the basement membrane (PMID:20479283, PMID:23293350, PMID:35914838). In neurons, CD99L2 promotes excitatory synapse development and neurite outgrowth while suppressing CREB/SRF-dependent immediate-early gene transcription from recycling endosomes, and it activates the protease CAPN1—with loss-of-function variants in CD99L2 causing X-linked spastic ataxia in humans (PMID:39808524, PMID:41690933). In primitive erythrocytes, CD99L2 is induced by Piezo1/shear stress signaling and anchors β-catenin at the plasma membrane to prevent Rap1-driven adhesion molecule expression, with its loss causing erythrocyte retention and hemolytic anemia (PMID:41915472).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2003 Medium

    Establishing CD99L2 as a distinct gene resolved whether the CD99 family had additional members, revealing an X-linked paralog with conserved functional regions and high neuronal expression.

    Evidence cDNA cloning, genomic organization, and in situ hybridization in mouse tissues

    PMID:12706889

    Open questions at the time
    • No functional data; expression pattern alone does not establish mechanism
    • Protein-level validation not shown
  2. 2007 Medium

    Demonstrating that CD99L2 mediates homophilic adhesion and that its blockade inhibits inflammation established it as a functional adhesion molecule relevant to leukocyte recruitment.

    Evidence L cell fibroblast transfection/aggregation assay and anti-CD99L2 antibody blockade in vivo

    PMID:18163232

    Open questions at the time
    • Single lab; homophilic versus heterophilic binding not fully distinguished
    • In vivo role could reflect indirect effects of antibody
  3. 2010 High

    Placing CD99L2 function at the endothelial basement membrane—independent of PECAM-1—resolved where in the multi-step extravasation cascade this molecule acts.

    Evidence Blocking antibodies combined with PECAM-1 KO, electron microscopy, and 3D confocal in murine cremaster and peritoneum models

    PMID:20479283

    Open questions at the time
    • Molecular mechanism of basement membrane traversal not identified
    • Whether CD99L2 cooperates with or acts redundantly to CD99 at this step unclear
  4. 2013 High

    Cell-type-specific conditional deletion proved that endothelial—not leukocyte—CD99L2 is the functional pool for extravasation, overturning the homophilic adhesion model, while discovery of CD99–CD99L2 heterodimerization via cytoplasmic domains explained how CD99L2 surface levels are regulated.

    Evidence Endothelial- and myeloid-specific Cre KO mice in multiple inflammation models; BiFC, co-IP, FRET, and cytoplasmic domain mutant rescue in CD99-deficient primary cells

    PMID:23293350 PMID:24133166

    Open questions at the time
    • Structural basis of cytoplasmic domain interaction unknown
    • Whether heterodimer has signaling functions beyond trafficking not tested
  5. 2015 High

    An independent global CD99L2 KO confirmed the extravasation phenotype with quantified reduction in both neutrophil and monocyte recruitment, strengthening confidence in the non-redundant role.

    Evidence Global CD99L2 knockout mice in thioglycollate peritonitis model with flow cytometry

    PMID:26321243

    Open questions at the time
    • Mechanism downstream of CD99L2 engagement still unresolved
    • Lymphocyte-specific requirements not tested in this model
  6. 2018 High

    Extension to the blood–brain barrier showed CD99L2 controls leukocyte entry into the CNS during neuroinflammation, with 3D imaging confirming the same basement-membrane trapping phenotype observed peripherally.

    Evidence Tie-2-Cre conditional KO mice in EAE model with 3D confocal and electron microscopy

    PMID:29791026

    Open questions at the time
    • Whether CD99L2 has additional barrier-specific functions beyond diapedesis not addressed
    • BBB integrity in the absence of inflammation not assessed
  7. 2022 High

    Translation to the human system established that CD99L2 recruits the lateral border recycling compartment and defined its precise sequential position between PECAM and CD99 during transendothelial migration.

    Evidence Antibody blockade and siRNA knockdown with LBRC recruitment assay on primary human endothelial cells and leukocytes

    PMID:35914838

    Open questions at the time
    • Molecular mechanism by which CD99L2 recruits the LBRC is unknown
    • Signaling events coupling CD99L2 engagement to LBRC mobilization not identified
  8. 2025 High

    Discovery of neuronal functions—promoting excitatory synapse development and suppressing CREB/SRF-driven immediate-early gene transcription from recycling endosomes—revealed a cell-autonomous signaling role entirely distinct from the endothelial adhesion function.

    Evidence CD99L2 KO mice with electrophysiology, live imaging of recycling endosome trafficking, luciferase reporter assays, and behavioral phenotyping

    PMID:39808524

    Open questions at the time
    • Signaling intermediates between CD99L2 and CREB/SRF not identified
    • Whether recycling endosome localization is required for transcriptional regulation not formally tested
  9. 2026 Medium

    Identification of CD99L2 as a CAPN1 activator and of loss-of-function variants causing X-linked spastic ataxia established a direct disease mechanism and linked the neuronal phenotype to a specific protease pathway.

    Evidence Exome/genome sequencing in patient families, domain-deletion constructs with localization and co-IP, transcriptome analysis in patient fibroblasts

    PMID:41690933

    Open questions at the time
    • Interaction methodology for CAPN1 not fully detailed; awaits independent validation
    • Mechanism by which CD99L2 activates CAPN1 unknown
    • Whether CAPN1 activation accounts for synaptic phenotypes not directly tested
  10. 2026 High

    The erythrocyte pathway—Piezo1/shear stress → CD99L2 induction → β-catenin membrane anchoring → suppression of Rap1/adhesion—revealed a mechanosensitive de-adhesion function with loss causing hemolytic anemia.

    Evidence Zebrafish and mouse loss-of-function models, co-IP for β-catenin binding, β-catenin localization imaging, Piezo1 signaling manipulation

    PMID:41915472

    Open questions at the time
    • Direct structural basis of CD99L2–β-catenin interaction not resolved
    • Whether this pathway operates in definitive erythropoiesis not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis for CD99L2's diverse protein interactions (CD99, CAPN1, β-catenin), the signaling mechanism linking CD99L2 to LBRC recruitment during diapedesis, and how the same transmembrane protein exerts distinct functions across endothelial, neuronal, and erythroid contexts.
  • No structural model of CD99L2 or its complexes
  • Signal transduction downstream of CD99L2 engagement at endothelial junctions remains unmapped
  • Cell-type-specific regulatory mechanisms (transcriptional, post-translational) not systematically defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098631 cell adhesion mediator activity 5 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 4 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-168256 Immune System 5 R-HSA-1500931 Cell-Cell communication 3 R-HSA-112316 Neuronal System 2 R-HSA-162582 Signal Transduction 2
Partners
CAPN1CD99CTNNB1PECAM1

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 CD99L2 was identified as a novel paralog of CD99, encoded on the X chromosome, and expressed ubiquitously with particularly high levels in neuronal cells as determined by in situ hybridization. Five putative functional regions were found to be highly conserved between CD99L2 and CD99 by amino acid sequence alignment. cDNA cloning, genomic organization analysis, in situ hybridization, comparative sequence analysis Gene Medium 12706889
2007 CD99L2 is expressed at cell borders of transfected cells and on mouse leukocytes and vascular endothelial cells. Transfection of L cell fibroblasts with CD99L2 conferred homophilic cell adhesion in a divalent cation-dependent manner, and anti-CD99L2 antibody blocked neutrophil and monocyte influx into sites of inflammation in vivo. Transfection of L cell fibroblasts, cell aggregation assay, antibody blockade in vivo inflammation model Cell communication & adhesion Medium 18163232
2010 CD99 and CD99L2 act independently of PECAM-1 during leukocyte extravasation. Blocking CD99 or CD99L2 trapped neutrophils between endothelial cells and the underlying basement membrane in vivo, indicating that both molecules are required for leukocytes to overcome the endothelial basement membrane. CD99 and CD99L2 also cooperate independently of PECAM-1 in TNF-α-stimulated cremaster models. Blocking antibodies, PECAM-1 gene disruption, electron microscopy, 3D confocal fluorescence microscopy, in vivo cremaster and peritoneum inflammation models Blood High 20479283
2013 CD99L2 expression on endothelial cells (but not on myeloid cells) is required for neutrophil extravasation into inflamed tissues. Endothelial-specific conditional gene ablation of CD99L2 impaired neutrophil recruitment into inflamed cremaster and peritoneum and also impaired activated T cell recruitment into inflamed skin, demonstrating that CD99L2 functions as an endothelial molecule and does not require homophilic interaction with leukocyte-expressed CD99L2. Conditional gene-deficient mice (endothelial- and myeloid-specific Cre drivers), in vivo inflammation models (cremaster, peritoneum, skin) Journal of immunology High 23293350
2013 Mouse CD99 physically interacts with CD99L2 through their cytoplasmic domains, forming heterodimers that are more efficiently localized at the plasma membrane than homodimers. CD99 promotes trafficking of CD99L2 to the plasma membrane; surface levels of CD99L2 were markedly reduced on thymocytes, splenic leukocytes, and CTL lines from CD99-deficient mice, and were rescued by reintroduction of wild-type but not cytoplasmic-domain-mutant CD99. Bimolecular fluorescence complementation, co-immunoprecipitation, FRET assay, flow cytometry, CD99-deficient mice, exogenous rescue with cytoplasmic domain mutants Journal of immunology High 24133166
2013 shRNA-mediated knockdown of mCD99L2 in murine B lymphoma (A20) cells resulted in decreased proliferation, G2 phase prolongation, altered morphology, and upregulation of NF-κB pathway activity, suggesting CD99L2 expression is linked to NF-κB signaling in B lymphoma cells. shRNA knockdown, MTT assay, flow cytometry, western blot, antibody arrays, NF-κB pathway analysis Oncology reports Low 23338758
2015 CD99L2-knockout mice show greater than 80% reduction in neutrophil infiltration and near-complete block in monocyte emigration in the thioglycollate peritonitis model. CD99L2 deficiency did not affect circulating leukocyte numbers or expression of ICAM-1, PECAM-1, or CD99 on endothelial cells. Global CD99L2 knockout mice, thioglycollate peritonitis model, flow cytometry, immunohistochemistry Experimental and molecular pathology High 26321243
2018 Tie-2-Cre conditional deletion of CD99L2 inhibits leukocyte entry into the CNS during EAE, reducing perivascular cuffs, inflammatory foci, demyelination, and pro-inflammatory cytokine expression. 3D analysis revealed accumulation of leukocytes between endothelial cells and the basement membrane, with unaffected luminal docking, indicating CD99L2 mediates leukocyte diapedesis through the endothelial basement membrane at the blood-brain barrier. Conditional Tie-2-Cre knockout mice, EAE model, 3D confocal analysis of vibratome sections, electron microscopy Journal of leukocyte biology High 29791026
2022 Human CD99L2 is constitutively expressed at endothelial cell borders and on leukocyte surfaces. Antibody blockade or genetic knockdown of CD99L2 significantly reduces transmigration of human neutrophils and monocytes across endothelial cells. CD99L2 acts at a specific, sequential step between PECAM and CD99 in transendothelial migration and promotes TEM by recruiting the lateral border recycling compartment (LBRC) to sites of TEM, specifically downstream of PECAM initiation. Antibody blockade, siRNA knockdown, in vitro transmigration assay with primary human cells, LBRC recruitment assay Journal of immunology High 35914838
2022 cd99l2 knockout in zebrafish (via TALEN) reduces recruitment of granulocytes and macrophages to wound sites. Expression of mfap4 was reduced in cd99l2 mutants, potentially contributing to impaired macrophage migration. Neutrophils and macrophages still used interstitial migration to reach wounds, implicating cd99l2 in leukocyte interstitial migration. TALEN-mediated knockout in zebrafish, caudal fin wounding assay, transgenic fluorescent reporter lines, RNA-seq Yi chuan = Hereditas Medium 36384956
2023 Porphyromonas gingivalis gingipains downregulate CD99 and CD99L2 expression on endothelial cells and leukocytes through inhibition of the PI3K/Akt pathway, impairing monocyte transendothelial migration despite promoting monocyte adhesion. In vitro endothelial cell infection assay, TEM assay, western blot, PI3K/Akt pathway inhibitor studies, in vivo mouse model Microbiology spectrum Medium 37199607
2025 CD99L2 is expressed primarily in neurons and positively regulates neurite outgrowth and excitatory synapse development. CD99L2 inversely regulates immediate-early genes (Arc, Egr1, c-Fos) by inhibiting CREB and SRF transcription factor activity. Neuronal inactivation increases transport of CD99L2 to the cell surface from recycling endosomes. CD99L2 knockout mice exhibit impaired excitatory synaptic transmission and plasticity in the hippocampus, and deficits in spatial memory and contextual fear conditioning. CD99L2 KO mice, live imaging of recycling endosome trafficking, luciferase reporter assays (CREB/SRF activity), electrophysiology, behavioral tests, neurite outgrowth assays Cell reports High 39808524
2026 CD99L2 serves as an activating interactor of the calcium-dependent protease CAPN1. CD99L2 mainly exists in a ubiquitinated form. Ablation of cytoplasmic or extracellular domains of CD99L2 leads to intracellular mislocalization and abrogation of the CD99L2–CAPN1 interaction. Loss-of-function variants in CD99L2 cause X-linked spastic ataxia in humans, with transcriptome analysis in patient fibroblasts revealing synaptic function-specific disturbances. Exome/genome sequencing (patient cohort), cellular interaction studies (co-IP implied), domain deletion constructs with localization assay, transcriptome analysis in patient fibroblasts Nature communications Medium 41690933
2026 CD99L2 is transiently induced in primitive erythrocytes by shear stress-activated Piezo1 signaling. CD99L2 binds and anchors β-catenin at the plasma membrane, preventing its nuclear translocation. Loss of CD99L2 leads to aberrant nuclear translocation of β-catenin, activation of Rap1 signaling, and persistent adhesion molecule expression, causing erythrocyte retention and hemolytic anemia. This pathway is conserved in mice and modulated by biomechanical forces. Zebrafish and mouse models, Piezo1 signaling manipulation, co-immunoprecipitation/binding assays for β-catenin, β-catenin localization imaging, Rap1 signaling assays, loss-of-function models Cell reports High 41915472

Source papers

Stage 0 corpus · 17 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 CD99 and CD99L2 act at the same site as, but independently of, PECAM-1 during leukocyte diapedesis. Blood 70 20479283
2003 Cloning, genomic organization, alternative transcripts and expression analysis of CD99L2, a novel paralog of human CD99, and identification of evolutionary conserved motifs. Gene 51 12706889
2007 The murine CD99-related molecule CD99-like 2 (CD99L2) is an adhesion molecule involved in the inflammatory response. Cell communication & adhesion 41 18163232
2012 Immune function genes CD99L2, JARID2 and TPO show association with autism spectrum disorder. Molecular autism 34 22681640
2013 Cutting edge: Endothelial-specific gene ablation of CD99L2 impairs leukocyte extravasation in vivo. Journal of immunology (Baltimore, Md. : 1950) 26 23293350
2023 Porphyromonas gingivalis Gingipains Destroy the Vascular Barrier and Reduce CD99 and CD99L2 Expression To Regulate Transendothelial Migration. Microbiology spectrum 13 37199607
2018 CD99L2 deficiency inhibits leukocyte entry into the central nervous system and ameliorates neuroinflammation. Journal of leukocyte biology 11 29791026
2013 Interaction of CD99 with its paralog CD99L2 positively regulates CD99L2 trafficking to cell surfaces. Journal of immunology (Baltimore, Md. : 1950) 11 24133166
2015 CD99-like 2 (CD99L2)-deficient mice are defective in the acute inflammatory response. Experimental and molecular pathology 7 26321243
2013 Effect of shRNA targeting mouse CD99L2 gene in a murine B cell lymphoma in vitro and in vivo. Oncology reports 6 23338758
2022 Human CD99L2 Regulates a Unique Step in Leukocyte Transmigration. Journal of immunology (Baltimore, Md. : 1950) 4 35914838
2025 Cd99l2 regulates excitatory synapse development and restrains immediate-early gene activation. Cell reports 3 39808524
2026 Loss of CD99L2 Contributed to Temozolomide Resistance and Glioblastoma Tumorigenesis Based on Genome-scale CRISPR/Cas9 Screening. Current pharmaceutical design 0 40692150
2026 Loss-of-function variants in the CAPN1 activator CD99L2 cause X-linked spastic ataxia. Nature communications 0 41690933
2026 Shear stress-induced Piezo1 activates CD99L2 to facilitate the initiation of blood circulation. Cell reports 0 41915472
2022 The role of the cd99l2 gene on leukocyte interstitial migration in zebrafish. Yi chuan = Hereditas 0 36384956
2010 [Preparation of RNA probe for cd99l2 gene of zebrafish labeled with digoxingenin-UTP]. Nan fang yi ke da xue xue bao = Journal of Southern Medical University 0 20501370