Affinage

CD99L2

CD99 antigen-like protein 2 · UniProt Q8TCZ2

Length
262 aa
Mass
28.0 kDa
Annotated
2026-06-09
17 papers in source corpus 14 papers cited in narrative 14 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CD99L2 is a type I transmembrane glycoprotein and homophilic, divalent-cation-dependent cell-cell adhesion molecule that functions across vascular, neuronal, and erythroid contexts (PMID:18163232). Its best-characterized role is in leukocyte extravasation: endothelial CD99L2 — not the leukocyte pool — is the critical functional protein required for neutrophil, monocyte, and T cell diapedesis, acting specifically at the step of crossing the endothelial basement membrane such that its blockade traps leukocytes between endothelial cells and the basement membrane (PMID:20479283, PMID:23293350, PMID:26321243, PMID:29791026). In human transendothelial migration it operates as a sequential gateway downstream of PECAM and upstream of CD99, promoting transmigration by recruiting the lateral border recycling compartment to migration sites (PMID:35914838). CD99L2 heterodimerizes with its paralog CD99 in a manner dependent on the CD99 cytoplasmic domain, and this interaction promotes CD99L2 trafficking to the plasma membrane (PMID:24133166). In neurons, CD99L2 promotes neurite outgrowth and excitatory synapse development, traffics to the surface from recycling endosomes upon neuronal inactivation, and inversely regulates immediate-early gene expression by inhibiting CREB and SRF activity, with knockout mice showing impaired hippocampal plasticity and memory deficits (PMID:39808524). In erythroid development it is a mechanoresponsive regulator induced by shear-stress-activated Piezo1 signaling that anchors β-catenin at the plasma membrane to restrain its nuclear translocation and Rap1 activation, enabling erythrocyte de-adhesion and maturation (PMID:41915472). CD99L2 also physically interacts with and activates the calcium-dependent protease CAPN1, and loss-of-function variants in CD99L2 cause X-linked spastic ataxia (PMID:41690933).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2003 Medium

    Established the molecular identity of CD99L2 as an X-linked CD99 paralog, framing it as a candidate adhesion molecule before any function was tested.

    Evidence cDNA cloning, genomic organization, comparative sequence alignment and in situ hybridization

    PMID:12706889

    Open questions at the time
    • No functional assay of the conserved motifs
    • Surface adhesion behavior not yet tested
  2. 2007 Medium

    Demonstrated CD99L2 is a functional adhesion molecule, answering whether the CD99 paralog had adhesive activity, and linked it to inflammatory leukocyte recruitment.

    Evidence Homophilic aggregation assay in transfected L cell fibroblasts plus in vivo blocking antibody inflammation model

    PMID:18163232

    Open questions at the time
    • Did not localize the step of extravasation affected
    • Did not distinguish endothelial vs leukocyte CD99L2
  3. 2010 High

    Positioned CD99/CD99L2 in the diapedesis cascade by showing they act independently of and downstream of PECAM-1, with blockade trapping neutrophils at the basement membrane.

    Evidence Blocking antibodies, PECAM-1 gene disruption, electron microscopy and 3D confocal imaging in inflamed cremaster tissue

    PMID:20479283

    Open questions at the time
    • Did not resolve which cell type's CD99L2 is required
    • Molecular mechanism of basement membrane crossing unknown
  4. 2013 High

    Resolved that endothelial, not myeloid, CD99L2 is the functional pool for leukocyte recruitment, settling the cell-of-origin question.

    Evidence Endothelial- and myeloid-specific conditional knockout mice across cremaster, peritoneum and skin inflammation models

    PMID:23293350

    Open questions at the time
    • Did not define molecular partners at the basement membrane step
  5. 2013 High

    Defined the CD99-CD99L2 physical interaction and its consequence, showing CD99 heterodimerizes with CD99L2 via its cytoplasmic domain to drive CD99L2 surface trafficking.

    Evidence BiFC, co-immunoprecipitation, FRET, cytoplasmic domain mutagenesis, and rescue of surface CD99L2 in CD99-deficient cells

    PMID:24133166

    Open questions at the time
    • Trafficking machinery downstream of CD99 binding not identified
    • Stoichiometry in vivo not determined
  6. 2013 Low

    Probed CD99L2 in a B lymphoma context, linking its downregulation to altered proliferation, Hodgkin/Reed-Sternberg-like phenotype and NF-κB activation.

    Evidence shRNA knockdown in murine A20 cells with flow cytometry, MTT, western blot, antibody arrays and in vivo tumor assay

    PMID:23338758

    Open questions at the time
    • NF-κB involvement is correlative (western blot only)
    • No direct mechanistic dissection
    • Single lab, not independently confirmed
  7. 2015 High

    Confirmed the magnitude of the extravasation defect with a second knockout line and excluded indirect effects on circulating leukocytes or other endothelial adhesion molecules.

    Evidence CD99L2 knockout mouse thioglycollate peritonitis model with leukocyte counts and flow cytometry for ICAM-1, PECAM, CD99

    PMID:26321243

    Open questions at the time
    • Mechanism of basement-membrane-specific block still undefined
  8. 2018 High

    Extended the diapedesis role to the blood-brain barrier, showing endothelial CD99L2 is required for leukocyte entry into the CNS during neuroinflammation at the basement membrane step.

    Evidence Tie-2-Cre endothelial conditional knockout in the EAE model with 3D vibratome confocal imaging and histopathology

    PMID:29791026

    Open questions at the time
    • Did not identify the basement membrane binding partner
    • Luminal docking explicitly unaffected, leaving the molecular trigger of crossing open
  9. 2022 High

    Placed human CD99L2 precisely in the TEM cascade between PECAM and CD99 and identified its mechanism as LBRC recruitment downstream of PECAM initiation.

    Evidence Antibody blockade and genetic knockdown in primary human endothelial cells with TEM assays and LBRC recruitment analysis

    PMID:35914838

    Open questions at the time
    • Molecular link between CD99L2 and LBRC trafficking machinery unresolved
  10. 2022 Medium

    Showed a conserved CD99L2 role in interstitial leukocyte migration beyond extravasation using a non-mammalian system.

    Evidence TALEN cd99l2 knockout in zebrafish with caudal fin injury, fluorescent reporter lines, RNA-seq and mfap4 analysis

    PMID:36384956

    Open questions at the time
    • Single lab, one publication
    • Mechanism of interstitial migration defect not dissected
  11. 2023 Medium

    Identified a pathogen-driven regulatory input, showing P. gingivalis gingipains suppress CD99/CD99L2 via the PI3K/Akt pathway to impair monocyte TEM.

    Evidence In vitro gingipain stimulation, in vivo infection, TEM assay, PI3K/Akt inhibitor analysis and flow cytometry

    PMID:37199607

    Open questions at the time
    • PI3K pathway involvement is pharmacological without direct mechanistic dissection of CD99L2 regulation
  12. 2025 High

    Revealed a distinct neuronal function, showing CD99L2 promotes synapse development and inversely controls immediate-early gene expression via CREB/SRF inhibition, with behavioral consequences.

    Evidence CD99L2 knockout mice with neurite/synapse assays, electrophysiology, immediate-early gene and CREB/SRF activity assays, recycling-endosome trafficking imaging and behavioral tests

    PMID:39808524

    Open questions at the time
    • Direct molecular link from membrane CD99L2 to CREB/SRF not defined
    • Neuronal adhesion partner not identified
  13. 2026 High

    Connected CD99L2 to mechanotransduction and Wnt signaling, showing Piezo1-induced CD99L2 anchors β-catenin at the membrane to enable erythrocyte de-adhesion and prevent hemolytic anemia.

    Evidence Zebrafish and mouse knockouts, Piezo1 activation, co-IP for CD99L2-β-catenin, β-catenin nuclear translocation and Rap1 signaling analysis

    PMID:41915472

    Open questions at the time
    • Structural basis of CD99L2-β-catenin binding unknown
    • How the same protein anchors β-catenin across cell types not unified
  14. 2026 High

    Identified CD99L2 as a CAPN1 activator and the cause of X-linked spastic ataxia, linking domain requirements, ubiquitination, and a Mendelian disease.

    Evidence Patient exome/genome sequencing, domain-deletion mutant localization studies, co-IP for CD99L2-CAPN1, ubiquitination and patient fibroblast transcriptome analysis

    PMID:41690933

    Open questions at the time
    • How CD99L2 activates CAPN1 enzymatically not resolved
    • Role of CD99L2 ubiquitination in function unclear
    • Substrates downstream of CAPN1 activation not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unknown how a single adhesion molecule mechanistically reconciles its diverse roles — basement-membrane crossing, LBRC recruitment, β-catenin anchoring, CREB/SRF control, and CAPN1 activation — and whether a unifying biochemical activity underlies them.
  • No structural model of CD99L2
  • Direct extracellular ligand at the basement membrane unidentified
  • Mechanism connecting surface adhesion to intracellular signaling outputs unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 2 GO:0098772 molecular function regulator activity 2 GO:0098631 cell adhesion mediator activity 1
Localization
GO:0005886 plasma membrane 3 GO:0005768 endosome 1
Pathway
R-HSA-168256 Immune System 5 R-HSA-112316 Neuronal System 1 R-HSA-162582 Signal Transduction 1 R-HSA-1643685 Disease 1
Partners
CAPN1CD99CTNNB1

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 CD99L2 is a paralog of CD99 encoded on the X chromosome, with alternative splicing generating species-specific transcript variants; amino acid sequence alignment identified five conserved functional regions between CD99L2 and CD99, indicating close evolutionary relationship from a common ancestor gene. cDNA cloning, genomic organization analysis, comparative sequence alignment, alternative splicing analysis, in situ hybridization Gene Medium 12706889
2007 CD99L2 mediates homophilic cell-cell adhesion in a divalent cation-dependent manner; transfection of L cell fibroblasts with CD99L2 conferred homophilic aggregation ability, and anti-CD99L2 antibody blocked neutrophil and monocyte influx into sites of inflammation in vivo. Cell transfection, homophilic aggregation assay, in vivo inflammation model with blocking antibodies Cell communication & adhesion Medium 18163232
2010 CD99 and CD99L2 act independently of PECAM-1 during leukocyte extravasation; blocking CD99 or CD99L2 in vivo traps neutrophils between endothelial cells and the underlying basement membrane, and CD99/CD99L2 are required even when the need for PECAM-1 is bypassed by TNF-alpha stimulation. Blocking antibodies in vitro and in vivo, PECAM-1 gene disruption, electron microscopy, 3D confocal fluorescence microscopy in inflamed cremaster tissue Blood High 20479283
2013 Endothelial-specific (but not myeloid-specific) gene ablation of CD99L2 impairs neutrophil extravasation in vivo, demonstrating that CD99L2 on endothelial cells, not on leukocytes themselves, is the critical functional pool for neutrophil recruitment; T cell recruitment into inflamed skin was also impaired by endothelial CD99L2 deletion. Conditional gene-deficient mice (endothelial-specific and myeloid-specific), multiple in vivo inflammation models (cremaster, peritoneum, skin) Journal of immunology (Baltimore, Md. : 1950) High 23293350
2013 Mouse CD99 physically interacts with CD99L2 forming heterodimers; this interaction is dependent on the cytoplasmic domain of CD99, and heterodimers are more efficiently localized to the plasma membrane than homodimers, thereby positively regulating CD99L2 trafficking to cell surfaces. Bimolecular fluorescence complementation (BiFC), co-immunoprecipitation, FRET assays, cytoplasmic domain mutant analysis, analysis of endogenous CD99L2 surface levels in CD99-deficient cells and rescue by exogenous wild-type CD99 Journal of immunology (Baltimore, Md. : 1950) High 24133166
2013 Knockdown of CD99L2 in murine B lymphoma (A20) cells results in G2 phase prolongation, reduced proliferative ability, H/RS-cell-like morphology, increased CD30 and CD15 expression, and upregulation of cytokines; NF-κB pathway activation is associated with mCD99L2 downregulation. shRNA knockdown, flow cytometry, MTT assay, western blot, antibody arrays, in vivo tumor growth assay Oncology reports Low 23338758
2015 CD99L2 knockout mice have a greater than 80% block in neutrophil infiltration and near-complete block in monocyte emigration in the thioglycollate peritonitis model; CD99L2 deficiency did not affect circulating leukocyte subset numbers, nor expression of ICAM-1, PECAM, or CD99 on endothelial cells. CD99L2 knockout mouse, thioglycollate peritonitis model, leukocyte counts, flow cytometry for endothelial adhesion molecule expression Experimental and molecular pathology High 26321243
2018 Tie-2-Cre-driven endothelial deletion of CD99L2 inhibits leukocyte entry into the CNS during EAE by blocking diapedesis through the endothelial basement membrane of BBB vessels, with accumulation of leukocytes between endothelial cells and the basement membrane, while luminal leukocyte docking was unaffected. Conditional knockout (Tie-2-Cre), EAE model (MOG35-55 immunization), 3D vibratome confocal microscopy, histopathological analysis of demyelination and inflammatory foci Journal of leukocyte biology High 29791026
2022 Human CD99L2 is constitutively expressed at endothelial cell borders and on leukocytes, and regulates a specific sequential step of transendothelial migration between PECAM and CD99; it promotes transmigration by recruiting the lateral border recycling compartment (LBRC) to TEM sites specifically downstream of PECAM initiation. Antibody blockade of human CD99L2, genetic knockdown in primary human endothelial cells, in vitro TEM assays with primary human neutrophils and monocytes, LBRC recruitment analysis Journal of immunology (Baltimore, Md. : 1950) High 35914838
2022 cd99l2 knockout in zebrafish (TALEN-mediated) reduces recruitment of granulocytes and macrophages to wound sites after caudal fin damage, and decreases expression of mfap4 (a macrophage marker), indicating a role for CD99L2 in leukocyte interstitial migration in addition to extravasation. TALEN knockout in zebrafish, caudal fin injury model, transgenic fluorescent reporter lines, RNA-seq, mfap4 expression analysis Yi chuan = Hereditas Medium 36384956
2023 P. gingivalis gingipains downregulate CD99 and CD99L2 expression on endothelial cells and leukocytes through inhibition of the PI3K/Akt pathway, impairing monocyte transendothelial migration while promoting monocyte adhesion. In vitro gingipain stimulation, in vivo mouse infection model, TEM assay, PI3K/Akt pathway inhibitor analysis, flow cytometry for CD99/CD99L2 surface expression Microbiology spectrum Medium 37199607
2025 CD99L2 positively regulates neurite outgrowth and excitatory synapse development in neurons; it inversely regulates immediate-early gene expression (Arc, Egr1, c-Fos) by inhibiting CREB and SRF transcription factor activity; neuronal inactivation promotes CD99L2 transport 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 knockout mice, neurite outgrowth assays, synaptic transmission electrophysiology, immediate-early gene expression analysis, CREB/SRF activity assays, live-cell imaging of CD99L2 trafficking from recycling endosomes, behavioral tests Cell reports High 39808524
2026 CD99L2 is a mechanoresponsive adhesion regulator transiently induced in primitive erythrocytes by shear stress-activated Piezo1 signaling; CD99L2 binds and anchors β-catenin at the plasma membrane, and its loss leads to nuclear translocation of β-catenin, Rap1 signaling activation, persistent adhesion molecule expression, erythrocyte retention, impaired maturation, and hemolytic anemia. Zebrafish and mouse models, CD99L2 knockout, Piezo1 activation experiments, co-immunoprecipitation for CD99L2-β-catenin interaction, β-catenin nuclear translocation assays, Rap1 signaling analysis Cell reports High 41915472
2026 CD99L2 protein occurs mainly in a ubiquitinated form and physically interacts with and activates the calcium-dependent protease CAPN1; ablation of cytoplasmic or extracellular domains of CD99L2 leads to intracellular mislocalization and loss of CAPN1 interaction; loss-of-function variants in CD99L2 cause X-linked spastic ataxia, with transcriptome analysis in patient fibroblasts revealing synaptic function-specific disturbances. Exome/genome sequencing in patient cohort, cellular studies of CD99L2 domain-deletion mutants (localization by microscopy), co-immunoprecipitation for CD99L2-CAPN1 interaction, ubiquitination analysis, transcriptome analysis in patient-derived fibroblasts Nature communications High 41690933

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 17 37199607
2018 CD99L2 deficiency inhibits leukocyte entry into the central nervous system and ameliorates neuroinflammation. Journal of leukocyte biology 12 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 8 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

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