{"gene":"CD99","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":1989,"finding":"The MIC2 (CD99) gene product is an integral membrane protein with a single long hydrophobic transmembrane domain; epitope mapping with six monoclonal antibodies localized all recognized epitopes to the extracellular region, establishing the protein's orientation in the plasma membrane.","method":"Epitope library screening with monoclonal antibodies, hydropathy plot analysis, plasmid expression vectors","journal":"Molecular immunology","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro epitope mapping and structural prediction, single lab, no mutagenesis validation","pmids":["2465491"],"is_preprint":false},{"year":1989,"finding":"CD99 (E2/MIC2 gene product) is a 32 kDa glycoprotein expressed on T-cell surfaces that is involved in spontaneous rosette formation with erythrocytes and T-cell adhesion processes; the protein is rich in proline residues, lacks N-linked glycosylation sites, and has a structure typical of an integral membrane protein.","method":"cDNA cloning, nucleotide sequencing, Northern blot, monoclonal antibody characterization","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cDNA isolation, sequencing, and functional adhesion assay in single lab with multiple methods","pmids":["2479542"],"is_preprint":false},{"year":1984,"finding":"MIC2X escapes X-chromosome inactivation on both structurally normal and abnormal inactive human X chromosomes.","method":"Cell hybrid analysis, expression assays on inactive X chromosomes","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — replicated in multiple cell types and corroborated by methylation studies","pmids":["6540985"],"is_preprint":false},{"year":1988,"finding":"The MIC2 HTF island (CpG-rich region at the 5' end) is unmethylated on both active and inactive X chromosomes and on the Y chromosome, correlating with the gene's escape from X-chromosome inactivation; this contrasts with X-inactivated genes whose HTF islands are highly methylated on the inactive X.","method":"HpaII restriction digestion, Southern blotting, methylation analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct biochemical methylation assay with functional inference, replicated across chromosomes","pmids":["2456574"],"is_preprint":false},{"year":1997,"finding":"The CD99 gene encodes two distinct proteins via alternative splicing: a major full-length form that induces LFA-1/ICAM-1-mediated homotypic adhesion of B lymphocytes, and a minor truncated form that inhibits this adhesion process and markedly down-regulates LFA-1 expression when overexpressed.","method":"Alternative splicing characterization, transfection of isoforms into IM-9 B cells, blocking antibodies to LFA-1 and ICAM-1, cell aggregation assays","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal gain/loss-of-function with molecular pathway defined (LFA-1/ICAM-1), replicated with blocking antibodies","pmids":["9278313"],"is_preprint":false},{"year":1998,"finding":"Downregulation of CD99 in B-cell lines leads to generation of cells with Hodgkin and Reed-Sternberg (H-RS) phenotype (multinuclearity, CD15 expression, decreased MHC class I and CD45RB, deregulated cytokine secretion); forced re-expression of CD99 or a constitutively active form of Rac abolishes these features, placing CD99 upstream of a Rac-Rho signaling pathway.","method":"Antisense CD99 transfection, forced CD99 expression, constitutively active Rac transfection, immunophenotyping, cytokine measurement","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal gain and loss-of-function with genetic epistasis (Rac rescue), multiple orthogonal readouts","pmids":["9834235"],"is_preprint":false},{"year":2000,"finding":"CD99 ligation upregulates alpha4beta1 integrin-dependent T-cell firm adhesion to vascular endothelium under physiological shear stress; this activation is dependent on the alpha4beta1-VCAM-1 pathway but does not activate the alphaLbeta2-ICAM-1 pathway.","method":"Flow chamber adhesion assay under shear stress, blocking antibodies to integrins and adhesion molecules, T cell line and peripheral blood lymphocyte studies","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — functional assay under physiological shear stress with pathway-specific blocking antibodies, multiple cell types tested","pmids":["11069091"],"is_preprint":false},{"year":2001,"finding":"Engagement of specific CD99 epitopes by the monoclonal antibody Ad20 rapidly induces caspase-independent programmed cell death in transformed T cell lines; this death pathway proceeds independently of CD3, CD4, CD45, and p56lck, and is not influenced by CD47 signaling.","method":"Morphological analysis, phosphatidylserine exposure (annexin V), propidium iodide uptake, comparison with Fas and TRAIL death pathways, signaling molecule blockade","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple death readouts and pathway exclusion experiments in single lab","pmids":["11290771"],"is_preprint":false},{"year":2002,"finding":"The full-length CD99 isoform (long form) promotes CD99-induced cell adhesion in Jurkat T cells, whereas co-expression of both long and short isoforms is required to trigger T-cell death; the two isoforms form covalent heterodimers that localize within glycosphingolipid rafts and induce sphingomyelin degradation; cholesterol depletion prevents raft localization and blocks apoptosis induction.","method":"Transfection of individual and combined CD99 isoforms in CD99-deficient Jurkat cells, heterodimer detection, raft fractionation, cholesterol depletion, sphingomyelin degradation assay","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution with defined isoforms, biochemical complex identification, lipid raft localization with functional consequence, multiple orthogonal methods","pmids":["12368226"],"is_preprint":false},{"year":2000,"finding":"CD99-induced homotypic aggregation of Jurkat T cells is mediated through a beta2-integrin-independent pathway requiring protein tyrosine kinase activity, protein kinase C activity, and actin filament polymerization, as demonstrated by inhibition with genistein, sphingosine, and cytochalasin B respectively.","method":"Homotypic aggregation assay, pharmacological inhibitors of PKC, PTK, and actin polymerization, anti-LFA-1 and anti-ICAM-1 blocking antibodies","journal":"Immunology letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pharmacological inhibitors with defined pathway exclusion, single lab","pmids":["10709783"],"is_preprint":false},{"year":2004,"finding":"Mouse CD99 is expressed on leukocytes and concentrated at endothelial cell contacts; CD99 mediates homophilic cell aggregation (blocked by anti-CD99 antibodies), participates in transendothelial migration of lymphocytes in vitro, and in vivo anti-CD99 antibodies inhibit T-cell recruitment to inflamed skin in a cutaneous delayed-type hypersensitivity model.","method":"cDNA cloning, CHO cell transfection aggregation assay, in vitro TEM assay, in vivo DTH model with antibody blockade","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — homophilic interaction established by transfection assay, in vitro and in vivo functional validation with antibody blockade","pmids":["15280198"],"is_preprint":false},{"year":2006,"finding":"CD99 acts as a tumor suppressor in osteosarcoma: forced CD99 expression reduces anoikis resistance, anchorage-independent growth, cell migration, and abrogates tumorigenicity and metastatic ability; mechanistically, CD99 expression induces caveolin-1 upregulation, the two proteins colocalize on the cell surface, and antisense caveolin-1 abrogates CD99's effect on migration; CD99 also inhibits c-Src kinase activity.","method":"CD99 transfection in osteosarcoma cell lines, xenograft assays, anchorage-independent growth, migration assays, co-localization studies, antisense oligonucleotides to caveolin-1, c-Src kinase activity assay","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — gain-of-function with multiple orthogonal in vitro and in vivo readouts, molecular mechanism via caveolin-1 and c-Src identified","pmids":["16421247"],"is_preprint":false},{"year":2007,"finding":"CD99 is a key mediator of neutrophil transendothelial migration (TEM); blocking CD99 on either neutrophils or endothelial cells with Fab fragments blocks >80% of PMN TEM in vitro, suggesting homophilic interaction; CD99-blocked neutrophils are arrested at a step distal to PECAM-blocked neutrophils within endothelial junctions, indicating CD99 and PECAM regulate distinct sequential diapedesis steps.","method":"In vitro TEM assay with HUVEC monolayers, Fab fragment blocking antibodies applied to neutrophils or endothelial cells separately, confocal microscopy, shear stress TEM assay","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal cell-side blocking, confocal localization of arrested cells, additive effect with PECAM blockade, two independent in vitro models","pmids":["17202377"],"is_preprint":false},{"year":2007,"finding":"The two CD99 isoforms have opposite functions in tumor malignancy: the full-length form (CD99wt) inhibits anchorage-independent growth, anoikis resistance, migration, and metastasis, whereas the short form (CD99sh) promotes these phenomena; the Ser168 residue of CD99 plays a pivotal role in the reversion of malignant phenotype; mechanistically, both isoforms regulate c-Src family kinase activity in opposite directions.","method":"Forced overexpression of CD99wt and CD99sh in osteosarcoma and prostate cancer cells, anchorage-independent growth assays, anoikis assays, migration assays, metastasis in vivo, Ser168 mutagenesis, c-Src kinase activity measurement","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis (Ser168), reconstitution of individual isoforms, multiple orthogonal in vitro and in vivo assays, mechanistic link to c-Src","pmids":["17471235"],"is_preprint":false},{"year":2008,"finding":"CD99 is essential for leukocyte diapedesis in vivo: in the thioglycollate peritonitis model, anti-murine CD99 antibody blocked neutrophil recruitment by >40% and monocyte recruitment by >80% at 18 h; blocking occurred at the luminal surface of venules; muCD99-transfected cells aggregate homophilically but do not bind cells expressing murine or human PECAM or human CD99, indicating species-specificity of the homophilic interaction.","method":"Murine CD99 cloning, in vitro cell transfection aggregation assay, in vivo thioglycollate peritonitis model, antibody blockade, intravital microscopy","journal":"Cell communication & adhesion","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo antibody blockade with quantitative leukocyte counts, transfection-based homophilic binding characterization","pmids":["18923973"],"is_preprint":false},{"year":2008,"finding":"CD99 physically associates with HLA class I molecules via their transmembrane domains in the trans-Golgi network (TGN) and at the cell surface; CD99 is required for IFN-gamma-induced upregulation of HLA class I surface expression; CD99 also binds p230/golgin-245 (a TGN vesicle trafficking protein) through its GRIP domain, and p230 overexpression leads to downmodulation of HLA class I surface expression.","method":"Co-immunoprecipitation, subcellular fractionation, IFN-gamma stimulation assays, p230/golgin-245 interaction studies, overexpression experiments","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, functional consequence (HLA class I regulation), multiple orthogonal methods in single rigorous study","pmids":["18849489"],"is_preprint":false},{"year":2010,"finding":"CD99 prevents neural differentiation of Ewing sarcoma cells and thereby contributes to oncogenesis; knockdown of CD99 reduces tumor formation and bone metastases in xenograft models, induces neurite outgrowth and beta-III tubulin expression; mechanistically, CD99 knockdown leads to increased phosphorylation of ERK1/2, suggesting CD99 modulates differentiation through the MAPK pathway.","method":"shRNA knockdown of CD99 in EWS cell lines, xenograft assays in immunodeficient mice, neurite outgrowth quantification, beta-III tubulin and neurofilament marker expression, ERK1/2 phosphorylation measurement","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function in vitro and in vivo with defined molecular readout (ERK1/2), multiple orthogonal assays","pmids":["20197622"],"is_preprint":false},{"year":2013,"finding":"CD99 suppresses osteosarcoma cell migration through inhibition of ROCK2 activity: CD99wt expression recruits N-cadherin and beta-catenin to adherens junctions, inhibits ACTR2, ARPC1A, ROCK2, and ezrin expression; mechanistically, CD99wt maintains c-Src in an inactive conformation, which inhibits ROCK2 signaling, causing ezrin decrease at the cell membrane and N-cadherin/beta-catenin translocation to the plasma membrane.","method":"CD99wt transfection in osteosarcoma cells, actin cytoskeleton imaging, co-localization of N-cadherin and beta-catenin, ROCK2 activity assays, c-Src activity measurement, ezrin localization","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — mechanistic cascade defined from CD99 through c-Src to ROCK2 to ezrin, multiple molecular readouts, single rigorous lab study","pmids":["23644663"],"is_preprint":false},{"year":2013,"finding":"Poliovirus receptor (PVR/CD155) regulates a step in TEM between PECAM and CD99; sequential antibody blocking experiments establish the order PECAM → PVR/DNAM-1 → CD99 in monocyte diapedesis; PVR resides in the lateral border recycling compartment (LBRC) similar to PECAM and CD99; endothelial PVR activation recruits the tyrosine phosphatase Shp-2 in a Src kinase-dependent manner.","method":"Sequential antibody blocking of TEM, confocal localization to LBRC, Shp-2 recruitment assay, Src kinase inhibition","journal":"The American journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistatic ordering by sequential blocking, localization data, single lab","pmids":["23333754"],"is_preprint":false},{"year":2015,"finding":"During leukocyte TEM, endothelial CD99 signals through a complex of its lysine-rich juxtamembrane cytoplasmic tail, A-kinase anchoring protein ezrin, and soluble adenylyl cyclase (sAC) to activate PKA; PKA then stimulates membrane trafficking from the lateral border recycling compartment (LBRC) to sites of TEM; pharmacologic or genetic inhibition of sAC or PKA arrests neutrophils and monocytes partway through endothelial junctions in vitro and in vivo without affecting leukocyte adhesion.","method":"Co-immunoprecipitation of CD99-ezrin-sAC complex, pharmacologic inhibition of sAC and PKA, genetic knockdown, in vitro TEM assay, in vivo assay, confocal microscopy of LBRC trafficking","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1 / Strong — biochemical complex identified by co-IP, multiple orthogonal inhibition methods, in vitro and in vivo validation, specific molecular mechanism established","pmids":["26101266"],"is_preprint":false},{"year":2015,"finding":"CD99 regulates neural differentiation of Ewing sarcoma cells through a CD99 → miR-34a → Notch → NF-κB signaling axis; CD99 silencing increases miR-34a (secreted into exosomes), which represses Notch pathway, leading to NF-κB inhibition and re-establishment of the neural differentiation program; delivery of exosomes from CD99-silenced EWS cells is sufficient to induce neural differentiation in recipient EWS cells.","method":"CD99 siRNA silencing, miR-34a quantification, Notch pathway analysis, NF-κB activity measurement, exosome isolation and transfer experiments","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — pathway defined by epistatic knockdown series plus exosome transfer functional validation, multiple orthogonal methods","pmids":["26616853"],"is_preprint":false},{"year":2016,"finding":"Anti-CD99 monoclonal antibody triggering induces methuosis (non-apoptotic vacuolar cell death) in Ewing sarcoma cells through formation of an IGF-1R/RAS/Rac1 complex that is internalized into RAB5-positive endocytic vacuoles; IGF-1R then recycles to the cell membrane while CD99 and RAS/Rac1 are sorted into immature LAMP-1-positive vacuoles whose excessive accumulation causes cell death; this process requires IGF-1R signaling and is enhanced by IGF-1.","method":"Anti-CD99 mAb treatment, co-immunoprecipitation of IGF-1R/RAS/Rac1 complex, endosomal sorting assays (RAB5/LAMP-1 markers), IGF-1R pathway inhibition, IGF-1 stimulation, EWS xenograft validation","journal":"Oncotarget","confidence":"High","confidence_rationale":"Tier 2 / Strong — biochemical complex identified, endosomal trafficking characterized, pathway inhibition and enhancement experiments, in vivo xenograft validation","pmids":["27835596"],"is_preprint":false},{"year":2017,"finding":"Anti-CD99 monoclonal antibodies induce death of AML and MDS cells in a SRC-family kinase-dependent manner, in the absence of immune effector cells or complement; CD99 expression enriches for functional leukemic stem cells (LSCs) as demonstrated by limiting dilution xenotransplant studies.","method":"Anti-CD99 mAb treatment with/without SRC family kinase inhibitors, xenotransplant limiting dilution assays, in vitro cytotoxicity assays in absence of immune effectors","journal":"Science translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — kinase-dependence established pharmacologically, functional LSC enrichment by xenotransplant, single lab","pmids":["28123069"],"is_preprint":false},{"year":2017,"finding":"Endothelial CD99 promotes leukocyte attachment to endothelium in inflamed vessels and supports rapid chemokine-induced arrest; CD99 on endothelial cells (not on leukocytes) is responsible for both attachment support and diapedesis; endothelial CD99 binds to paired immunoglobulin-like receptors (PILRs) on neutrophils in a heterophilic interaction that increases shear resistance of neutrophil attachment to ICAM-1.","method":"CD99 gene inactivation (knockout), intravital video microscopy of cremaster inflammation, co-precipitation of CD99 with PILRs from adherent neutrophils, soluble CD99-biotin tag transfer to PILRs, flow assay with P-selectin/ICAM-1/CD99 coimmobilization, anti-PILR antibody blocking","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1 / Strong — genetic knockout, intravital microscopy, biochemical identification of heterophilic PILR ligand with multiple orthogonal assays","pmids":["28223280"],"is_preprint":false},{"year":2001,"finding":"CD99 promoter activity is positively regulated by an Sp1-binding site at position -95; EBV-encoded LMP1 represses CD99 transcription through NF-κB activation domains in LMP1's cytoplasmic carboxyl terminus, independently of the Sp1 site; NF-κB inhibition restores CD99 promoter activity suppressed by LMP1.","method":"Promoter deletion constructs, luciferase reporter assays, Sp1 site mutagenesis, NF-κB inhibition experiments","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1 / Strong — promoter mutagenesis combined with reporter assays and NF-κB rescue, multiple constructs tested","pmids":["11369656"],"is_preprint":false},{"year":2002,"finding":"CD99 short form (splice variant) expression in breast cancer cells increases cell motility through a signaling pathway dependent on src kinase and focal adhesion kinase (FAK); kinase-negative mutant src transfectants showed 80% less motility than mock cells.","method":"CD99 splice variant transfection, pharmacological inhibitors (PP1 for Src, phenylarsine oxide for FAK), kinase-negative mutant src transfection","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and genetic inhibition of Src, two orthogonal approaches, single lab","pmids":["12216109"],"is_preprint":false},{"year":2012,"finding":"Anti-CD99 antibody ligation induces upregulation of HSP70 on the cell surface and in the cytoplasm of B- and T-leukemia cell lines and primary BCP-ALL cells; CD99-induced HSP70 upregulation on leukemia cells enables NK cell-mediated cytotoxicity.","method":"Anti-CD99 antibody treatment, HSP70 surface and intracellular quantification by flow cytometry, NK92 cell cytotoxicity assay","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — antibody-induced signaling with two orthogonal readouts (surface and intracellular HSP70) and functional NK cytotoxicity consequence, single lab","pmids":["23152061"],"is_preprint":false},{"year":2019,"finding":"CD99 long isoform in AML cells transiently increases ERK and SRC phosphorylation followed by a dramatic decrease; overexpression of the long isoform induces increased reactive oxygen species, DNA damage, apoptosis, and decreased cell viability, and in murine leukemia models delays disease progression and reduces bone marrow engraftment.","method":"CD99 long isoform transfection in leukemia cell lines, ERK/SRC phosphorylation measurement, ROS assay, DNA damage markers, apoptosis assays, murine xenograft models","journal":"Haematologica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function with defined molecular signaling readouts (ERK/SRC), in vivo validation, single lab","pmids":["31371417"],"is_preprint":false},{"year":2019,"finding":"CD99 ligands are expressed on monocytes, NK cells, and dendritic cells (but not on B and T cells); interaction of CD99 with its ligand upregulates IL-6 and TNF-α (but not IFN-γ) in anti-CD3-activated T cells and in CD3-negative mononuclear cells; this cytokine upregulation requires concomitant T cell activation signal.","method":"Recombinant CD99 protein production, CD99 ligand expression analysis by FACS, cytokine measurement (IL-6, TNF-α, IFN-γ) by ELISA/multiplex assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — recombinant protein used to probe ligand interactions and cytokine induction, multiple cell populations tested, single lab","pmids":["31120992"],"is_preprint":false},{"year":2020,"finding":"The GDF6 prodomain is a ligand for the CD99 extracellular domain; binding of the GDF6 prodomain to CD99 recruits CSK (C-terminal Src kinase) to the YQKKK motif in the intracellular domain of CD99, thereby inhibiting Src activity; GDF6 silencing causes Src hyperactivation and p21-dependent growth arrest in Ewing sarcoma cells; two GDF6 prodomain mutants linked to Klippel-Feil syndrome are hyperactive in this CD99-Src signaling pathway.","method":"Co-immunoprecipitation of GDF6 prodomain with CD99, domain mapping experiments, CSK recruitment assay to CD99 YQKKK motif, Src activity measurement, GDF6 silencing with growth arrest phenotype, disease mutant functional analysis","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — biochemical ligand-receptor interaction identified, intracellular signaling motif mapped, CSK recruitment demonstrated, in-frame disease mutants tested, multiple orthogonal methods","pmids":["33147457"],"is_preprint":false},{"year":2014,"finding":"Anti-CD99 antibody triggering in Ewing sarcoma induces cell death through Mdm2 degradation and p53 reactivation; overexpression of Mdm2 or p53 silencing decreases CD99-triggered death; the p53 pathway activation is accompanied by induction of p21, bax, and mitochondrial depolarization; normal mesenchymal stem cells (lacking EWS-FLI1) do not show p53 activation and are resistant, indicating dependence on oncogenic context.","method":"Anti-CD99 diabody (dAbd C7) treatment, Mdm2 overexpression rescue, p53 siRNA knockdown, nutlin-3 enhancement, p21/bax induction, mitochondrial depolarization assay, EWS xenograft experiments","journal":"Clinical cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal genetic rescue/knockdown experiments with pathway characterization, in vitro and in vivo validation","pmids":["25501132"],"is_preprint":false},{"year":2011,"finding":"CD99 upregulation in Hodgkin/Reed-Sternberg cells induces PRDM1/BLIMP1 expression through a CD99 → miR-9 (decrease) → PRDM1 upregulation axis; miR-9 directly targets PRDM1 mRNA; CD99 overexpression leads to CD30 and CD15 decrease, CD38 increase, and restoration of B-cell markers (PAX5, CD79α, CD19), suggesting CD99 promotes terminal B-cell differentiation.","method":"CD99 overexpression in cHL cell lines, miR-9 quantification, miR-9 inhibition experiments, PRDM1 expression measurement, B-cell marker analysis by flow cytometry","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistatic pathway defined by combining CD99 overexpression and miR-9 inhibition, multiple markers, single lab","pmids":["22020966"],"is_preprint":false},{"year":2019,"finding":"CD99 silencing in Ewing sarcoma cells leads to release of exosomes with oncosuppressive functions that reduce proliferation and migration and induce a more differentiated phenotype in recipient EWS cells; the key functional driver is miR-199a-3p loaded into CD99-deprived exosomes, which acts through modulation of the AP-1 signaling pathway.","method":"CD99 shRNA silencing, exosome isolation and transfer experiments, recipient cell proliferation and migration assays, miRNA profiling of exosomes, AP-1 signaling pathway analysis, miR-199a-3p functional validation","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — exosome transfer with functional consequence, miRNA cargo identified and validated, AP-1 pathway mechanistic link, single lab","pmids":["31209202"],"is_preprint":false},{"year":2019,"finding":"Nrf2 transcriptionally activates CD99 expression (identified by dual-luciferase reporter assay and ChIP); CD99 overexpression confers cisplatin resistance in ovarian cancer cells, and CD99 knockdown sensitizes cells to cisplatin; forced CD99 re-expression can rescue Nrf2-knockdown-mediated cisplatin sensitivity.","method":"Dual-luciferase reporter gene assay, chromatin immunoprecipitation (ChIP), CD99 overexpression and knockdown, CCK-8 cell viability after cisplatin treatment","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — direct transcription factor binding shown by ChIP and reporter assay, functional rescue experiment, single lab","pmids":["31472965"],"is_preprint":false},{"year":2021,"finding":"Mosaic loss of chromosome Y (LOY) in leukocytes results in reduced CD99 protein abundance on the cell surface in all six types of leukocytes studied, consistent with CD99's pseudoautosomal gene location; CD proteins encoded by autosomal genes are unaffected by LOY.","method":"CITE-seq (simultaneous single-cell RNA and surface protein quantification), comparison of LOY vs. non-LOY cells across six leukocyte types","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — single-cell multimodal quantification linking chromosomal aneuploidy to protein-level consequence, multiple cell types, single study","pmids":["34312421"],"is_preprint":false}],"current_model":"CD99 (MIC2) is a pseudoautosomal, highly O-glycosylated single-pass transmembrane glycoprotein that exists as two alternatively spliced isoforms (full-length and short truncated) with opposite functional outputs: the full-length isoform suppresses tumor malignancy, migration, and promotes differentiation by maintaining c-Src in an inactive conformation and inhibiting ROCK2, whereas the short isoform promotes invasion and metastasis; during leukocyte transendothelial migration (TEM), endothelial CD99 signals through an ezrin/soluble adenylyl cyclase/PKA complex to stimulate lateral border recycling compartment (LBRC) membrane trafficking and facilitates diapedesis, and heterophilically engages PILRs on neutrophils to support chemokine-induced leukocyte arrest; CD99 also regulates LFA-1/ICAM-1-mediated lymphocyte adhesion, alpha4beta1 integrin activation, and HLA class I surface trafficking via interaction with p230/golgin-245 in the TGN; in Ewing sarcoma, CD99 prevents neural differentiation through ERK/MAPK and NF-κB/miR-34a/Notch pathways and is a receptor for GDF6 prodomain that recruits CSK to inhibit Src; engagement of CD99 by specific antibodies induces non-apoptotic methuosis death in EWS cells via an IGF-1R/RAS/Rac1 complex, and caspase-independent death in T cells requiring heterodimer formation between the two isoforms within glycosphingolipid rafts."},"narrative":{"mechanistic_narrative":"CD99 (MIC2) is a pseudoautosomal, single-pass transmembrane glycoprotein that controls leukocyte trafficking and acts as a context-dependent regulator of tumor malignancy [PMID:2479542, PMID:17471235]. It is encoded by a gene whose CpG island remains unmethylated on the inactive X and the Y chromosome, allowing escape from X-inactivation and expression from both sex chromosomes [PMID:6540985, PMID:2456574]; loss of chromosome Y in leukocytes correspondingly lowers surface CD99 [PMID:34312421]. Alternative splicing produces a full-length form and a short truncated form with opposing outputs: the full-length isoform suppresses anchorage-independent growth, anoikis resistance, migration, and metastasis, whereas the short form promotes these phenotypes, with the two isoforms regulating c-Src family kinase activity in opposite directions and Ser168 required for phenotype reversion [PMID:17471235]. The full-length isoform restrains migration by maintaining c-Src in an inactive conformation, thereby inhibiting ROCK2 and ezrin and driving N-cadherin/beta-catenin to adherens junctions [PMID:23644663]. In leukocyte transendothelial migration, endothelial CD99 acts at a step distal to PECAM, signaling through a juxtamembrane complex of ezrin, soluble adenylyl cyclase, and PKA to drive membrane trafficking from the lateral border recycling compartment toward sites of diapedesis [PMID:17202377, PMID:26101266], and additionally engages PILRs on neutrophils heterophilically to support chemokine-induced arrest [PMID:28223280]. CD99 also activates alpha4beta1-dependent T-cell adhesion, regulates LFA-1/ICAM-1-mediated lymphocyte aggregation in an isoform-specific manner, and traffics HLA class I to the surface via interaction with p230/golgin-245 in the TGN [PMID:9278313, PMID:11069091, PMID:18849489]. In Ewing sarcoma, CD99 blocks neural differentiation through ERK/MAPK and a miR-34a/Notch/NF-kB axis [PMID:20197622, PMID:26616853], and the GDF6 prodomain is a ligand whose binding recruits CSK to the CD99 YQKKK motif to inhibit Src [PMID:33147457]; antibody engagement of CD99 kills tumor and leukemic cells through non-apoptotic methuosis involving an IGF-1R/RAS/Rac1 complex and through Mdm2 degradation/p53 reactivation [PMID:27835596, PMID:25501132].","teleology":[{"year":1984,"claim":"Established that the CD99/MIC2 locus has the unusual genetic behavior of escaping X-chromosome inactivation, explaining its biallelic expression and pseudoautosomal nature.","evidence":"Cell hybrid analysis and expression assays on inactive X chromosomes, with methylation analysis of the 5' CpG island","pmids":["6540985","2456574"],"confidence":"High","gaps":["Does not address protein function","Does not link expression level to any cellular phenotype"]},{"year":1989,"claim":"Defined CD99 as a proline-rich, glycosylated single-pass integral membrane protein with an extracellular epitope-bearing domain, and first implicated it in T-cell adhesion/rosette formation.","evidence":"cDNA cloning, sequencing, hydropathy analysis, monoclonal antibody epitope mapping, and adhesion assays","pmids":["2465491","2479542"],"confidence":"Medium","gaps":["No signaling partners identified","Adhesion mechanism and ligand unknown","No mutagenesis validation of topology"]},{"year":1997,"claim":"Showed that alternative splicing produces full-length and truncated isoforms with opposite effects on LFA-1/ICAM-1-mediated adhesion, introducing the central theme of isoform antagonism.","evidence":"Isoform transfection into B cells with LFA-1/ICAM-1 blocking antibodies and aggregation assays","pmids":["9278313"],"confidence":"High","gaps":["Molecular basis of opposing isoform activity unresolved","No structural explanation for short-form dominance"]},{"year":2000,"claim":"Demonstrated CD99 acts upstream of integrin activation, stimulating alpha4beta1-VCAM-1-dependent firm adhesion under shear without engaging the LFA-1/ICAM-1 axis, and that aggregation requires PTK/PKC/actin signaling.","evidence":"Flow chamber adhesion under shear with integrin-specific blocking, plus pharmacological inhibitors of PTK, PKC, and actin polymerization","pmids":["11069091","10709783"],"confidence":"High","gaps":["Direct CD99 effector linking it to integrin activation not identified","Distinction between cis and trans signaling unclear"]},{"year":2002,"claim":"Resolved how isoforms encode opposite outputs in T cells: covalent heterodimers within glycosphingolipid rafts are required for death signaling while the long form alone drives adhesion, tying death induction to raft integrity.","evidence":"Reconstitution of individual and combined isoforms in CD99-deficient Jurkat cells, raft fractionation, cholesterol depletion, sphingomyelin degradation assay","pmids":["12368226","11290771"],"confidence":"High","gaps":["Downstream caspase-independent death effectors not defined","Physiological trigger for heterodimerization unknown"]},{"year":2006,"claim":"Identified CD99 as a tumor suppressor whose anti-migratory, anti-metastatic action operates through caveolin-1 upregulation and c-Src inhibition, establishing the c-Src axis in solid tumors.","evidence":"CD99 transfection in osteosarcoma, xenografts, migration and anchorage-independence assays, caveolin-1 antisense, c-Src kinase activity assay","pmids":["16421247"],"confidence":"High","gaps":["How CD99 inhibits c-Src biochemically not shown here","Caveolin-1 dependence of metastasis not directly tested in vivo"]},{"year":2007,"claim":"Confirmed reciprocal isoform function in malignancy and pinpointed Ser168 as a determinant of phenotype reversion, unifying the suppressor/promoter dichotomy with bidirectional c-Src regulation.","evidence":"Forced expression of full-length and short isoforms with Ser168 mutagenesis, in vivo metastasis, c-Src activity assays","pmids":["17471235"],"confidence":"High","gaps":["Mechanism by which Ser168 alters c-Src regulation unresolved","Whether Ser168 is phosphorylated not established"]},{"year":2007,"claim":"Placed CD99 as a distinct, sequential mediator of neutrophil diapedesis acting downstream of PECAM, defining a stepwise junction-crossing model.","evidence":"In vitro TEM with cell-side-specific Fab blocking, confocal localization of arrested cells, additivity with PECAM blockade","pmids":["17202377"],"confidence":"High","gaps":["Molecular signaling driving the CD99 step not yet defined","Identity of the homophilic binding interface unknown"]},{"year":2008,"claim":"Established CD99 as essential for diapedesis in vivo and species-specific in its homophilic binding, and revealed a TGN trafficking role coupling CD99 to HLA class I surface expression via p230/golgin-245.","evidence":"Murine peritonitis with antibody blockade and intravital microscopy; co-IP of CD99 with HLA class I and p230, IFN-gamma stimulation","pmids":["18923973","18849489"],"confidence":"High","gaps":["How the GRIP-domain p230 interaction mechanistically gates HLA trafficking unclear","Connection between TEM and TGN functions not integrated"]},{"year":2010,"claim":"Defined CD99 as an oncogenic block to neural differentiation in Ewing sarcoma operating through suppression of ERK1/2, providing a therapeutic rationale for CD99 targeting.","evidence":"shRNA knockdown in EWS lines, xenografts, neurite/beta-III tubulin readouts, ERK1/2 phosphorylation","pmids":["20197622"],"confidence":"High","gaps":["Direct link between CD99 and ERK regulation not mapped","Differentiation effectors downstream of ERK undefined"]},{"year":2013,"claim":"Connected CD99 anti-migratory function to a defined cascade (inactive c-Src to ROCK2 inhibition to ezrin loss and junctional N-cadherin/beta-catenin), and ordered PVR between PECAM and CD99 in diapedesis.","evidence":"CD99wt transfection with cytoskeletal imaging, ROCK2 and c-Src activity assays; sequential TEM blocking with LBRC localization and Shp-2 recruitment","pmids":["23644663","23333754"],"confidence":"High","gaps":["Stoichiometry of CD99-c-Src interaction unknown","How CD99 and PVR coordinate within LBRC unclear"]},{"year":2015,"claim":"Delineated the endothelial CD99 signaling machine for diapedesis (ezrin/sAC/PKA driving LBRC trafficking) and a parallel CD99 to miR-34a/Notch/NF-kB axis controlling EWS differentiation.","evidence":"Co-IP of CD99-ezrin-sAC complex with sAC/PKA inhibition in vitro and in vivo; CD99 silencing with miR-34a/Notch/NF-kB readouts and exosome transfer","pmids":["26101266","26616853"],"confidence":"High","gaps":["How CD99 cytoplasmic tail nucleates the AKAP complex structurally undefined","Whether the two signaling roles share components unknown"]},{"year":2016,"claim":"Showed that antibody engagement of CD99 kills Ewing sarcoma cells by methuosis through an internalized IGF-1R/RAS/Rac1 complex, revealing a non-apoptotic death modality exploitable therapeutically.","evidence":"Anti-CD99 mAb with co-IP of IGF-1R/RAS/Rac1, RAB5/LAMP-1 endosomal sorting, IGF-1R inhibition, xenograft validation","pmids":["27835596"],"confidence":"High","gaps":["Trigger for complex assembly upon CD99 ligation unclear","Why immature vacuole accumulation is lethal not mechanistically resolved"]},{"year":2017,"claim":"Extended CD99 antibody-induced, SRC-dependent killing to AML/MDS and identified CD99 as a leukemic stem cell marker, and identified endothelial CD99-PILR heterophilic engagement supporting leukocyte arrest.","evidence":"Anti-CD99 mAb with SRC-kinase inhibition, limiting-dilution xenotransplant; CD99 knockout, intravital microscopy, CD99-PILR co-precipitation and flow assays","pmids":["28123069","28223280"],"confidence":"High","gaps":["How antibody ligation engages SRC for death not detailed","Relative contribution of homophilic versus PILR heterophilic binding in vivo unresolved"]},{"year":2020,"claim":"Identified GDF6 prodomain as a bona fide CD99 ligand that recruits CSK to the intracellular YQKKK motif to inhibit Src, mechanistically grounding CD99's growth-restraining c-Src control and linking it to Klippel-Feil syndrome mutants.","evidence":"Co-IP and domain mapping of GDF6 prodomain-CD99, CSK recruitment to YQKKK, Src activity and growth-arrest assays, disease-mutant functional analysis","pmids":["33147457"],"confidence":"High","gaps":["Whether GDF6-CD99 signaling operates in TEM or immune contexts untested","Structural basis of prodomain-ectodomain recognition unknown"]},{"year":null,"claim":"How a single glycoprotein integrates its opposing isoform outputs, multiple heterophilic ligands (PILR, GDF6 prodomain), and distinct effector axes (c-Src/CSK, ezrin/sAC/PKA, IGF-1R/RAS/Rac1) into context-specific outcomes remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural model of CD99 signaling complexes","Determinants selecting adhesion versus death versus trafficking outputs unknown","Physiological ligand usage across cell types not mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[4,10,14]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[23,29]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[6,17,29]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[15,19]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,10,15]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[15]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[10,12,19,23]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[16,20,21,30]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[17,29]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[8,21,30]}],"complexes":["CD99-ezrin-soluble adenylyl cyclase (sAC) complex","CD99 long/short isoform heterodimer (glycosphingolipid rafts)","IGF-1R/RAS/Rac1 complex"],"partners":["EZR","PILRA","GDF6","CSK","HLA CLASS I","GOLGA4","CAV1","SRC"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P14209","full_name":"CD99 antigen","aliases":["12E7","E2 antigen","Protein MIC2","T-cell surface glycoprotein E2"],"length_aa":185,"mass_kda":18.8,"function":"Involved in T-cell adhesion processes and in spontaneous rosette formation with erythrocytes. Plays a role in a late step of leukocyte extravasation helping leukocytes to overcome the endothelial basement membrane. Acts at the same site as, but independently of, PECAM1. Involved in T-cell adhesion processes (By similarity)","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/P14209/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CD99","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":[{"gene":"SLC16A1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/CD99","total_profiled":1310},"omim":[{"mim_id":"616065","title":"PILR-ALPHA-ASSOCIATED NEURAL PROTEIN; PIANP","url":"https://www.omim.org/entry/616065"},{"mim_id":"612219","title":"EWING SARCOMA; ES","url":"https://www.omim.org/entry/612219"},{"mim_id":"605342","title":"PAIRED IMMUNOGLOBULIN-LIKE TYPE 2 RECEPTOR, BETA; PILRB","url":"https://www.omim.org/entry/605342"},{"mim_id":"605341","title":"PAIRED IMMUNOGLOBULIN-LIKE TYPE 2 RECEPTOR, ALPHA; PILRA","url":"https://www.omim.org/entry/605341"},{"mim_id":"600711","title":"ETS VARIANT TRANSCRIPTION FACTOR 4; ETV4","url":"https://www.omim.org/entry/600711"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Golgi apparatus","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CD99"},"hgnc":{"alias_symbol":[],"prev_symbol":["MIC2","MIC2X","MIC2Y"]},"alphafold":{"accession":"P14209","domains":[{"cath_id":"-","chopping":"2-151","consensus_level":"medium","plddt":62.9992,"start":2,"end":151}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P14209","model_url":"https://alphafold.ebi.ac.uk/files/AF-P14209-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P14209-F1-predicted_aligned_error_v6.png","plddt_mean":60.84},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CD99","jax_strain_url":"https://www.jax.org/strain/search?query=CD99"},"sequence":{"accession":"P14209","fasta_url":"https://rest.uniprot.org/uniprotkb/P14209.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P14209/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P14209"}},"corpus_meta":[{"pmid":"1848471","id":"PMC_1848471","title":"MIC2 is a specific marker for Ewing's sarcoma and peripheral primitive neuroectodermal tumors. 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through inhibition of ROCK2 activity.","date":"2013","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/23644663","citation_count":42,"is_preprint":false},{"pmid":"8504302","id":"PMC_8504302","title":"The genomic organisation of the human pseudoautosomal gene MIC2 and the detection of a related locus.","date":"1993","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/8504302","citation_count":42,"is_preprint":false},{"pmid":"18849489","id":"PMC_18849489","title":"Regulation of HLA class I surface expression requires CD99 and p230/golgin-245 interaction.","date":"2008","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/18849489","citation_count":42,"is_preprint":false},{"pmid":"18163232","id":"PMC_18163232","title":"The murine CD99-related molecule CD99-like 2 (CD99L2) is an adhesion molecule involved in the inflammatory response.","date":"2007","source":"Cell communication & 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Regulates Src and Ewing Sarcoma Growth.","date":"2020","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/33147457","citation_count":23,"is_preprint":false},{"pmid":"31001265","id":"PMC_31001265","title":"Targeting Tumor Vascular CD99 Inhibits Tumor Growth.","date":"2019","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31001265","citation_count":23,"is_preprint":false},{"pmid":"10492040","id":"PMC_10492040","title":"Relation of neurological marker expression and EWS gene fusion types in MIC2/CD99-positive tumors of the Ewing family.","date":"1999","source":"Human pathology","url":"https://pubmed.ncbi.nlm.nih.gov/10492040","citation_count":23,"is_preprint":false},{"pmid":"32535112","id":"PMC_32535112","title":"Anti-CD99 scFv-ELP nanoworms for the treatment of acute myeloid leukemia.","date":"2020","source":"Nanomedicine : nanotechnology, biology, and medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32535112","citation_count":22,"is_preprint":false},{"pmid":"12216109","id":"PMC_12216109","title":"Functional involvement of src and focal adhesion kinase in a CD99 splice variant-induced motility of human breast cancer cells.","date":"2002","source":"Experimental & molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/12216109","citation_count":22,"is_preprint":false},{"pmid":"28223280","id":"PMC_28223280","title":"Endothelial CD99 supports arrest of mouse neutrophils in venules and binds to neutrophil PILRs.","date":"2017","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/28223280","citation_count":20,"is_preprint":false},{"pmid":"27764235","id":"PMC_27764235","title":"Investigating CD99 Expression in Leukemia Propagating Cells in Childhood T Cell Acute Lymphoblastic Leukemia.","date":"2016","source":"PloS 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pathophysiology?","date":"2021","source":"Proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/34383378","citation_count":19,"is_preprint":false},{"pmid":"23152061","id":"PMC_23152061","title":"CD99 ligation upregulates HSP70 on acute lymphoblastic leukemia cells and concomitantly increases NK cytotoxicity.","date":"2012","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/23152061","citation_count":18,"is_preprint":false},{"pmid":"25411252","id":"PMC_25411252","title":"Structural basis of Toxoplasma gondii MIC2-associated protein interaction with MIC2.","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25411252","citation_count":17,"is_preprint":false},{"pmid":"30514763","id":"PMC_30514763","title":"Protein O-fucosyltransferase 2-mediated O-glycosylation of the adhesin MIC2 is dispensable for Toxoplasma gondii tachyzoite infection.","date":"2018","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30514763","citation_count":17,"is_preprint":false},{"pmid":"37199607","id":"PMC_37199607","title":"Porphyromonas gingivalis Gingipains Destroy the Vascular Barrier and Reduce CD99 and CD99L2 Expression To Regulate Transendothelial Migration.","date":"2023","source":"Microbiology spectrum","url":"https://pubmed.ncbi.nlm.nih.gov/37199607","citation_count":17,"is_preprint":false},{"pmid":"18382710","id":"PMC_18382710","title":"Immunohistochemical study of CD99 and EMA expression in ependymomas.","date":"2008","source":"Medscape journal of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/18382710","citation_count":17,"is_preprint":false},{"pmid":"11369656","id":"PMC_11369656","title":"CD99 expression is positively regulated by Sp1 and is negatively regulated by Epstein-Barr virus latent membrane protein 1 through nuclear factor-kappaB.","date":"2001","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/11369656","citation_count":17,"is_preprint":false},{"pmid":"23145531","id":"PMC_23145531","title":"CD99 expression in Merkel cell carcinoma: a case series with an unusual paranuclear dot-like staining pattern.","date":"2012","source":"Journal of cutaneous pathology","url":"https://pubmed.ncbi.nlm.nih.gov/23145531","citation_count":16,"is_preprint":false},{"pmid":"17725386","id":"PMC_17725386","title":"Production, characterization, and functional analysis of newly established CD99 monoclonal antibodies MT99/1 and MT99/2.","date":"2007","source":"Hybridoma (2005)","url":"https://pubmed.ncbi.nlm.nih.gov/17725386","citation_count":16,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49804,"output_tokens":9294,"usd":0.144411,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":19470,"output_tokens":5393,"usd":0.116087,"stage2_stop_reason":"end_turn"},"total_usd":0.260498,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1989,\n      \"finding\": \"The MIC2 (CD99) gene product is an integral membrane protein with a single long hydrophobic transmembrane domain; epitope mapping with six monoclonal antibodies localized all recognized epitopes to the extracellular region, establishing the protein's orientation in the plasma membrane.\",\n      \"method\": \"Epitope library screening with monoclonal antibodies, hydropathy plot analysis, plasmid expression vectors\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro epitope mapping and structural prediction, single lab, no mutagenesis validation\",\n      \"pmids\": [\"2465491\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1989,\n      \"finding\": \"CD99 (E2/MIC2 gene product) is a 32 kDa glycoprotein expressed on T-cell surfaces that is involved in spontaneous rosette formation with erythrocytes and T-cell adhesion processes; the protein is rich in proline residues, lacks N-linked glycosylation sites, and has a structure typical of an integral membrane protein.\",\n      \"method\": \"cDNA cloning, nucleotide sequencing, Northern blot, monoclonal antibody characterization\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cDNA isolation, sequencing, and functional adhesion assay in single lab with multiple methods\",\n      \"pmids\": [\"2479542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1984,\n      \"finding\": \"MIC2X escapes X-chromosome inactivation on both structurally normal and abnormal inactive human X chromosomes.\",\n      \"method\": \"Cell hybrid analysis, expression assays on inactive X chromosomes\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — replicated in multiple cell types and corroborated by methylation studies\",\n      \"pmids\": [\"6540985\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1988,\n      \"finding\": \"The MIC2 HTF island (CpG-rich region at the 5' end) is unmethylated on both active and inactive X chromosomes and on the Y chromosome, correlating with the gene's escape from X-chromosome inactivation; this contrasts with X-inactivated genes whose HTF islands are highly methylated on the inactive X.\",\n      \"method\": \"HpaII restriction digestion, Southern blotting, methylation analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct biochemical methylation assay with functional inference, replicated across chromosomes\",\n      \"pmids\": [\"2456574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The CD99 gene encodes two distinct proteins via alternative splicing: a major full-length form that induces LFA-1/ICAM-1-mediated homotypic adhesion of B lymphocytes, and a minor truncated form that inhibits this adhesion process and markedly down-regulates LFA-1 expression when overexpressed.\",\n      \"method\": \"Alternative splicing characterization, transfection of isoforms into IM-9 B cells, blocking antibodies to LFA-1 and ICAM-1, cell aggregation assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal gain/loss-of-function with molecular pathway defined (LFA-1/ICAM-1), replicated with blocking antibodies\",\n      \"pmids\": [\"9278313\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Downregulation of CD99 in B-cell lines leads to generation of cells with Hodgkin and Reed-Sternberg (H-RS) phenotype (multinuclearity, CD15 expression, decreased MHC class I and CD45RB, deregulated cytokine secretion); forced re-expression of CD99 or a constitutively active form of Rac abolishes these features, placing CD99 upstream of a Rac-Rho signaling pathway.\",\n      \"method\": \"Antisense CD99 transfection, forced CD99 expression, constitutively active Rac transfection, immunophenotyping, cytokine measurement\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal gain and loss-of-function with genetic epistasis (Rac rescue), multiple orthogonal readouts\",\n      \"pmids\": [\"9834235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"CD99 ligation upregulates alpha4beta1 integrin-dependent T-cell firm adhesion to vascular endothelium under physiological shear stress; this activation is dependent on the alpha4beta1-VCAM-1 pathway but does not activate the alphaLbeta2-ICAM-1 pathway.\",\n      \"method\": \"Flow chamber adhesion assay under shear stress, blocking antibodies to integrins and adhesion molecules, T cell line and peripheral blood lymphocyte studies\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — functional assay under physiological shear stress with pathway-specific blocking antibodies, multiple cell types tested\",\n      \"pmids\": [\"11069091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Engagement of specific CD99 epitopes by the monoclonal antibody Ad20 rapidly induces caspase-independent programmed cell death in transformed T cell lines; this death pathway proceeds independently of CD3, CD4, CD45, and p56lck, and is not influenced by CD47 signaling.\",\n      \"method\": \"Morphological analysis, phosphatidylserine exposure (annexin V), propidium iodide uptake, comparison with Fas and TRAIL death pathways, signaling molecule blockade\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple death readouts and pathway exclusion experiments in single lab\",\n      \"pmids\": [\"11290771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The full-length CD99 isoform (long form) promotes CD99-induced cell adhesion in Jurkat T cells, whereas co-expression of both long and short isoforms is required to trigger T-cell death; the two isoforms form covalent heterodimers that localize within glycosphingolipid rafts and induce sphingomyelin degradation; cholesterol depletion prevents raft localization and blocks apoptosis induction.\",\n      \"method\": \"Transfection of individual and combined CD99 isoforms in CD99-deficient Jurkat cells, heterodimer detection, raft fractionation, cholesterol depletion, sphingomyelin degradation assay\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution with defined isoforms, biochemical complex identification, lipid raft localization with functional consequence, multiple orthogonal methods\",\n      \"pmids\": [\"12368226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"CD99-induced homotypic aggregation of Jurkat T cells is mediated through a beta2-integrin-independent pathway requiring protein tyrosine kinase activity, protein kinase C activity, and actin filament polymerization, as demonstrated by inhibition with genistein, sphingosine, and cytochalasin B respectively.\",\n      \"method\": \"Homotypic aggregation assay, pharmacological inhibitors of PKC, PTK, and actin polymerization, anti-LFA-1 and anti-ICAM-1 blocking antibodies\",\n      \"journal\": \"Immunology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pharmacological inhibitors with defined pathway exclusion, single lab\",\n      \"pmids\": [\"10709783\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Mouse CD99 is expressed on leukocytes and concentrated at endothelial cell contacts; CD99 mediates homophilic cell aggregation (blocked by anti-CD99 antibodies), participates in transendothelial migration of lymphocytes in vitro, and in vivo anti-CD99 antibodies inhibit T-cell recruitment to inflamed skin in a cutaneous delayed-type hypersensitivity model.\",\n      \"method\": \"cDNA cloning, CHO cell transfection aggregation assay, in vitro TEM assay, in vivo DTH model with antibody blockade\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — homophilic interaction established by transfection assay, in vitro and in vivo functional validation with antibody blockade\",\n      \"pmids\": [\"15280198\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CD99 acts as a tumor suppressor in osteosarcoma: forced CD99 expression reduces anoikis resistance, anchorage-independent growth, cell migration, and abrogates tumorigenicity and metastatic ability; mechanistically, CD99 expression induces caveolin-1 upregulation, the two proteins colocalize on the cell surface, and antisense caveolin-1 abrogates CD99's effect on migration; CD99 also inhibits c-Src kinase activity.\",\n      \"method\": \"CD99 transfection in osteosarcoma cell lines, xenograft assays, anchorage-independent growth, migration assays, co-localization studies, antisense oligonucleotides to caveolin-1, c-Src kinase activity assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — gain-of-function with multiple orthogonal in vitro and in vivo readouts, molecular mechanism via caveolin-1 and c-Src identified\",\n      \"pmids\": [\"16421247\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CD99 is a key mediator of neutrophil transendothelial migration (TEM); blocking CD99 on either neutrophils or endothelial cells with Fab fragments blocks >80% of PMN TEM in vitro, suggesting homophilic interaction; CD99-blocked neutrophils are arrested at a step distal to PECAM-blocked neutrophils within endothelial junctions, indicating CD99 and PECAM regulate distinct sequential diapedesis steps.\",\n      \"method\": \"In vitro TEM assay with HUVEC monolayers, Fab fragment blocking antibodies applied to neutrophils or endothelial cells separately, confocal microscopy, shear stress TEM assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal cell-side blocking, confocal localization of arrested cells, additive effect with PECAM blockade, two independent in vitro models\",\n      \"pmids\": [\"17202377\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The two CD99 isoforms have opposite functions in tumor malignancy: the full-length form (CD99wt) inhibits anchorage-independent growth, anoikis resistance, migration, and metastasis, whereas the short form (CD99sh) promotes these phenomena; the Ser168 residue of CD99 plays a pivotal role in the reversion of malignant phenotype; mechanistically, both isoforms regulate c-Src family kinase activity in opposite directions.\",\n      \"method\": \"Forced overexpression of CD99wt and CD99sh in osteosarcoma and prostate cancer cells, anchorage-independent growth assays, anoikis assays, migration assays, metastasis in vivo, Ser168 mutagenesis, c-Src kinase activity measurement\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis (Ser168), reconstitution of individual isoforms, multiple orthogonal in vitro and in vivo assays, mechanistic link to c-Src\",\n      \"pmids\": [\"17471235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CD99 is essential for leukocyte diapedesis in vivo: in the thioglycollate peritonitis model, anti-murine CD99 antibody blocked neutrophil recruitment by >40% and monocyte recruitment by >80% at 18 h; blocking occurred at the luminal surface of venules; muCD99-transfected cells aggregate homophilically but do not bind cells expressing murine or human PECAM or human CD99, indicating species-specificity of the homophilic interaction.\",\n      \"method\": \"Murine CD99 cloning, in vitro cell transfection aggregation assay, in vivo thioglycollate peritonitis model, antibody blockade, intravital microscopy\",\n      \"journal\": \"Cell communication & adhesion\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo antibody blockade with quantitative leukocyte counts, transfection-based homophilic binding characterization\",\n      \"pmids\": [\"18923973\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CD99 physically associates with HLA class I molecules via their transmembrane domains in the trans-Golgi network (TGN) and at the cell surface; CD99 is required for IFN-gamma-induced upregulation of HLA class I surface expression; CD99 also binds p230/golgin-245 (a TGN vesicle trafficking protein) through its GRIP domain, and p230 overexpression leads to downmodulation of HLA class I surface expression.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation, IFN-gamma stimulation assays, p230/golgin-245 interaction studies, overexpression experiments\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, functional consequence (HLA class I regulation), multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"18849489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CD99 prevents neural differentiation of Ewing sarcoma cells and thereby contributes to oncogenesis; knockdown of CD99 reduces tumor formation and bone metastases in xenograft models, induces neurite outgrowth and beta-III tubulin expression; mechanistically, CD99 knockdown leads to increased phosphorylation of ERK1/2, suggesting CD99 modulates differentiation through the MAPK pathway.\",\n      \"method\": \"shRNA knockdown of CD99 in EWS cell lines, xenograft assays in immunodeficient mice, neurite outgrowth quantification, beta-III tubulin and neurofilament marker expression, ERK1/2 phosphorylation measurement\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function in vitro and in vivo with defined molecular readout (ERK1/2), multiple orthogonal assays\",\n      \"pmids\": [\"20197622\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CD99 suppresses osteosarcoma cell migration through inhibition of ROCK2 activity: CD99wt expression recruits N-cadherin and beta-catenin to adherens junctions, inhibits ACTR2, ARPC1A, ROCK2, and ezrin expression; mechanistically, CD99wt maintains c-Src in an inactive conformation, which inhibits ROCK2 signaling, causing ezrin decrease at the cell membrane and N-cadherin/beta-catenin translocation to the plasma membrane.\",\n      \"method\": \"CD99wt transfection in osteosarcoma cells, actin cytoskeleton imaging, co-localization of N-cadherin and beta-catenin, ROCK2 activity assays, c-Src activity measurement, ezrin localization\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mechanistic cascade defined from CD99 through c-Src to ROCK2 to ezrin, multiple molecular readouts, single rigorous lab study\",\n      \"pmids\": [\"23644663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Poliovirus receptor (PVR/CD155) regulates a step in TEM between PECAM and CD99; sequential antibody blocking experiments establish the order PECAM → PVR/DNAM-1 → CD99 in monocyte diapedesis; PVR resides in the lateral border recycling compartment (LBRC) similar to PECAM and CD99; endothelial PVR activation recruits the tyrosine phosphatase Shp-2 in a Src kinase-dependent manner.\",\n      \"method\": \"Sequential antibody blocking of TEM, confocal localization to LBRC, Shp-2 recruitment assay, Src kinase inhibition\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistatic ordering by sequential blocking, localization data, single lab\",\n      \"pmids\": [\"23333754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"During leukocyte TEM, endothelial CD99 signals through a complex of its lysine-rich juxtamembrane cytoplasmic tail, A-kinase anchoring protein ezrin, and soluble adenylyl cyclase (sAC) to activate PKA; PKA then stimulates membrane trafficking from the lateral border recycling compartment (LBRC) to sites of TEM; pharmacologic or genetic inhibition of sAC or PKA arrests neutrophils and monocytes partway through endothelial junctions in vitro and in vivo without affecting leukocyte adhesion.\",\n      \"method\": \"Co-immunoprecipitation of CD99-ezrin-sAC complex, pharmacologic inhibition of sAC and PKA, genetic knockdown, in vitro TEM assay, in vivo assay, confocal microscopy of LBRC trafficking\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — biochemical complex identified by co-IP, multiple orthogonal inhibition methods, in vitro and in vivo validation, specific molecular mechanism established\",\n      \"pmids\": [\"26101266\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CD99 regulates neural differentiation of Ewing sarcoma cells through a CD99 → miR-34a → Notch → NF-κB signaling axis; CD99 silencing increases miR-34a (secreted into exosomes), which represses Notch pathway, leading to NF-κB inhibition and re-establishment of the neural differentiation program; delivery of exosomes from CD99-silenced EWS cells is sufficient to induce neural differentiation in recipient EWS cells.\",\n      \"method\": \"CD99 siRNA silencing, miR-34a quantification, Notch pathway analysis, NF-κB activity measurement, exosome isolation and transfer experiments\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — pathway defined by epistatic knockdown series plus exosome transfer functional validation, multiple orthogonal methods\",\n      \"pmids\": [\"26616853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Anti-CD99 monoclonal antibody triggering induces methuosis (non-apoptotic vacuolar cell death) in Ewing sarcoma cells through formation of an IGF-1R/RAS/Rac1 complex that is internalized into RAB5-positive endocytic vacuoles; IGF-1R then recycles to the cell membrane while CD99 and RAS/Rac1 are sorted into immature LAMP-1-positive vacuoles whose excessive accumulation causes cell death; this process requires IGF-1R signaling and is enhanced by IGF-1.\",\n      \"method\": \"Anti-CD99 mAb treatment, co-immunoprecipitation of IGF-1R/RAS/Rac1 complex, endosomal sorting assays (RAB5/LAMP-1 markers), IGF-1R pathway inhibition, IGF-1 stimulation, EWS xenograft validation\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — biochemical complex identified, endosomal trafficking characterized, pathway inhibition and enhancement experiments, in vivo xenograft validation\",\n      \"pmids\": [\"27835596\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Anti-CD99 monoclonal antibodies induce death of AML and MDS cells in a SRC-family kinase-dependent manner, in the absence of immune effector cells or complement; CD99 expression enriches for functional leukemic stem cells (LSCs) as demonstrated by limiting dilution xenotransplant studies.\",\n      \"method\": \"Anti-CD99 mAb treatment with/without SRC family kinase inhibitors, xenotransplant limiting dilution assays, in vitro cytotoxicity assays in absence of immune effectors\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — kinase-dependence established pharmacologically, functional LSC enrichment by xenotransplant, single lab\",\n      \"pmids\": [\"28123069\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Endothelial CD99 promotes leukocyte attachment to endothelium in inflamed vessels and supports rapid chemokine-induced arrest; CD99 on endothelial cells (not on leukocytes) is responsible for both attachment support and diapedesis; endothelial CD99 binds to paired immunoglobulin-like receptors (PILRs) on neutrophils in a heterophilic interaction that increases shear resistance of neutrophil attachment to ICAM-1.\",\n      \"method\": \"CD99 gene inactivation (knockout), intravital video microscopy of cremaster inflammation, co-precipitation of CD99 with PILRs from adherent neutrophils, soluble CD99-biotin tag transfer to PILRs, flow assay with P-selectin/ICAM-1/CD99 coimmobilization, anti-PILR antibody blocking\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — genetic knockout, intravital microscopy, biochemical identification of heterophilic PILR ligand with multiple orthogonal assays\",\n      \"pmids\": [\"28223280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"CD99 promoter activity is positively regulated by an Sp1-binding site at position -95; EBV-encoded LMP1 represses CD99 transcription through NF-κB activation domains in LMP1's cytoplasmic carboxyl terminus, independently of the Sp1 site; NF-κB inhibition restores CD99 promoter activity suppressed by LMP1.\",\n      \"method\": \"Promoter deletion constructs, luciferase reporter assays, Sp1 site mutagenesis, NF-κB inhibition experiments\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — promoter mutagenesis combined with reporter assays and NF-κB rescue, multiple constructs tested\",\n      \"pmids\": [\"11369656\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"CD99 short form (splice variant) expression in breast cancer cells increases cell motility through a signaling pathway dependent on src kinase and focal adhesion kinase (FAK); kinase-negative mutant src transfectants showed 80% less motility than mock cells.\",\n      \"method\": \"CD99 splice variant transfection, pharmacological inhibitors (PP1 for Src, phenylarsine oxide for FAK), kinase-negative mutant src transfection\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and genetic inhibition of Src, two orthogonal approaches, single lab\",\n      \"pmids\": [\"12216109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Anti-CD99 antibody ligation induces upregulation of HSP70 on the cell surface and in the cytoplasm of B- and T-leukemia cell lines and primary BCP-ALL cells; CD99-induced HSP70 upregulation on leukemia cells enables NK cell-mediated cytotoxicity.\",\n      \"method\": \"Anti-CD99 antibody treatment, HSP70 surface and intracellular quantification by flow cytometry, NK92 cell cytotoxicity assay\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — antibody-induced signaling with two orthogonal readouts (surface and intracellular HSP70) and functional NK cytotoxicity consequence, single lab\",\n      \"pmids\": [\"23152061\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CD99 long isoform in AML cells transiently increases ERK and SRC phosphorylation followed by a dramatic decrease; overexpression of the long isoform induces increased reactive oxygen species, DNA damage, apoptosis, and decreased cell viability, and in murine leukemia models delays disease progression and reduces bone marrow engraftment.\",\n      \"method\": \"CD99 long isoform transfection in leukemia cell lines, ERK/SRC phosphorylation measurement, ROS assay, DNA damage markers, apoptosis assays, murine xenograft models\",\n      \"journal\": \"Haematologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function with defined molecular signaling readouts (ERK/SRC), in vivo validation, single lab\",\n      \"pmids\": [\"31371417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CD99 ligands are expressed on monocytes, NK cells, and dendritic cells (but not on B and T cells); interaction of CD99 with its ligand upregulates IL-6 and TNF-α (but not IFN-γ) in anti-CD3-activated T cells and in CD3-negative mononuclear cells; this cytokine upregulation requires concomitant T cell activation signal.\",\n      \"method\": \"Recombinant CD99 protein production, CD99 ligand expression analysis by FACS, cytokine measurement (IL-6, TNF-α, IFN-γ) by ELISA/multiplex assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — recombinant protein used to probe ligand interactions and cytokine induction, multiple cell populations tested, single lab\",\n      \"pmids\": [\"31120992\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The GDF6 prodomain is a ligand for the CD99 extracellular domain; binding of the GDF6 prodomain to CD99 recruits CSK (C-terminal Src kinase) to the YQKKK motif in the intracellular domain of CD99, thereby inhibiting Src activity; GDF6 silencing causes Src hyperactivation and p21-dependent growth arrest in Ewing sarcoma cells; two GDF6 prodomain mutants linked to Klippel-Feil syndrome are hyperactive in this CD99-Src signaling pathway.\",\n      \"method\": \"Co-immunoprecipitation of GDF6 prodomain with CD99, domain mapping experiments, CSK recruitment assay to CD99 YQKKK motif, Src activity measurement, GDF6 silencing with growth arrest phenotype, disease mutant functional analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — biochemical ligand-receptor interaction identified, intracellular signaling motif mapped, CSK recruitment demonstrated, in-frame disease mutants tested, multiple orthogonal methods\",\n      \"pmids\": [\"33147457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Anti-CD99 antibody triggering in Ewing sarcoma induces cell death through Mdm2 degradation and p53 reactivation; overexpression of Mdm2 or p53 silencing decreases CD99-triggered death; the p53 pathway activation is accompanied by induction of p21, bax, and mitochondrial depolarization; normal mesenchymal stem cells (lacking EWS-FLI1) do not show p53 activation and are resistant, indicating dependence on oncogenic context.\",\n      \"method\": \"Anti-CD99 diabody (dAbd C7) treatment, Mdm2 overexpression rescue, p53 siRNA knockdown, nutlin-3 enhancement, p21/bax induction, mitochondrial depolarization assay, EWS xenograft experiments\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal genetic rescue/knockdown experiments with pathway characterization, in vitro and in vivo validation\",\n      \"pmids\": [\"25501132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CD99 upregulation in Hodgkin/Reed-Sternberg cells induces PRDM1/BLIMP1 expression through a CD99 → miR-9 (decrease) → PRDM1 upregulation axis; miR-9 directly targets PRDM1 mRNA; CD99 overexpression leads to CD30 and CD15 decrease, CD38 increase, and restoration of B-cell markers (PAX5, CD79α, CD19), suggesting CD99 promotes terminal B-cell differentiation.\",\n      \"method\": \"CD99 overexpression in cHL cell lines, miR-9 quantification, miR-9 inhibition experiments, PRDM1 expression measurement, B-cell marker analysis by flow cytometry\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistatic pathway defined by combining CD99 overexpression and miR-9 inhibition, multiple markers, single lab\",\n      \"pmids\": [\"22020966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CD99 silencing in Ewing sarcoma cells leads to release of exosomes with oncosuppressive functions that reduce proliferation and migration and induce a more differentiated phenotype in recipient EWS cells; the key functional driver is miR-199a-3p loaded into CD99-deprived exosomes, which acts through modulation of the AP-1 signaling pathway.\",\n      \"method\": \"CD99 shRNA silencing, exosome isolation and transfer experiments, recipient cell proliferation and migration assays, miRNA profiling of exosomes, AP-1 signaling pathway analysis, miR-199a-3p functional validation\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — exosome transfer with functional consequence, miRNA cargo identified and validated, AP-1 pathway mechanistic link, single lab\",\n      \"pmids\": [\"31209202\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Nrf2 transcriptionally activates CD99 expression (identified by dual-luciferase reporter assay and ChIP); CD99 overexpression confers cisplatin resistance in ovarian cancer cells, and CD99 knockdown sensitizes cells to cisplatin; forced CD99 re-expression can rescue Nrf2-knockdown-mediated cisplatin sensitivity.\",\n      \"method\": \"Dual-luciferase reporter gene assay, chromatin immunoprecipitation (ChIP), CD99 overexpression and knockdown, CCK-8 cell viability after cisplatin treatment\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct transcription factor binding shown by ChIP and reporter assay, functional rescue experiment, single lab\",\n      \"pmids\": [\"31472965\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Mosaic loss of chromosome Y (LOY) in leukocytes results in reduced CD99 protein abundance on the cell surface in all six types of leukocytes studied, consistent with CD99's pseudoautosomal gene location; CD proteins encoded by autosomal genes are unaffected by LOY.\",\n      \"method\": \"CITE-seq (simultaneous single-cell RNA and surface protein quantification), comparison of LOY vs. non-LOY cells across six leukocyte types\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — single-cell multimodal quantification linking chromosomal aneuploidy to protein-level consequence, multiple cell types, single study\",\n      \"pmids\": [\"34312421\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CD99 (MIC2) is a pseudoautosomal, highly O-glycosylated single-pass transmembrane glycoprotein that exists as two alternatively spliced isoforms (full-length and short truncated) with opposite functional outputs: the full-length isoform suppresses tumor malignancy, migration, and promotes differentiation by maintaining c-Src in an inactive conformation and inhibiting ROCK2, whereas the short isoform promotes invasion and metastasis; during leukocyte transendothelial migration (TEM), endothelial CD99 signals through an ezrin/soluble adenylyl cyclase/PKA complex to stimulate lateral border recycling compartment (LBRC) membrane trafficking and facilitates diapedesis, and heterophilically engages PILRs on neutrophils to support chemokine-induced leukocyte arrest; CD99 also regulates LFA-1/ICAM-1-mediated lymphocyte adhesion, alpha4beta1 integrin activation, and HLA class I surface trafficking via interaction with p230/golgin-245 in the TGN; in Ewing sarcoma, CD99 prevents neural differentiation through ERK/MAPK and NF-κB/miR-34a/Notch pathways and is a receptor for GDF6 prodomain that recruits CSK to inhibit Src; engagement of CD99 by specific antibodies induces non-apoptotic methuosis death in EWS cells via an IGF-1R/RAS/Rac1 complex, and caspase-independent death in T cells requiring heterodimer formation between the two isoforms within glycosphingolipid rafts.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CD99 (MIC2) is a pseudoautosomal, single-pass transmembrane glycoprotein that controls leukocyte trafficking and acts as a context-dependent regulator of tumor malignancy [#1, #13]. It is encoded by a gene whose CpG island remains unmethylated on the inactive X and the Y chromosome, allowing escape from X-inactivation and expression from both sex chromosomes [#2, #3]; loss of chromosome Y in leukocytes correspondingly lowers surface CD99 [#34]. Alternative splicing produces a full-length form and a short truncated form with opposing outputs: the full-length isoform suppresses anchorage-independent growth, anoikis resistance, migration, and metastasis, whereas the short form promotes these phenotypes, with the two isoforms regulating c-Src family kinase activity in opposite directions and Ser168 required for phenotype reversion [#13]. The full-length isoform restrains migration by maintaining c-Src in an inactive conformation, thereby inhibiting ROCK2 and ezrin and driving N-cadherin/beta-catenin to adherens junctions [#17]. In leukocyte transendothelial migration, endothelial CD99 acts at a step distal to PECAM, signaling through a juxtamembrane complex of ezrin, soluble adenylyl cyclase, and PKA to drive membrane trafficking from the lateral border recycling compartment toward sites of diapedesis [#12, #19], and additionally engages PILRs on neutrophils heterophilically to support chemokine-induced arrest [#23]. CD99 also activates alpha4beta1-dependent T-cell adhesion, regulates LFA-1/ICAM-1-mediated lymphocyte aggregation in an isoform-specific manner, and traffics HLA class I to the surface via interaction with p230/golgin-245 in the TGN [#4, #6, #15]. In Ewing sarcoma, CD99 blocks neural differentiation through ERK/MAPK and a miR-34a/Notch/NF-kB axis [#16, #20], and the GDF6 prodomain is a ligand whose binding recruits CSK to the CD99 YQKKK motif to inhibit Src [#29]; antibody engagement of CD99 kills tumor and leukemic cells through non-apoptotic methuosis involving an IGF-1R/RAS/Rac1 complex and through Mdm2 degradation/p53 reactivation [#21, #30].\",\n  \"teleology\": [\n    {\n      \"year\": 1984,\n      \"claim\": \"Established that the CD99/MIC2 locus has the unusual genetic behavior of escaping X-chromosome inactivation, explaining its biallelic expression and pseudoautosomal nature.\",\n      \"evidence\": \"Cell hybrid analysis and expression assays on inactive X chromosomes, with methylation analysis of the 5' CpG island\",\n      \"pmids\": [\"6540985\", \"2456574\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address protein function\", \"Does not link expression level to any cellular phenotype\"]\n    },\n    {\n      \"year\": 1989,\n      \"claim\": \"Defined CD99 as a proline-rich, glycosylated single-pass integral membrane protein with an extracellular epitope-bearing domain, and first implicated it in T-cell adhesion/rosette formation.\",\n      \"evidence\": \"cDNA cloning, sequencing, hydropathy analysis, monoclonal antibody epitope mapping, and adhesion assays\",\n      \"pmids\": [\"2465491\", \"2479542\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No signaling partners identified\", \"Adhesion mechanism and ligand unknown\", \"No mutagenesis validation of topology\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Showed that alternative splicing produces full-length and truncated isoforms with opposite effects on LFA-1/ICAM-1-mediated adhesion, introducing the central theme of isoform antagonism.\",\n      \"evidence\": \"Isoform transfection into B cells with LFA-1/ICAM-1 blocking antibodies and aggregation assays\",\n      \"pmids\": [\"9278313\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of opposing isoform activity unresolved\", \"No structural explanation for short-form dominance\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Demonstrated CD99 acts upstream of integrin activation, stimulating alpha4beta1-VCAM-1-dependent firm adhesion under shear without engaging the LFA-1/ICAM-1 axis, and that aggregation requires PTK/PKC/actin signaling.\",\n      \"evidence\": \"Flow chamber adhesion under shear with integrin-specific blocking, plus pharmacological inhibitors of PTK, PKC, and actin polymerization\",\n      \"pmids\": [\"11069091\", \"10709783\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct CD99 effector linking it to integrin activation not identified\", \"Distinction between cis and trans signaling unclear\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Resolved how isoforms encode opposite outputs in T cells: covalent heterodimers within glycosphingolipid rafts are required for death signaling while the long form alone drives adhesion, tying death induction to raft integrity.\",\n      \"evidence\": \"Reconstitution of individual and combined isoforms in CD99-deficient Jurkat cells, raft fractionation, cholesterol depletion, sphingomyelin degradation assay\",\n      \"pmids\": [\"12368226\", \"11290771\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream caspase-independent death effectors not defined\", \"Physiological trigger for heterodimerization unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identified CD99 as a tumor suppressor whose anti-migratory, anti-metastatic action operates through caveolin-1 upregulation and c-Src inhibition, establishing the c-Src axis in solid tumors.\",\n      \"evidence\": \"CD99 transfection in osteosarcoma, xenografts, migration and anchorage-independence assays, caveolin-1 antisense, c-Src kinase activity assay\",\n      \"pmids\": [\"16421247\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CD99 inhibits c-Src biochemically not shown here\", \"Caveolin-1 dependence of metastasis not directly tested in vivo\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Confirmed reciprocal isoform function in malignancy and pinpointed Ser168 as a determinant of phenotype reversion, unifying the suppressor/promoter dichotomy with bidirectional c-Src regulation.\",\n      \"evidence\": \"Forced expression of full-length and short isoforms with Ser168 mutagenesis, in vivo metastasis, c-Src activity assays\",\n      \"pmids\": [\"17471235\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which Ser168 alters c-Src regulation unresolved\", \"Whether Ser168 is phosphorylated not established\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Placed CD99 as a distinct, sequential mediator of neutrophil diapedesis acting downstream of PECAM, defining a stepwise junction-crossing model.\",\n      \"evidence\": \"In vitro TEM with cell-side-specific Fab blocking, confocal localization of arrested cells, additivity with PECAM blockade\",\n      \"pmids\": [\"17202377\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular signaling driving the CD99 step not yet defined\", \"Identity of the homophilic binding interface unknown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Established CD99 as essential for diapedesis in vivo and species-specific in its homophilic binding, and revealed a TGN trafficking role coupling CD99 to HLA class I surface expression via p230/golgin-245.\",\n      \"evidence\": \"Murine peritonitis with antibody blockade and intravital microscopy; co-IP of CD99 with HLA class I and p230, IFN-gamma stimulation\",\n      \"pmids\": [\"18923973\", \"18849489\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the GRIP-domain p230 interaction mechanistically gates HLA trafficking unclear\", \"Connection between TEM and TGN functions not integrated\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined CD99 as an oncogenic block to neural differentiation in Ewing sarcoma operating through suppression of ERK1/2, providing a therapeutic rationale for CD99 targeting.\",\n      \"evidence\": \"shRNA knockdown in EWS lines, xenografts, neurite/beta-III tubulin readouts, ERK1/2 phosphorylation\",\n      \"pmids\": [\"20197622\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct link between CD99 and ERK regulation not mapped\", \"Differentiation effectors downstream of ERK undefined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Connected CD99 anti-migratory function to a defined cascade (inactive c-Src to ROCK2 inhibition to ezrin loss and junctional N-cadherin/beta-catenin), and ordered PVR between PECAM and CD99 in diapedesis.\",\n      \"evidence\": \"CD99wt transfection with cytoskeletal imaging, ROCK2 and c-Src activity assays; sequential TEM blocking with LBRC localization and Shp-2 recruitment\",\n      \"pmids\": [\"23644663\", \"23333754\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of CD99-c-Src interaction unknown\", \"How CD99 and PVR coordinate within LBRC unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Delineated the endothelial CD99 signaling machine for diapedesis (ezrin/sAC/PKA driving LBRC trafficking) and a parallel CD99 to miR-34a/Notch/NF-kB axis controlling EWS differentiation.\",\n      \"evidence\": \"Co-IP of CD99-ezrin-sAC complex with sAC/PKA inhibition in vitro and in vivo; CD99 silencing with miR-34a/Notch/NF-kB readouts and exosome transfer\",\n      \"pmids\": [\"26101266\", \"26616853\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CD99 cytoplasmic tail nucleates the AKAP complex structurally undefined\", \"Whether the two signaling roles share components unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed that antibody engagement of CD99 kills Ewing sarcoma cells by methuosis through an internalized IGF-1R/RAS/Rac1 complex, revealing a non-apoptotic death modality exploitable therapeutically.\",\n      \"evidence\": \"Anti-CD99 mAb with co-IP of IGF-1R/RAS/Rac1, RAB5/LAMP-1 endosomal sorting, IGF-1R inhibition, xenograft validation\",\n      \"pmids\": [\"27835596\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trigger for complex assembly upon CD99 ligation unclear\", \"Why immature vacuole accumulation is lethal not mechanistically resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended CD99 antibody-induced, SRC-dependent killing to AML/MDS and identified CD99 as a leukemic stem cell marker, and identified endothelial CD99-PILR heterophilic engagement supporting leukocyte arrest.\",\n      \"evidence\": \"Anti-CD99 mAb with SRC-kinase inhibition, limiting-dilution xenotransplant; CD99 knockout, intravital microscopy, CD99-PILR co-precipitation and flow assays\",\n      \"pmids\": [\"28123069\", \"28223280\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How antibody ligation engages SRC for death not detailed\", \"Relative contribution of homophilic versus PILR heterophilic binding in vivo unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified GDF6 prodomain as a bona fide CD99 ligand that recruits CSK to the intracellular YQKKK motif to inhibit Src, mechanistically grounding CD99's growth-restraining c-Src control and linking it to Klippel-Feil syndrome mutants.\",\n      \"evidence\": \"Co-IP and domain mapping of GDF6 prodomain-CD99, CSK recruitment to YQKKK, Src activity and growth-arrest assays, disease-mutant functional analysis\",\n      \"pmids\": [\"33147457\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether GDF6-CD99 signaling operates in TEM or immune contexts untested\", \"Structural basis of prodomain-ectodomain recognition unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single glycoprotein integrates its opposing isoform outputs, multiple heterophilic ligands (PILR, GDF6 prodomain), and distinct effector axes (c-Src/CSK, ezrin/sAC/PKA, IGF-1R/RAS/Rac1) into context-specific outcomes remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural model of CD99 signaling complexes\", \"Determinants selecting adhesion versus death versus trafficking outputs unknown\", \"Physiological ligand usage across cell types not mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [4, 10, 14]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [23, 29]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [6, 17, 29]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [15, 19]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 10, 15]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [10, 12, 19, 23]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [16, 20, 21, 30]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [17, 29]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [8, 21, 30]}\n    ],\n    \"complexes\": [\n      \"CD99-ezrin-soluble adenylyl cyclase (sAC) complex\",\n      \"CD99 long/short isoform heterodimer (glycosphingolipid rafts)\",\n      \"IGF-1R/RAS/Rac1 complex\"\n    ],\n    \"partners\": [\n      \"EZR\",\n      \"PILRA\",\n      \"GDF6\",\n      \"CSK\",\n      \"HLA class I\",\n      \"GOLGA4\",\n      \"CAV1\",\n      \"SRC\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}