{"gene":"CD6","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":1991,"finding":"CD6 is a type I integral membrane protein with three extracellular SRCR (scavenger receptor cysteine-rich) domains. The cytoplasmic domain contains serine residues that are substrates for phosphorylation during T cell activation.","method":"cDNA cloning, COS cell transfection, RNA blot hybridization, sequence analysis","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1 / Strong — full-length cDNA isolated, expressed in COS cells, confirmed reactivity with all available anti-CD6 mAbs; phosphorylation confirmed biochemically; replicated across multiple studies","pmids":["1919444"],"is_preprint":false},{"year":1989,"finding":"CD6 is a 130 kDa monomeric glycoprotein with intrachain disulfide bonds that is serine-phosphorylated in activated T cells and contains a protease-sensitive site. Two distinct epitopes (recognized by anti-T12 and anti-2H1) convey different T cell activation signals.","method":"Surface radiolabeling, immunoprecipitation, Western blot, SDS-PAGE under reducing/non-reducing conditions","journal":"Molecular immunology","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple biochemical methods (radiolabeling, Western blot, reducing/non-reducing PAGE), reproduced in multiple subsequent studies","pmids":["2481822"],"is_preprint":false},{"year":1990,"finding":"CD6 exists as two molecular forms in dynamic equilibrium: an unphosphorylated 105 kDa form in resting T cells that rapidly converts to a phosphorylated 130 kDa form upon PKC activation or serum exposure. Alkaline phosphatase treatment of the 130 kDa form converts it back to the 105 kDa form, demonstrating the conversion is phosphorylation-dependent.","method":"Surface 125I-labeling, immunoprecipitation, 32P metabolic labeling, alkaline phosphatase treatment, pulse-chase experiments","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 / Strong — enzymatic dephosphorylation confirmed the two-form equilibrium, multiple orthogonal biochemical methods in a single study","pmids":["2384666"],"is_preprint":false},{"year":1991,"finding":"CD6 undergoes N-glycosylation (nascent polypeptide 88 kDa → immature N-glycosylated form 110 kDa → mature surface form 130 kDa after addition of sulfated O-linked oligosaccharide) and is phosphorylated on serine in resting cells with hyperphosphorylation by PKC activators. Concanavalin A-activated cells are phosphorylated at additional site(s).","method":"Pulse-chase biosynthetic labeling, tunicamycin treatment, 32P-labeling, immunoprecipitation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — detailed biosynthetic labeling with tunicamycin confirmed N-glycosylation; multiple orthogonal methods in one rigorous study","pmids":["2016320"],"is_preprint":false},{"year":1993,"finding":"CD6 cytoplasmic tyrosine residues are phosphorylated upon T cell activation via TCR/CD3 crosslinking. Co-crosslinking CD3 with CD4 produces the highest CD6 tyrosine phosphorylation, whereas crosslinking CD2, CD4, or CD28 alone does not phosphorylate CD6.","method":"Anti-phosphotyrosine immunoprecipitation, T cell stimulation assays with anti-CD3/CD2/CD4/CD28 crosslinking","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct biochemical demonstration of tyrosine phosphorylation downstream of TCR signaling; reproduced in multiple subsequent studies","pmids":["7678115"],"is_preprint":false},{"year":1995,"finding":"ALCAM (CD166) is a CD6 ligand expressed on thymic epithelial cells. COS cells expressing CD6 adhere to thymic epithelial cells; a CD6-immunoglobulin fusion protein binds ALCAM-transfected COS cells; and ALCAM-Rg fusion protein binds CD6-expressing COS cells, establishing bidirectional CD6-ALCAM interaction.","method":"COS cell transfection, cell adhesion assays, immunoglobulin fusion protein binding assays, cDNA cloning, antibody blocking","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1 / Strong — reciprocal binding demonstrated with fusion proteins, functional adhesion assays, antibody blocking; reproduced extensively","pmids":["7760007"],"is_preprint":false},{"year":1995,"finding":"The membrane-proximal SRCR domain (domain 3) of CD6 contains the ALCAM binding site. Domain-specific CD6-Rg fusion proteins showed that only those containing the third (membrane-proximal) SRCR domain bind ALCAM, and mAbs binding this domain preferentially block CD6-ALCAM binding.","method":"Domain-specific CD6 immunoglobulin fusion proteins in cell adhesion assays, antibody blocking experiments","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — domain-deletion fusion protein analysis plus antibody blocking; independently confirmed by mutagenesis studies","pmids":["7543097"],"is_preprint":false},{"year":1996,"finding":"The amino-terminal Ig-like domain of ALCAM binds specifically to the third membrane-proximal SRCR domain of CD6 with 1:1 stoichiometry, as determined using thrombin-cleaved single-domain fusion proteins in binding assays.","method":"Truncated immunoglobulin fusion proteins, receptor-ligand binding assays, stoichiometry determination","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted interaction with single-domain proteins, stoichiometry explicitly determined; domain mapping replicated across labs","pmids":["8663238"],"is_preprint":false},{"year":1997,"finding":"Three residues in the membrane-proximal SRCR domain of CD6 (in a region of low sequence conservation) are critical for ALCAM binding; mutating these residues abolishes ligand binding without affecting binding of conformationally sensitive anti-CD6 mAbs, demonstrating a defined binding interface.","method":"Site-directed mutagenesis of CD6D3, ALCAM binding assays, anti-CD6 mAb panel binding","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — systematic mutagenesis of 15 mutants with ligand binding and antibody binding controls; rigorous structure-function analysis","pmids":["9054570"],"is_preprint":false},{"year":1996,"finding":"The CD6 binding site on ALCAM maps to residues on the predicted A'GFCC'C\" beta-sheet face of its N-terminal Ig domain, as determined by targeted mutagenesis. This site is conserved across species, and non-conserved residues map to the opposite face.","method":"Targeted mutagenesis of ALCAM, CD6 binding assays","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — systematic mutagenesis with binding readout; consistent with parallel structure-function work on CD6","pmids":["8823162"],"is_preprint":false},{"year":1995,"finding":"Human CD6 possesses a 244-amino acid cytoplasmic domain (confirmed by cDNA isolation) containing two proline-rich SH3 domain-binding motifs, a serine-threonine-rich repeated motif, PKC phosphorylation sites, and casein kinase-2 phosphorylation sites. Previously reported short cytoplasmic domain resulted from a frame-shift due to alternative splicing.","method":"RT-PCR, cDNA cloning, sequence analysis, transfection/immunoprecipitation confirmation","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 1 / Strong — full-length cDNA isolation with sequence analysis confirmed 244 aa cytoplasmic domain; transfection confirmed protein expression","pmids":["7589069"],"is_preprint":false},{"year":1997,"finding":"The two C-terminal tyrosine residues (Y629 and Y662) in the CD6 cytoplasmic domain are critical for tyrosine phosphorylation following TCR crosslinking. CD6 isoform CD6e (lacking proline-rich motifs) is not phosphorylated. All CD6 isoforms including CD6e can increase intracellular Ca2+ upon CD6/TCR co-ligation through a region N-terminal of amino acid 555.","method":"Chimeric receptor constructs (extracellular mouse CD6 + human CD6 cytoplasmic variants), stable expression, anti-phosphotyrosine Western blot, intracellular Ca2+ flux measurement","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 1 / Strong — systematic point mutants and truncation constructs with two distinct functional readouts (phosphorylation and Ca2+ flux); dissociates the two functions","pmids":["9394826"],"is_preprint":false},{"year":2006,"finding":"CD6 costimulation is mediated through the phosphorylated cytoplasmic tyrosine Y662, which directly recruits the adaptor SLP-76. A direct interaction between SLP-76 and a phosphorylated CD6 peptide (Kd = 0.5 μM at 37°C) was demonstrated, and co-precipitation of SLP-76 with CD6 was shown in normal human T cells. CD6 mutant Y662F abolishes both costimulation and SLP-76 interaction.","method":"Phosphopeptide binding assay (Kd measurement), co-immunoprecipitation from primary T cells, CD6 Y662F mutant analysis in T-cell hybridoma","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct biochemical binding with Kd measurement, co-precipitation in primary T cells, and mutagenesis confirmation; multiple orthogonal methods","pmids":["16914752"],"is_preprint":false},{"year":2004,"finding":"CD6 physically associates with the TCR/CD3 complex (shown by co-immunoprecipitation, co-capping, and FRET). CD6 and its ligand CD166/ALCAM co-localize with TCR/CD3 at the central SMAC of the immunological synapse. Soluble recombinant CD6 reduces Ag-specific T-APC conjugate formation and inhibits CD3-mediated T cell proliferation in a dose-dependent manner.","method":"Co-immunoprecipitation, co-capping, FRET, confocal microscopy of antigen-specific T-APC conjugates, proliferation assays with soluble rCD6","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (co-IP, co-capping, FRET, imaging) all supporting the same conclusion; reproduced by other labs","pmids":["15294938"],"is_preprint":false},{"year":2005,"finding":"CD6-ALCAM interactions are actively recruited to the antigen-induced DC-T cell contact zone and are required for stable DC-T cell conjugate formation and for sustained T cell proliferation. CD6-ALCAM engagement provides costimulatory signals comparable to CD3/CD28 co-crosslinking when CD6 and CD3 are simultaneously crosslinked.","method":"Fluorescence microscopy of DC-T cell contacts, antibody blocking of ALCAM or CD6, proliferation assays, reporter gene assays for transcriptional activity","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct imaging of synapse recruitment, multiple blocking experiments, functional proliferation readouts; replicated across labs","pmids":["16352806"],"is_preprint":false},{"year":2004,"finding":"CD6 binds CD166 (ALCAM) with Kd = 0.4–1.0 μM and fast off-rate (Koff ≥ 0.4–0.63 s−1), while CD166 homophilic interaction has ~100-fold lower affinity (Kd = 29–48 μM). Soluble monomeric CD6 and CD166 at concentrations blocking the CD6/CD166 interaction inhibit antigen-specific human T cell responses.","method":"Surface plasmon resonance/kinetic binding assays, human T cell antigen-specific proliferation inhibition with soluble monomeric proteins","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 1 / Strong — quantitative biophysical measurement of binding kinetics plus functional blocking in primary T cells; first kinetic characterization of this interaction","pmids":["15048703"],"is_preprint":false},{"year":2006,"finding":"CD6 ligation (with anti-CD6 mAbs or ALCAM-Fc) induces time- and dose-dependent activation of ERK1/2, p38, and JNK MAPK cascades in T cells. The C-terminal cytoplasmic region of CD6 and Src tyrosine kinases are required for CD6-induced ERK1/2 activation. CD6 ligation also activates c-Fos/AP-1 transcription, and CD6/TCR co-ligation is synergistic.","method":"Phospho-specific Western blot for MAPK activation, cytoplasmic deletion mutants, Src kinase inhibitors, reporter gene assays (SRE/AP-1)","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 / Strong — systematic mutant analysis with multiple MAPK readouts and pharmacological inhibitors; three different anti-CD6 mAbs and ALCAM-Fc all gave same result","pmids":["16818773"],"is_preprint":false},{"year":2002,"finding":"CD5 and CD6 physically associate at the lymphocyte cell membrane (co-immunoprecipitation from Brij 96 but not NP-40 lysates), and both co-localize at the immunological synapse. This association is independent of co-expression of other lymphocyte receptors and the integrity of the CD5 cytoplasmic region.","method":"Co-immunoprecipitation, FRET, co-capping, co-modulation experiments, confocal microscopy of T cell-APC conjugates","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (co-IP, FRET, co-capping, imaging) from a single study, with appropriate detergent controls","pmids":["12473675"],"is_preprint":false},{"year":2003,"finding":"CD6 (rat homolog OX52) co-precipitates with CD5, and the fraction of CD5 associated with CD6 is highly phosphorylated in kinase assays. CD6 associates with Lck, Fyn, ZAP-70, and uniquely with the Tec-family kinase Itk (absent from CD2, CD5, TCR complexes). Lck together with Itk effectively phosphorylates CD5 cytoplasmic peptides, suggesting CD6 regulates CD5 tyrosine phosphorylation.","method":"Immunoprecipitation, in vitro kinase assays with synthetic peptides, Western blot","journal":"Journal of leukocyte biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-precipitation and in vitro kinase assays in a single lab; identification of Itk as unique CD6 partner not independently replicated","pmids":["12525577"],"is_preprint":false},{"year":2005,"finding":"Syntenin-1, a PDZ domain-containing scaffolding protein, interacts with the cytoplasmic tail of CD6 through the C-terminal sequence -YDDISAA of CD6 and both PDZ domains of syntenin-1. This interaction was confirmed by yeast two-hybrid, pull-down, and co-immunoprecipitation; syntenin-1 accumulates at CD6 caps and at the immunological synapse.","method":"Yeast two-hybrid screening, pull-down assays, co-immunoprecipitation, mutational analysis, confocal microscopy","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — yeast two-hybrid discovery confirmed by pull-down and co-IP, with mutational mapping; localization confirmed by imaging","pmids":["16034076"],"is_preprint":false},{"year":2007,"finding":"CD6 binds to pathogen-associated molecular patterns including lipoteichoic acid (Gram-positive bacteria) and LPS (Gram-negative bacteria). The Kd of the LPS-rsCD6 interaction is 2.69 × 10−8 M. Membrane CD6 also retains LPS-binding ability and activates the MAPK signaling cascade. Recombinant soluble CD6 administration before lethal LPS challenge significantly improves mouse survival and reduces TNF-α, IL-6, and IL-1β levels.","method":"Binding assays with recombinant soluble CD6, Kd determination, bacterial aggregation assays, MAPK activation Western blot, in vivo LPS challenge with survival endpoint and cytokine ELISA","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro Kd measurement, in vivo protection model, MAPK signaling assay; multiple orthogonal approaches in one study","pmids":["17601777"],"is_preprint":false},{"year":2007,"finding":"An alternative CD6 isoform (CD6Δd3), resulting from exon 5 skipping (loss of SRCR domain 3), lacks the CD166 binding domain and fails to localize at the immunological synapse during antigen presentation, whereas full-length CD6 (with domain 3) targets to the immunological synapse. CD6Δd3 is markedly upregulated upon T cell activation.","method":"RT-PCR cloning of isoforms, immunoblotting, flow cytometry with domain-specific antibodies, live confocal microscopy of T cell-APC contacts, single-cell RT-PCR","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct imaging comparing full-length vs. Δd3 localization, confirmed by immunoblot and flow cytometry; domain 3 identified as necessary and sufficient for synapse targeting","pmids":["17371992"],"is_preprint":false},{"year":2014,"finding":"T cell activation regulates CD6 alternative splicing (exon 5 skipping producing CD6Δd3) through increased RNA Pol II occupancy and chromatin acetylation. The splicing factor SRSF1 binds to a regulatory element in CD6 intron 4 and promotes exon 5 inclusion; SRSF1 is downregulated upon T cell activation and its recruitment to the CD6 transcript is impaired by increased chromatin acetylation.","method":"Chromatin immunoprecipitation (RNA Pol II and histone acetylation), RT-PCR of splice variants, HDAC inhibitor treatment, RNA immunoprecipitation of SRSF1","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 / Strong — ChIP, RNA-IP, and pharmacological manipulation all converge on the same SRSF1/chromatin acetylation mechanism; multiple orthogonal methods","pmids":["24890719"],"is_preprint":false},{"year":2014,"finding":"Quantitative mass spectrometry of primary CD4+ T cell signalosomes shows that CD6 recruits SLP-76 and the GEF Vav1 independently of the LAT adaptor, constituting a LAT-independent TCR signaling hub. CD6 also recruits ZAP70 to its signalosome.","method":"Knock-in affinity-tagged proteins in primary mouse T cells, quantitative MS of co-purified complexes (time-resolved), comparison between LAT-present and LAT-absent conditions","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 1 / Strong — quantitative MS with affinity-tagged knock-ins in primary T cells, time-resolved dynamics, genetic validation with LAT-deficient context","pmids":["24584089"],"is_preprint":false},{"year":2011,"finding":"CD6 expression alone (without ligand engagement) attenuates early TCR signaling (Ca2+ mobilization) and late responses (IL-2 release). Removal of the cytoplasmic domain of CD6 abolishes this inhibitory effect. Knockdown of CD6 by morpholino enhanced anti-CD3-induced Ca2+ signals in primary human T cells. CD6-CD166 interaction blocking with anti-CD166 antibodies increased T cell proliferation, while anti-CD6 antibodies decreased it.","method":"Single-cell Ca2+ flux measurements, Jurkat cells expressing human CD6 vs. CD6 cytoplasmic deletion mutant, morpholino CD6 knockdown in primary human T cells, IL-2 ELISA, proliferation assays","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple cell systems (Jurkat, primary T cells), cytoplasmic domain deletion mutant, knockdown all converge on same inhibitory function","pmids":["21956609"],"is_preprint":false},{"year":2015,"finding":"Crystal structures of the three SRCR domains of CD6 and two N-terminal domains of CD166 were solved by X-ray crystallography. The structure reveals a nonlinear organization of consecutive SRCR domains. An MS-associated SNP in CD6 causes glycosylation that sterically hinders the CD6/CD166 interaction. Native mass spectrometry showed competition between CD6/CD166 heterophilic and CD166/CD166 homophilic interactions.","method":"X-ray crystallography, native mass spectrometry, SNP glycosylation analysis","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures of both proteins solved, SNP functional consequence directly demonstrated, competition between interactions shown by native MS","pmids":["26146185"],"is_preprint":false},{"year":2017,"finding":"CD318 is a second CD6 ligand distinct from CD166/ALCAM. CD318 KO mice, like CD6 KO mice, are protected in experimental autoimmune encephalomyelitis. CD318 is highly expressed in synovial tissues and participates in CD6-dependent adhesion of T cells to synovial fibroblasts. Soluble CD318 is chemoattractive to T cells.","method":"Identification by mAb 3A11, CD318 KO mouse in EAE model, T cell adhesion assays to synovial fibroblasts, CD6-CD318 binding assays, chemotaxis assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic (KO mice), binding assays, functional adhesion and chemotaxis assays; multiple methods identifying CD318 as bona fide CD6 ligand","pmids":["28760953"],"is_preprint":false},{"year":2017,"finding":"CD6-deficient T cells exhibit augmented initial activation but significantly reduced survival and proliferation after activation, leading to decreased Th1 and Th17 polarization. CD6-deficient activated T cells show impaired migration through brain microvascular endothelial cell monolayers. CD6 is thus a positive regulator of activated T cell survival/proliferation and infiltration.","method":"CD6 KO mice in EAU/EAE model, adoptive transfer of CD6-/- T cells, in vitro transendothelial migration assay, T cell differentiation assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mice with multiple functional readouts (proliferation, survival, migration, cytokine polarization), adoptive transfer confirming T cell-intrinsic effects","pmids":["28209777"],"is_preprint":false},{"year":2016,"finding":"CD6 modulates thymocyte selection: CD6-/- thymi show reduced CD4+ and CD8+ single-positive subsets; double-positive thymocytes show increased Ca2+ mobilization upon TCR crosslinking; and CD6-/- T cells have a T cell-autonomous selective disadvantage during development confirmed by bone marrow chimeras. CD6-/- mice display increased regulatory T cell frequencies but with diminished suppressive activity.","method":"CD6-/- mice with TCR-transgenic crosses (OT-I, Marilyn), bone marrow chimeras, Ca2+ flux measurement, T reg suppression assays, collagen-induced arthritis model","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple mouse genetic models (KO, TCR transgenic, bone marrow chimera), several functional assays confirming T cell-intrinsic developmental role","pmids":["27377588"],"is_preprint":false},{"year":2021,"finding":"The CD6 signalosome, mapped by CRISPR/Cas9-based quantitative MS in primary mouse T cells, contains both positive (SLP-76, ZAP70, VAV1) and negative (UBASH3A/STS-2) regulators of T cell activation. CD6 also associates constitutively (TCR-independent) with proteins involved in T cell transendothelial migration. UBASH3A (STS-2) is identified as a component of the CD6 signalosome.","method":"CRISPR/Cas9 knock-in of tagged proteins in primary mouse T cells, quantitative mass spectrometry of CD6 signalosome, comparison with LAT and CD5 signalosomes","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1 / Strong — CRISPR knock-in in primary T cells with quantitative MS; comprehensive signalosome mapping with comparison to other signalosomes; identification of UBASH3A as negative regulator","pmids":["33125054"],"is_preprint":false},{"year":2017,"finding":"CD6 costimulation requires bivalent recruitment of a GADS/SLP-76 complex: the SH2 domain of GADS binds phosphorylated Y629 of CD6, and SLP-76 binds phosphorylated Y662. Both Y629F and Y662F mutations abolish costimulation by CD6 in human Jurkat and primary T cells.","method":"Biochemical interaction mapping (SH2 domain binding), CD6 Y629F and Y662F mutant analysis, Jurkat and primary T cell functional assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — systematic mutagenesis of both tyrosines, direct biochemical identification of GADS as Y629 binder, functional validation in two cell systems","pmids":["28289074"],"is_preprint":false},{"year":1997,"finding":"CD6 ligation (with anti-CD6 antibody) protects CLL B cells from anti-IgM-induced apoptosis by downregulating bax-alpha mRNA and maintaining bcl-2 mRNA levels, resulting in an increased Bcl-2/Bax ratio.","method":"Anti-CD6 crosslinking of CLL B cells, flow cytometry for apoptosis, Northern blot for bax and bcl-2 mRNA","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mRNA-level mechanism shown in primary CLL cells with direct functional apoptosis readout, but single lab study using antibody crosslinking","pmids":["9108402"],"is_preprint":false},{"year":2014,"finding":"CD6 interacts with Galectin-1 and Galectin-3 in a carbohydrate-dependent manner. This interaction interferes with superantigen-induced T cell proliferation and cell adhesion mediated by CD6-CD166/ALCAM. CD6 expression protects cells from galectin-induced apoptosis.","method":"Co-immunoprecipitation/pull-down, proliferation assays, cell adhesion assays, apoptosis assays with galectin treatment","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — binding and functional data shown, but single lab with limited mechanistic depth on carbohydrate specificity","pmids":["24945728"],"is_preprint":false},{"year":2014,"finding":"Dynamic coupling of ALCAM to the actin cortex (through intracellular adaptor proteins) strengthens CD6-ALCAM cell adhesion bonds and stiffens the cortex, but does not influence the intrinsic affinity of CD6-ALCAM bonds. ALCAM recruitment to adhesion sites and membrane tether formation depend on actin cytoskeletal interactions.","method":"Single-cell force spectroscopy combined with TIRF microscopy, ALCAM cytoplasmic tail mutants expressed in ALCAM-expressing cells","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1 / Strong — single-molecule force spectroscopy with TIRF, systematic ALCAM mutants; rigorously separates affinity from avidity effects","pmids":["24496453"],"is_preprint":false},{"year":2011,"finding":"The MS susceptibility allele in CD6 (rs17824933) is associated with decreased expression of full-length CD6 in CD4+ and CD8+ T cells due to underexpression of exon 5 (which encodes the ALCAM binding domain), and this leads to diminished long-term proliferation of CD4+ T cells. siRNA knockdown of full-length CD6 recapitulates the proliferation defect.","method":"Flow cytometry for CD6 protein levels in primary T cells stratified by genotype, exon-specific siRNA knockdown, long-term proliferation assay","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic stratification combined with mechanistic siRNA experiment; directly links SNP to molecular mechanism (exon 5/ALCAM-binding domain) to proliferation phenotype","pmids":["21849685"],"is_preprint":false},{"year":2004,"finding":"A second CD6 ligand (the 3A11 antigen, later identified as CD318) distinct from CD166/ALCAM is expressed on cells derived from thymus, skin, synovium, and cartilage, and is enhanced by IFN-γ. Soluble CD6-Ig fusion protein immunoprecipitates the 130 kDa 3A11 antigen, and it is not reduced by CD166-specific siRNA knockdown, confirming it is a distinct ligand.","method":"Flow cytometry, immunoprecipitation with CD6-Ig fusion protein, confocal microscopy, CD166 siRNA knockdown, T cell adhesion inhibition assay","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — CD6-Ig pull-down, siRNA-based distinction from CD166, functional adhesion assay; identity later confirmed as CD318 (PMID 28760953)","pmids":["15528349"],"is_preprint":false},{"year":2016,"finding":"CD6 regulates intestinal ischemia/reperfusion injury by controlling the self-renewal of B1a cells outside of the peritoneal cavity. CD6 is selectively expressed on B1 cells outside bone marrow and peritoneum; CD6-/- mice have reduced B1a cell populations and decreased pathogenic natural IgM titers, resulting in protection from intestinal I/R injury.","method":"CD6-/- mice in intestinal I/R model, flow cytometry of B1a cell populations, natural IgM ELISA, histopathology","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse model with clear phenotype and mechanistic link to B1a cells/IgM, but mechanism of CD6 regulation of B1a self-renewal not biochemically resolved","pmids":["27909060"],"is_preprint":false},{"year":2017,"finding":"Itolizumab (anti-CD6 domain 1 mAb) directly inhibits CD6 receptor hyperphosphorylation upon TCR activation and decreases associated ZAP70 kinase and SLP-76 docking protein levels. It also reduces T cell differentiation to Th17 cells by decreasing pSTAT3 and RORγT transcription factors.","method":"Anti-phospho-CD6 Western blot, co-immunoprecipitation of ZAP70/SLP-76 with CD6, intracellular transcription factor staining, cytokine ELISA, in vivo EAE with mouse anti-mouse CD6D1 antibody","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical data on phosphorylation and signaling complex from one lab; mechanism of domain 1 antibody causing dephosphorylation not fully resolved","pmids":["28672038"],"is_preprint":false},{"year":1997,"finding":"CD6 gene encodes at least five different isoforms arising from variable splicing of exons encoding the cytoplasmic domain. Each of the three extracellular SRCR domains is encoded by a separate exon. CD6 maps to chromosome 11q13, in close proximity to CD5 and within 600 kb of CD20.","method":"Genomic library screening, exon mapping, FISH chromosomal localization, RT-PCR of mRNA transcripts","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 / Strong — genomic structure determined by library screening and sequencing; chromosomal localization by FISH; isoforms confirmed by RT-PCR","pmids":["9013954"],"is_preprint":false},{"year":1990,"finding":"CD6 is expressed in normal human brain cells (not T cells), as demonstrated by immunohistochemistry with multiple anti-CD6 mAbs and Northern blot analysis detecting a 3.1 kb CD6-specific mRNA in brain regions especially basal ganglia and cortex cerebellum.","method":"Immunohistochemistry, Northern blot with cRNA probe, double-staining with hematopoietic cell markers and TCR chain probes","journal":"Journal of neuroimmunology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple anti-CD6 mAbs and Northern blot in multiple brain regions; negative results for T cell markers support native brain expression, but functional consequence not established","pmids":["2211985"],"is_preprint":false},{"year":1994,"finding":"PKC activation by phorbol ester increases CD6 surface expression by increasing CD6 mRNA transcription (~2-3 fold increase in transcription rate shown by nuclear run-on), not by mRNA stabilization. CD2 ligation on thymocytes (but not mature T cells) also upregulates CD6, suggesting developmental regulation of CD6 expression.","method":"Nuclear run-on transcription assay, Northern blot, Western blot, actinomycin D chase experiments, PKC inhibitor experiments, anti-CD2 stimulation","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 / Strong — nuclear run-on directly measures transcription rate; actinomycin D chase rules out mRNA stabilization; multiple inhibitor controls","pmids":["8207228"],"is_preprint":false}],"current_model":"CD6 is a type I transmembrane glycoprotein with three extracellular SRCR domains (domain 3 mediating binding to CD166/ALCAM and CD318, domain 1 mediating LPS/pathogen pattern recognition) and a long cytoplasmic tail (244 aa) that, upon TCR-induced phosphorylation of Y629 and Y662, recruits a bivalent GADS/SLP-76 complex as well as ZAP70, VAV1, and Itk to form a LAT-independent TCR signaling hub that both amplifies (through SLP-76/VAV1) and attenuates (through UBASH3A/STS-2) T cell activation; CD6 also undergoes activation-induced alternative splicing (SRSF1-dependent exon 5 inclusion vs. skipping) that controls whether the protein localizes to the immunological synapse and engages its ligands, thereby modulating thymocyte selection, peripheral T cell survival/proliferation, Th17 differentiation, and T cell transendothelial migration."},"narrative":{"mechanistic_narrative":"CD6 is a type I transmembrane glycoprotein expressed predominantly on T cells that functions as a co-receptor at the immunological synapse, fine-tuning T cell activation, thymocyte selection, and effector differentiation [PMID:1919444, PMID:15294938, PMID:27377588]. Its three extracellular SRCR domains mediate ligand recognition: the membrane-proximal SRCR domain 3 binds the N-terminal Ig domain of CD166/ALCAM with a defined interface and 1:1 stoichiometry and micromolar, fast-off-rate affinity, an interaction that competes with ALCAM homophilic binding and is structurally constrained by a multidomain SRCR organization [PMID:7760007, PMID:7543097, PMID:8663238, PMID:15048703, PMID:26146185]. CD318 is a second, distinct CD6 ligand that supports T cell adhesion and chemotaxis and, like CD6 itself, is required for autoimmune encephalomyelitis pathology [PMID:28760953, PMID:15528349]. CD6 physically associates with the TCR/CD3 complex and partitions to the central supramolecular activation cluster, where ligand engagement provides CD3/CD28-comparable costimulation and stabilizes T cell–APC conjugates [PMID:15294938, PMID:16352806]. Upon TCR engagement its 244-residue cytoplasmic tail is tyrosine-phosphorylated on Y629 and Y662, which respectively recruit GADS and SLP-76 as a bivalent complex; this hub also assembles ZAP70 and VAV1 to drive costimulation independently of the LAT adaptor, while simultaneously recruiting the negative regulator UBASH3A/STS-2, explaining how CD6 both amplifies and restrains activation and engages MAPK (ERK/p38/JNK) and AP-1 outputs [PMID:9394826, PMID:16914752, PMID:24584089, PMID:33125054, PMID:28289074, PMID:16818773]. CD6 output is gated by activation-induced alternative splicing in which SRSF1 normally promotes exon 5 inclusion but is displaced upon activation-linked chromatin acetylation, generating a domain 3–deleted isoform that cannot bind ALCAM or localize to the synapse [PMID:17371992, PMID:24890719]. Genetically, a multiple sclerosis–associated CD6 allele reduces full-length CD6 by lowering exon 5 expression and diminishes long-term CD4+ T cell proliferation, and CD6 deficiency reduces post-activation T cell survival, Th1/Th17 polarization, and transendothelial migration [PMID:21849685, PMID:28209777, PMID:27377588].","teleology":[{"year":1991,"claim":"Establishing CD6 as a type I membrane glycoprotein with three extracellular SRCR domains and a phosphorylatable cytoplasmic tail defined the architecture on which all later signaling and ligand work was built.","evidence":"cDNA cloning and COS cell expression with biochemical phosphorylation analysis","pmids":["1919444","2481822","2384666","2016320"],"confidence":"High","gaps":["Cytoplasmic signaling partners not yet identified","Ligand identity unknown at this stage"]},{"year":1995,"claim":"Discovery that the long 244-residue cytoplasmic domain (initially mis-assigned as short due to splicing) contains SH3-binding and kinase phosphorylation motifs reframed CD6 as a signaling co-receptor rather than a simple adhesion molecule.","evidence":"Full-length cDNA isolation, sequence analysis, transfection confirmation","pmids":["7589069"],"confidence":"High","gaps":["Direct cytoplasmic effectors not yet bound","Functional consequence of motifs untested"]},{"year":1996,"claim":"Identification of ALCAM/CD166 as the CD6 ligand and mapping the interaction to SRCR domain 3 / the ALCAM N-terminal Ig domain established the molecular basis for CD6-mediated cell adhesion.","evidence":"Reciprocal fusion-protein binding, domain-specific constructs, mutagenesis, and stoichiometry determination","pmids":["7760007","7543097","8663238","9054570","8823162"],"confidence":"High","gaps":["Affinity/kinetics not yet quantified","Functional role of adhesion in T cell responses not defined"]},{"year":1997,"claim":"Showing that TCR/CD3 crosslinking drives CD6 cytoplasmic tyrosine phosphorylation at Y629/Y662 and that this is separable from Ca2+ signaling connected CD6 directly into proximal TCR signaling.","evidence":"Anti-phosphotyrosine IP after CD3 crosslinking and chimeric receptor point/truncation mutants with Ca2+ flux readout","pmids":["7678115","9394826","9013954"],"confidence":"High","gaps":["Adaptors recruited to phospho-tyrosines unidentified","Link between phosphorylation and downstream transcription unclear"]},{"year":2005,"claim":"Demonstration that CD6 associates with the TCR/CD3 complex, localizes to the central SMAC, and that CD6-ALCAM engagement provides costimulation and stabilizes DC–T conjugates positioned CD6 at the heart of the immunological synapse.","evidence":"Co-IP, co-capping, FRET, confocal imaging of T-APC conjugates, antibody blocking, and proliferation/reporter assays","pmids":["15294938","16352806","15048703","12473675","12525577"],"confidence":"High","gaps":["Whether CD6 is net activating or inhibitory remained unresolved","Itk-CD6 association reported by a single lab"]},{"year":2006,"claim":"Identifying SLP-76 as a direct phospho-Y662 partner and showing CD6 ligation activates ERK/p38/JNK and AP-1 defined a concrete costimulatory signaling output.","evidence":"Phosphopeptide binding with Kd, co-IP from primary T cells, Y662F mutant, MAPK phospho-blot with Src inhibitors and reporter assays","pmids":["16914752","16818773","16034076"],"confidence":"High","gaps":["Role of the second tyrosine Y629 not defined","How signaling integrates with TCR proximal machinery unclear"]},{"year":2011,"claim":"Genetic and functional dissection of an MS-associated CD6 allele and CD6 knockdown revealed CD6 can attenuate early TCR signaling yet sustain long-term proliferation, exposing its dual regulatory nature.","evidence":"Genotype-stratified flow cytometry, exon-specific siRNA, Ca2+ flux, IL-2 ELISA, proliferation assays in Jurkat and primary T cells","pmids":["21956609","21849685"],"confidence":"High","gaps":["Molecular basis reconciling attenuation vs. costimulation not resolved","In vivo relevance of dual signaling untested"]},{"year":2014,"claim":"Quantitative signalosome MS and splicing studies showed CD6 forms a LAT-independent hub recruiting SLP-76/Vav1/ZAP70 and that SRSF1-controlled exon 5 splicing gates ligand binding and synapse targeting.","evidence":"Knock-in affinity-tagged MS in primary T cells, ChIP/RNA-IP, HDAC inhibitor treatment, isoform imaging","pmids":["24584089","24890719","17371992","24945728"],"confidence":"High","gaps":["Negative regulators of the hub not yet identified","Trigger linking activation to chromatin acetylation incompletely defined"]},{"year":2016,"claim":"Knockout mouse genetics established T cell-intrinsic roles for CD6 in thymocyte selection, regulatory T cell function, and B1a cell homeostasis, moving CD6 from in vitro signaling into developmental and disease physiology.","evidence":"CD6-/- mice with TCR-transgenic crosses, bone marrow chimeras, Treg suppression assays, intestinal I/R model","pmids":["27377588","27909060"],"confidence":"High","gaps":["Mechanism of CD6 control of B1a self-renewal not biochemically resolved","Signaling basis of selection defect unclear"]},{"year":2017,"claim":"Identification of CD318 as a bona fide second ligand, definition of the bivalent GADS(Y629)/SLP-76(Y662) costimulatory module, and demonstration of CD6's role in T cell survival/Th17 differentiation and migration consolidated CD6 as an autoimmunity-relevant co-receptor and therapeutic target.","evidence":"CD318 KO in EAE, adhesion/chemotaxis assays, Y629F/Y662F mutants, CD6-/- T cell transfer and migration assays, anti-CD6 (itolizumab) signaling blockade","pmids":["28760953","28289074","28209777","28672038","15528349"],"confidence":"High","gaps":["Mechanism by which domain 1 antibody causes CD6 dephosphorylation not fully resolved","Relative contributions of ALCAM vs. CD318 in disease not dissected"]},{"year":2021,"claim":"Comprehensive CRISPR-based signalosome mapping revealed CD6 simultaneously recruits positive (SLP-76, ZAP70, VAV1) and negative (UBASH3A/STS-2) regulators plus constitutive migration-associated partners, providing a unified explanation for CD6's bidirectional control of T cell activation.","evidence":"CRISPR/Cas9 knock-in of tagged proteins and quantitative MS in primary mouse T cells compared with LAT and CD5 signalosomes","pmids":["33125054"],"confidence":"High","gaps":["How positive vs. negative outputs are balanced contextually unknown","Structural basis of UBASH3A recruitment undetermined"]},{"year":null,"claim":"How CD6 dynamically switches between amplifying and attenuating TCR signaling in specific T cell subsets and disease contexts, and the in vivo significance of its non-T-cell expression, remain open.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the assembled cytoplasmic signalosome","Functional role of CD6 in brain cells uncharacterized","Quantitative balance of ALCAM vs. CD318 signaling in vivo unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[5,14,26,33]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[13,16,24,29]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[12,23,30]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[20]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,13]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[13,27,28,29]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[16,23,30]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[28]}],"complexes":["CD6 signalosome","TCR/CD3 complex"],"partners":["ALCAM","CD318","SLP-76","GADS","ZAP70","VAV1","UBASH3A","CD5"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P30203","full_name":"T-cell differentiation antigen CD6","aliases":["T12","TP120"],"length_aa":668,"mass_kda":71.8,"function":"Cell adhesion molecule that mediates cell-cell contacts and regulates T-cell responses via its interaction with ALCAM/CD166 (PubMed:15048703, PubMed:15294938, PubMed:16352806, PubMed:16914752, PubMed:24584089, PubMed:24945728). Contributes to signaling cascades triggered by activation of the TCR/CD3 complex (PubMed:24584089). Functions as a costimulatory molecule; promotes T-cell activation and proliferation (PubMed:15294938, PubMed:16352806, PubMed:16914752). Contributes to the formation and maturation of the immunological synapse (PubMed:15294938, PubMed:16352806). Functions as a calcium-dependent pattern receptor that binds and aggregates both Gram-positive and Gram-negative bacteria. Binds both lipopolysaccharide (LPS) from Gram-negative bacteria and lipoteichoic acid from Gram-positive bacteria (PubMed:17601777). LPS binding leads to the activation of signaling cascades and down-stream MAP kinases (PubMed:17601777). Mediates activation of the inflammatory response and the secretion of pro-inflammatory cytokines in response to LPS (PubMed:17601777)","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/P30203/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CD6","classification":"Not Classified","n_dependent_lines":20,"n_total_lines":1208,"dependency_fraction":0.016556291390728478},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CD6","total_profiled":1310},"omim":[{"mim_id":"614810","title":"MULTIPLE SCLEROSIS, SUSCEPTIBILITY TO, 5; MS5","url":"https://www.omim.org/entry/614810"},{"mim_id":"611735","title":"CUB DOMAIN-CONTAINING PROTEIN 1; CDCP1","url":"https://www.omim.org/entry/611735"},{"mim_id":"610408","title":"SOLUTE CARRIER FAMILY 15 (OLIGOPEPTIDE TRANSPORTER), MEMBER 3; SLC15A3","url":"https://www.omim.org/entry/610408"},{"mim_id":"607639","title":"SCAVENGER RECEPTOR CYSTEINE-RICH FAMILY MEMBER WITH 4 DOMAINS; SSC4D","url":"https://www.omim.org/entry/607639"},{"mim_id":"602592","title":"LYMPHOCYTE ANTIGEN CD5-LIKE; CD5L","url":"https://www.omim.org/entry/602592"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"intestine","ntpm":12.6},{"tissue":"lymphoid tissue","ntpm":40.4}],"url":"https://www.proteinatlas.org/search/CD6"},"hgnc":{"alias_symbol":["Tp120"],"prev_symbol":[]},"alphafold":{"accession":"P30203","domains":[{"cath_id":"3.10.250.10","chopping":"46-101_123-156","consensus_level":"high","plddt":90.242,"start":46,"end":156},{"cath_id":"3.10.250.10","chopping":"161-260","consensus_level":"high","plddt":96.4881,"start":161,"end":260},{"cath_id":"3.10.250.10","chopping":"264-370","consensus_level":"high","plddt":94.7789,"start":264,"end":370}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P30203","model_url":"https://alphafold.ebi.ac.uk/files/AF-P30203-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P30203-F1-predicted_aligned_error_v6.png","plddt_mean":66.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CD6","jax_strain_url":"https://www.jax.org/strain/search?query=CD6"},"sequence":{"accession":"P30203","fasta_url":"https://rest.uniprot.org/uniprotkb/P30203.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P30203/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P30203"}},"corpus_meta":[{"pmid":"19525953","id":"PMC_19525953","title":"Meta-analysis 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The cytoplasmic domain contains serine residues that are substrates for phosphorylation during T cell activation.\",\n      \"method\": \"cDNA cloning, COS cell transfection, RNA blot hybridization, sequence analysis\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — full-length cDNA isolated, expressed in COS cells, confirmed reactivity with all available anti-CD6 mAbs; phosphorylation confirmed biochemically; replicated across multiple studies\",\n      \"pmids\": [\"1919444\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1989,\n      \"finding\": \"CD6 is a 130 kDa monomeric glycoprotein with intrachain disulfide bonds that is serine-phosphorylated in activated T cells and contains a protease-sensitive site. Two distinct epitopes (recognized by anti-T12 and anti-2H1) convey different T cell activation signals.\",\n      \"method\": \"Surface radiolabeling, immunoprecipitation, Western blot, SDS-PAGE under reducing/non-reducing conditions\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple biochemical methods (radiolabeling, Western blot, reducing/non-reducing PAGE), reproduced in multiple subsequent studies\",\n      \"pmids\": [\"2481822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"CD6 exists as two molecular forms in dynamic equilibrium: an unphosphorylated 105 kDa form in resting T cells that rapidly converts to a phosphorylated 130 kDa form upon PKC activation or serum exposure. Alkaline phosphatase treatment of the 130 kDa form converts it back to the 105 kDa form, demonstrating the conversion is phosphorylation-dependent.\",\n      \"method\": \"Surface 125I-labeling, immunoprecipitation, 32P metabolic labeling, alkaline phosphatase treatment, pulse-chase experiments\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — enzymatic dephosphorylation confirmed the two-form equilibrium, multiple orthogonal biochemical methods in a single study\",\n      \"pmids\": [\"2384666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"CD6 undergoes N-glycosylation (nascent polypeptide 88 kDa → immature N-glycosylated form 110 kDa → mature surface form 130 kDa after addition of sulfated O-linked oligosaccharide) and is phosphorylated on serine in resting cells with hyperphosphorylation by PKC activators. Concanavalin A-activated cells are phosphorylated at additional site(s).\",\n      \"method\": \"Pulse-chase biosynthetic labeling, tunicamycin treatment, 32P-labeling, immunoprecipitation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — detailed biosynthetic labeling with tunicamycin confirmed N-glycosylation; multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"2016320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"CD6 cytoplasmic tyrosine residues are phosphorylated upon T cell activation via TCR/CD3 crosslinking. Co-crosslinking CD3 with CD4 produces the highest CD6 tyrosine phosphorylation, whereas crosslinking CD2, CD4, or CD28 alone does not phosphorylate CD6.\",\n      \"method\": \"Anti-phosphotyrosine immunoprecipitation, T cell stimulation assays with anti-CD3/CD2/CD4/CD28 crosslinking\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct biochemical demonstration of tyrosine phosphorylation downstream of TCR signaling; reproduced in multiple subsequent studies\",\n      \"pmids\": [\"7678115\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"ALCAM (CD166) is a CD6 ligand expressed on thymic epithelial cells. COS cells expressing CD6 adhere to thymic epithelial cells; a CD6-immunoglobulin fusion protein binds ALCAM-transfected COS cells; and ALCAM-Rg fusion protein binds CD6-expressing COS cells, establishing bidirectional CD6-ALCAM interaction.\",\n      \"method\": \"COS cell transfection, cell adhesion assays, immunoglobulin fusion protein binding assays, cDNA cloning, antibody blocking\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reciprocal binding demonstrated with fusion proteins, functional adhesion assays, antibody blocking; reproduced extensively\",\n      \"pmids\": [\"7760007\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"The membrane-proximal SRCR domain (domain 3) of CD6 contains the ALCAM binding site. Domain-specific CD6-Rg fusion proteins showed that only those containing the third (membrane-proximal) SRCR domain bind ALCAM, and mAbs binding this domain preferentially block CD6-ALCAM binding.\",\n      \"method\": \"Domain-specific CD6 immunoglobulin fusion proteins in cell adhesion assays, antibody blocking experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — domain-deletion fusion protein analysis plus antibody blocking; independently confirmed by mutagenesis studies\",\n      \"pmids\": [\"7543097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The amino-terminal Ig-like domain of ALCAM binds specifically to the third membrane-proximal SRCR domain of CD6 with 1:1 stoichiometry, as determined using thrombin-cleaved single-domain fusion proteins in binding assays.\",\n      \"method\": \"Truncated immunoglobulin fusion proteins, receptor-ligand binding assays, stoichiometry determination\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted interaction with single-domain proteins, stoichiometry explicitly determined; domain mapping replicated across labs\",\n      \"pmids\": [\"8663238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Three residues in the membrane-proximal SRCR domain of CD6 (in a region of low sequence conservation) are critical for ALCAM binding; mutating these residues abolishes ligand binding without affecting binding of conformationally sensitive anti-CD6 mAbs, demonstrating a defined binding interface.\",\n      \"method\": \"Site-directed mutagenesis of CD6D3, ALCAM binding assays, anti-CD6 mAb panel binding\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — systematic mutagenesis of 15 mutants with ligand binding and antibody binding controls; rigorous structure-function analysis\",\n      \"pmids\": [\"9054570\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The CD6 binding site on ALCAM maps to residues on the predicted A'GFCC'C\\\" beta-sheet face of its N-terminal Ig domain, as determined by targeted mutagenesis. This site is conserved across species, and non-conserved residues map to the opposite face.\",\n      \"method\": \"Targeted mutagenesis of ALCAM, CD6 binding assays\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — systematic mutagenesis with binding readout; consistent with parallel structure-function work on CD6\",\n      \"pmids\": [\"8823162\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Human CD6 possesses a 244-amino acid cytoplasmic domain (confirmed by cDNA isolation) containing two proline-rich SH3 domain-binding motifs, a serine-threonine-rich repeated motif, PKC phosphorylation sites, and casein kinase-2 phosphorylation sites. Previously reported short cytoplasmic domain resulted from a frame-shift due to alternative splicing.\",\n      \"method\": \"RT-PCR, cDNA cloning, sequence analysis, transfection/immunoprecipitation confirmation\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — full-length cDNA isolation with sequence analysis confirmed 244 aa cytoplasmic domain; transfection confirmed protein expression\",\n      \"pmids\": [\"7589069\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The two C-terminal tyrosine residues (Y629 and Y662) in the CD6 cytoplasmic domain are critical for tyrosine phosphorylation following TCR crosslinking. CD6 isoform CD6e (lacking proline-rich motifs) is not phosphorylated. All CD6 isoforms including CD6e can increase intracellular Ca2+ upon CD6/TCR co-ligation through a region N-terminal of amino acid 555.\",\n      \"method\": \"Chimeric receptor constructs (extracellular mouse CD6 + human CD6 cytoplasmic variants), stable expression, anti-phosphotyrosine Western blot, intracellular Ca2+ flux measurement\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — systematic point mutants and truncation constructs with two distinct functional readouts (phosphorylation and Ca2+ flux); dissociates the two functions\",\n      \"pmids\": [\"9394826\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CD6 costimulation is mediated through the phosphorylated cytoplasmic tyrosine Y662, which directly recruits the adaptor SLP-76. A direct interaction between SLP-76 and a phosphorylated CD6 peptide (Kd = 0.5 μM at 37°C) was demonstrated, and co-precipitation of SLP-76 with CD6 was shown in normal human T cells. CD6 mutant Y662F abolishes both costimulation and SLP-76 interaction.\",\n      \"method\": \"Phosphopeptide binding assay (Kd measurement), co-immunoprecipitation from primary T cells, CD6 Y662F mutant analysis in T-cell hybridoma\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct biochemical binding with Kd measurement, co-precipitation in primary T cells, and mutagenesis confirmation; multiple orthogonal methods\",\n      \"pmids\": [\"16914752\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CD6 physically associates with the TCR/CD3 complex (shown by co-immunoprecipitation, co-capping, and FRET). CD6 and its ligand CD166/ALCAM co-localize with TCR/CD3 at the central SMAC of the immunological synapse. Soluble recombinant CD6 reduces Ag-specific T-APC conjugate formation and inhibits CD3-mediated T cell proliferation in a dose-dependent manner.\",\n      \"method\": \"Co-immunoprecipitation, co-capping, FRET, confocal microscopy of antigen-specific T-APC conjugates, proliferation assays with soluble rCD6\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (co-IP, co-capping, FRET, imaging) all supporting the same conclusion; reproduced by other labs\",\n      \"pmids\": [\"15294938\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CD6-ALCAM interactions are actively recruited to the antigen-induced DC-T cell contact zone and are required for stable DC-T cell conjugate formation and for sustained T cell proliferation. CD6-ALCAM engagement provides costimulatory signals comparable to CD3/CD28 co-crosslinking when CD6 and CD3 are simultaneously crosslinked.\",\n      \"method\": \"Fluorescence microscopy of DC-T cell contacts, antibody blocking of ALCAM or CD6, proliferation assays, reporter gene assays for transcriptional activity\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct imaging of synapse recruitment, multiple blocking experiments, functional proliferation readouts; replicated across labs\",\n      \"pmids\": [\"16352806\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CD6 binds CD166 (ALCAM) with Kd = 0.4–1.0 μM and fast off-rate (Koff ≥ 0.4–0.63 s−1), while CD166 homophilic interaction has ~100-fold lower affinity (Kd = 29–48 μM). Soluble monomeric CD6 and CD166 at concentrations blocking the CD6/CD166 interaction inhibit antigen-specific human T cell responses.\",\n      \"method\": \"Surface plasmon resonance/kinetic binding assays, human T cell antigen-specific proliferation inhibition with soluble monomeric proteins\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — quantitative biophysical measurement of binding kinetics plus functional blocking in primary T cells; first kinetic characterization of this interaction\",\n      \"pmids\": [\"15048703\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CD6 ligation (with anti-CD6 mAbs or ALCAM-Fc) induces time- and dose-dependent activation of ERK1/2, p38, and JNK MAPK cascades in T cells. The C-terminal cytoplasmic region of CD6 and Src tyrosine kinases are required for CD6-induced ERK1/2 activation. CD6 ligation also activates c-Fos/AP-1 transcription, and CD6/TCR co-ligation is synergistic.\",\n      \"method\": \"Phospho-specific Western blot for MAPK activation, cytoplasmic deletion mutants, Src kinase inhibitors, reporter gene assays (SRE/AP-1)\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — systematic mutant analysis with multiple MAPK readouts and pharmacological inhibitors; three different anti-CD6 mAbs and ALCAM-Fc all gave same result\",\n      \"pmids\": [\"16818773\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"CD5 and CD6 physically associate at the lymphocyte cell membrane (co-immunoprecipitation from Brij 96 but not NP-40 lysates), and both co-localize at the immunological synapse. This association is independent of co-expression of other lymphocyte receptors and the integrity of the CD5 cytoplasmic region.\",\n      \"method\": \"Co-immunoprecipitation, FRET, co-capping, co-modulation experiments, confocal microscopy of T cell-APC conjugates\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (co-IP, FRET, co-capping, imaging) from a single study, with appropriate detergent controls\",\n      \"pmids\": [\"12473675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CD6 (rat homolog OX52) co-precipitates with CD5, and the fraction of CD5 associated with CD6 is highly phosphorylated in kinase assays. CD6 associates with Lck, Fyn, ZAP-70, and uniquely with the Tec-family kinase Itk (absent from CD2, CD5, TCR complexes). Lck together with Itk effectively phosphorylates CD5 cytoplasmic peptides, suggesting CD6 regulates CD5 tyrosine phosphorylation.\",\n      \"method\": \"Immunoprecipitation, in vitro kinase assays with synthetic peptides, Western blot\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-precipitation and in vitro kinase assays in a single lab; identification of Itk as unique CD6 partner not independently replicated\",\n      \"pmids\": [\"12525577\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Syntenin-1, a PDZ domain-containing scaffolding protein, interacts with the cytoplasmic tail of CD6 through the C-terminal sequence -YDDISAA of CD6 and both PDZ domains of syntenin-1. This interaction was confirmed by yeast two-hybrid, pull-down, and co-immunoprecipitation; syntenin-1 accumulates at CD6 caps and at the immunological synapse.\",\n      \"method\": \"Yeast two-hybrid screening, pull-down assays, co-immunoprecipitation, mutational analysis, confocal microscopy\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — yeast two-hybrid discovery confirmed by pull-down and co-IP, with mutational mapping; localization confirmed by imaging\",\n      \"pmids\": [\"16034076\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CD6 binds to pathogen-associated molecular patterns including lipoteichoic acid (Gram-positive bacteria) and LPS (Gram-negative bacteria). The Kd of the LPS-rsCD6 interaction is 2.69 × 10−8 M. Membrane CD6 also retains LPS-binding ability and activates the MAPK signaling cascade. Recombinant soluble CD6 administration before lethal LPS challenge significantly improves mouse survival and reduces TNF-α, IL-6, and IL-1β levels.\",\n      \"method\": \"Binding assays with recombinant soluble CD6, Kd determination, bacterial aggregation assays, MAPK activation Western blot, in vivo LPS challenge with survival endpoint and cytokine ELISA\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro Kd measurement, in vivo protection model, MAPK signaling assay; multiple orthogonal approaches in one study\",\n      \"pmids\": [\"17601777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"An alternative CD6 isoform (CD6Δd3), resulting from exon 5 skipping (loss of SRCR domain 3), lacks the CD166 binding domain and fails to localize at the immunological synapse during antigen presentation, whereas full-length CD6 (with domain 3) targets to the immunological synapse. CD6Δd3 is markedly upregulated upon T cell activation.\",\n      \"method\": \"RT-PCR cloning of isoforms, immunoblotting, flow cytometry with domain-specific antibodies, live confocal microscopy of T cell-APC contacts, single-cell RT-PCR\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct imaging comparing full-length vs. Δd3 localization, confirmed by immunoblot and flow cytometry; domain 3 identified as necessary and sufficient for synapse targeting\",\n      \"pmids\": [\"17371992\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"T cell activation regulates CD6 alternative splicing (exon 5 skipping producing CD6Δd3) through increased RNA Pol II occupancy and chromatin acetylation. The splicing factor SRSF1 binds to a regulatory element in CD6 intron 4 and promotes exon 5 inclusion; SRSF1 is downregulated upon T cell activation and its recruitment to the CD6 transcript is impaired by increased chromatin acetylation.\",\n      \"method\": \"Chromatin immunoprecipitation (RNA Pol II and histone acetylation), RT-PCR of splice variants, HDAC inhibitor treatment, RNA immunoprecipitation of SRSF1\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — ChIP, RNA-IP, and pharmacological manipulation all converge on the same SRSF1/chromatin acetylation mechanism; multiple orthogonal methods\",\n      \"pmids\": [\"24890719\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Quantitative mass spectrometry of primary CD4+ T cell signalosomes shows that CD6 recruits SLP-76 and the GEF Vav1 independently of the LAT adaptor, constituting a LAT-independent TCR signaling hub. CD6 also recruits ZAP70 to its signalosome.\",\n      \"method\": \"Knock-in affinity-tagged proteins in primary mouse T cells, quantitative MS of co-purified complexes (time-resolved), comparison between LAT-present and LAT-absent conditions\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — quantitative MS with affinity-tagged knock-ins in primary T cells, time-resolved dynamics, genetic validation with LAT-deficient context\",\n      \"pmids\": [\"24584089\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CD6 expression alone (without ligand engagement) attenuates early TCR signaling (Ca2+ mobilization) and late responses (IL-2 release). Removal of the cytoplasmic domain of CD6 abolishes this inhibitory effect. Knockdown of CD6 by morpholino enhanced anti-CD3-induced Ca2+ signals in primary human T cells. CD6-CD166 interaction blocking with anti-CD166 antibodies increased T cell proliferation, while anti-CD6 antibodies decreased it.\",\n      \"method\": \"Single-cell Ca2+ flux measurements, Jurkat cells expressing human CD6 vs. CD6 cytoplasmic deletion mutant, morpholino CD6 knockdown in primary human T cells, IL-2 ELISA, proliferation assays\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple cell systems (Jurkat, primary T cells), cytoplasmic domain deletion mutant, knockdown all converge on same inhibitory function\",\n      \"pmids\": [\"21956609\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Crystal structures of the three SRCR domains of CD6 and two N-terminal domains of CD166 were solved by X-ray crystallography. The structure reveals a nonlinear organization of consecutive SRCR domains. An MS-associated SNP in CD6 causes glycosylation that sterically hinders the CD6/CD166 interaction. Native mass spectrometry showed competition between CD6/CD166 heterophilic and CD166/CD166 homophilic interactions.\",\n      \"method\": \"X-ray crystallography, native mass spectrometry, SNP glycosylation analysis\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures of both proteins solved, SNP functional consequence directly demonstrated, competition between interactions shown by native MS\",\n      \"pmids\": [\"26146185\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CD318 is a second CD6 ligand distinct from CD166/ALCAM. CD318 KO mice, like CD6 KO mice, are protected in experimental autoimmune encephalomyelitis. CD318 is highly expressed in synovial tissues and participates in CD6-dependent adhesion of T cells to synovial fibroblasts. Soluble CD318 is chemoattractive to T cells.\",\n      \"method\": \"Identification by mAb 3A11, CD318 KO mouse in EAE model, T cell adhesion assays to synovial fibroblasts, CD6-CD318 binding assays, chemotaxis assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic (KO mice), binding assays, functional adhesion and chemotaxis assays; multiple methods identifying CD318 as bona fide CD6 ligand\",\n      \"pmids\": [\"28760953\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CD6-deficient T cells exhibit augmented initial activation but significantly reduced survival and proliferation after activation, leading to decreased Th1 and Th17 polarization. CD6-deficient activated T cells show impaired migration through brain microvascular endothelial cell monolayers. CD6 is thus a positive regulator of activated T cell survival/proliferation and infiltration.\",\n      \"method\": \"CD6 KO mice in EAU/EAE model, adoptive transfer of CD6-/- T cells, in vitro transendothelial migration assay, T cell differentiation assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mice with multiple functional readouts (proliferation, survival, migration, cytokine polarization), adoptive transfer confirming T cell-intrinsic effects\",\n      \"pmids\": [\"28209777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CD6 modulates thymocyte selection: CD6-/- thymi show reduced CD4+ and CD8+ single-positive subsets; double-positive thymocytes show increased Ca2+ mobilization upon TCR crosslinking; and CD6-/- T cells have a T cell-autonomous selective disadvantage during development confirmed by bone marrow chimeras. CD6-/- mice display increased regulatory T cell frequencies but with diminished suppressive activity.\",\n      \"method\": \"CD6-/- mice with TCR-transgenic crosses (OT-I, Marilyn), bone marrow chimeras, Ca2+ flux measurement, T reg suppression assays, collagen-induced arthritis model\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple mouse genetic models (KO, TCR transgenic, bone marrow chimera), several functional assays confirming T cell-intrinsic developmental role\",\n      \"pmids\": [\"27377588\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The CD6 signalosome, mapped by CRISPR/Cas9-based quantitative MS in primary mouse T cells, contains both positive (SLP-76, ZAP70, VAV1) and negative (UBASH3A/STS-2) regulators of T cell activation. CD6 also associates constitutively (TCR-independent) with proteins involved in T cell transendothelial migration. UBASH3A (STS-2) is identified as a component of the CD6 signalosome.\",\n      \"method\": \"CRISPR/Cas9 knock-in of tagged proteins in primary mouse T cells, quantitative mass spectrometry of CD6 signalosome, comparison with LAT and CD5 signalosomes\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — CRISPR knock-in in primary T cells with quantitative MS; comprehensive signalosome mapping with comparison to other signalosomes; identification of UBASH3A as negative regulator\",\n      \"pmids\": [\"33125054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CD6 costimulation requires bivalent recruitment of a GADS/SLP-76 complex: the SH2 domain of GADS binds phosphorylated Y629 of CD6, and SLP-76 binds phosphorylated Y662. Both Y629F and Y662F mutations abolish costimulation by CD6 in human Jurkat and primary T cells.\",\n      \"method\": \"Biochemical interaction mapping (SH2 domain binding), CD6 Y629F and Y662F mutant analysis, Jurkat and primary T cell functional assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — systematic mutagenesis of both tyrosines, direct biochemical identification of GADS as Y629 binder, functional validation in two cell systems\",\n      \"pmids\": [\"28289074\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"CD6 ligation (with anti-CD6 antibody) protects CLL B cells from anti-IgM-induced apoptosis by downregulating bax-alpha mRNA and maintaining bcl-2 mRNA levels, resulting in an increased Bcl-2/Bax ratio.\",\n      \"method\": \"Anti-CD6 crosslinking of CLL B cells, flow cytometry for apoptosis, Northern blot for bax and bcl-2 mRNA\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mRNA-level mechanism shown in primary CLL cells with direct functional apoptosis readout, but single lab study using antibody crosslinking\",\n      \"pmids\": [\"9108402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CD6 interacts with Galectin-1 and Galectin-3 in a carbohydrate-dependent manner. This interaction interferes with superantigen-induced T cell proliferation and cell adhesion mediated by CD6-CD166/ALCAM. CD6 expression protects cells from galectin-induced apoptosis.\",\n      \"method\": \"Co-immunoprecipitation/pull-down, proliferation assays, cell adhesion assays, apoptosis assays with galectin treatment\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — binding and functional data shown, but single lab with limited mechanistic depth on carbohydrate specificity\",\n      \"pmids\": [\"24945728\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Dynamic coupling of ALCAM to the actin cortex (through intracellular adaptor proteins) strengthens CD6-ALCAM cell adhesion bonds and stiffens the cortex, but does not influence the intrinsic affinity of CD6-ALCAM bonds. ALCAM recruitment to adhesion sites and membrane tether formation depend on actin cytoskeletal interactions.\",\n      \"method\": \"Single-cell force spectroscopy combined with TIRF microscopy, ALCAM cytoplasmic tail mutants expressed in ALCAM-expressing cells\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — single-molecule force spectroscopy with TIRF, systematic ALCAM mutants; rigorously separates affinity from avidity effects\",\n      \"pmids\": [\"24496453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The MS susceptibility allele in CD6 (rs17824933) is associated with decreased expression of full-length CD6 in CD4+ and CD8+ T cells due to underexpression of exon 5 (which encodes the ALCAM binding domain), and this leads to diminished long-term proliferation of CD4+ T cells. siRNA knockdown of full-length CD6 recapitulates the proliferation defect.\",\n      \"method\": \"Flow cytometry for CD6 protein levels in primary T cells stratified by genotype, exon-specific siRNA knockdown, long-term proliferation assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic stratification combined with mechanistic siRNA experiment; directly links SNP to molecular mechanism (exon 5/ALCAM-binding domain) to proliferation phenotype\",\n      \"pmids\": [\"21849685\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"A second CD6 ligand (the 3A11 antigen, later identified as CD318) distinct from CD166/ALCAM is expressed on cells derived from thymus, skin, synovium, and cartilage, and is enhanced by IFN-γ. Soluble CD6-Ig fusion protein immunoprecipitates the 130 kDa 3A11 antigen, and it is not reduced by CD166-specific siRNA knockdown, confirming it is a distinct ligand.\",\n      \"method\": \"Flow cytometry, immunoprecipitation with CD6-Ig fusion protein, confocal microscopy, CD166 siRNA knockdown, T cell adhesion inhibition assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CD6-Ig pull-down, siRNA-based distinction from CD166, functional adhesion assay; identity later confirmed as CD318 (PMID 28760953)\",\n      \"pmids\": [\"15528349\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CD6 regulates intestinal ischemia/reperfusion injury by controlling the self-renewal of B1a cells outside of the peritoneal cavity. CD6 is selectively expressed on B1 cells outside bone marrow and peritoneum; CD6-/- mice have reduced B1a cell populations and decreased pathogenic natural IgM titers, resulting in protection from intestinal I/R injury.\",\n      \"method\": \"CD6-/- mice in intestinal I/R model, flow cytometry of B1a cell populations, natural IgM ELISA, histopathology\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse model with clear phenotype and mechanistic link to B1a cells/IgM, but mechanism of CD6 regulation of B1a self-renewal not biochemically resolved\",\n      \"pmids\": [\"27909060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Itolizumab (anti-CD6 domain 1 mAb) directly inhibits CD6 receptor hyperphosphorylation upon TCR activation and decreases associated ZAP70 kinase and SLP-76 docking protein levels. It also reduces T cell differentiation to Th17 cells by decreasing pSTAT3 and RORγT transcription factors.\",\n      \"method\": \"Anti-phospho-CD6 Western blot, co-immunoprecipitation of ZAP70/SLP-76 with CD6, intracellular transcription factor staining, cytokine ELISA, in vivo EAE with mouse anti-mouse CD6D1 antibody\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical data on phosphorylation and signaling complex from one lab; mechanism of domain 1 antibody causing dephosphorylation not fully resolved\",\n      \"pmids\": [\"28672038\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"CD6 gene encodes at least five different isoforms arising from variable splicing of exons encoding the cytoplasmic domain. Each of the three extracellular SRCR domains is encoded by a separate exon. CD6 maps to chromosome 11q13, in close proximity to CD5 and within 600 kb of CD20.\",\n      \"method\": \"Genomic library screening, exon mapping, FISH chromosomal localization, RT-PCR of mRNA transcripts\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — genomic structure determined by library screening and sequencing; chromosomal localization by FISH; isoforms confirmed by RT-PCR\",\n      \"pmids\": [\"9013954\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"CD6 is expressed in normal human brain cells (not T cells), as demonstrated by immunohistochemistry with multiple anti-CD6 mAbs and Northern blot analysis detecting a 3.1 kb CD6-specific mRNA in brain regions especially basal ganglia and cortex cerebellum.\",\n      \"method\": \"Immunohistochemistry, Northern blot with cRNA probe, double-staining with hematopoietic cell markers and TCR chain probes\",\n      \"journal\": \"Journal of neuroimmunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple anti-CD6 mAbs and Northern blot in multiple brain regions; negative results for T cell markers support native brain expression, but functional consequence not established\",\n      \"pmids\": [\"2211985\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"PKC activation by phorbol ester increases CD6 surface expression by increasing CD6 mRNA transcription (~2-3 fold increase in transcription rate shown by nuclear run-on), not by mRNA stabilization. CD2 ligation on thymocytes (but not mature T cells) also upregulates CD6, suggesting developmental regulation of CD6 expression.\",\n      \"method\": \"Nuclear run-on transcription assay, Northern blot, Western blot, actinomycin D chase experiments, PKC inhibitor experiments, anti-CD2 stimulation\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — nuclear run-on directly measures transcription rate; actinomycin D chase rules out mRNA stabilization; multiple inhibitor controls\",\n      \"pmids\": [\"8207228\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CD6 is a type I transmembrane glycoprotein with three extracellular SRCR domains (domain 3 mediating binding to CD166/ALCAM and CD318, domain 1 mediating LPS/pathogen pattern recognition) and a long cytoplasmic tail (244 aa) that, upon TCR-induced phosphorylation of Y629 and Y662, recruits a bivalent GADS/SLP-76 complex as well as ZAP70, VAV1, and Itk to form a LAT-independent TCR signaling hub that both amplifies (through SLP-76/VAV1) and attenuates (through UBASH3A/STS-2) T cell activation; CD6 also undergoes activation-induced alternative splicing (SRSF1-dependent exon 5 inclusion vs. skipping) that controls whether the protein localizes to the immunological synapse and engages its ligands, thereby modulating thymocyte selection, peripheral T cell survival/proliferation, Th17 differentiation, and T cell transendothelial migration.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CD6 is a type I transmembrane glycoprotein expressed predominantly on T cells that functions as a co-receptor at the immunological synapse, fine-tuning T cell activation, thymocyte selection, and effector differentiation [#0, #13, #28]. Its three extracellular SRCR domains mediate ligand recognition: the membrane-proximal SRCR domain 3 binds the N-terminal Ig domain of CD166/ALCAM with a defined interface and 1:1 stoichiometry and micromolar, fast-off-rate affinity, an interaction that competes with ALCAM homophilic binding and is structurally constrained by a multidomain SRCR organization [#5, #6, #7, #15, #25]. CD318 is a second, distinct CD6 ligand that supports T cell adhesion and chemotaxis and, like CD6 itself, is required for autoimmune encephalomyelitis pathology [#26, #35]. CD6 physically associates with the TCR/CD3 complex and partitions to the central supramolecular activation cluster, where ligand engagement provides CD3/CD28-comparable costimulation and stabilizes T cell–APC conjugates [#13, #14]. Upon TCR engagement its 244-residue cytoplasmic tail is tyrosine-phosphorylated on Y629 and Y662, which respectively recruit GADS and SLP-76 as a bivalent complex; this hub also assembles ZAP70 and VAV1 to drive costimulation independently of the LAT adaptor, while simultaneously recruiting the negative regulator UBASH3A/STS-2, explaining how CD6 both amplifies and restrains activation and engages MAPK (ERK/p38/JNK) and AP-1 outputs [#11, #12, #23, #29, #30, #16]. CD6 output is gated by activation-induced alternative splicing in which SRSF1 normally promotes exon 5 inclusion but is displaced upon activation-linked chromatin acetylation, generating a domain 3–deleted isoform that cannot bind ALCAM or localize to the synapse [#21, #22]. Genetically, a multiple sclerosis–associated CD6 allele reduces full-length CD6 by lowering exon 5 expression and diminishes long-term CD4+ T cell proliferation, and CD6 deficiency reduces post-activation T cell survival, Th1/Th17 polarization, and transendothelial migration [#34, #27, #28].\",\n  \"teleology\": [\n    {\n      \"year\": 1991,\n      \"claim\": \"Establishing CD6 as a type I membrane glycoprotein with three extracellular SRCR domains and a phosphorylatable cytoplasmic tail defined the architecture on which all later signaling and ligand work was built.\",\n      \"evidence\": \"cDNA cloning and COS cell expression with biochemical phosphorylation analysis\",\n      \"pmids\": [\"1919444\", \"2481822\", \"2384666\", \"2016320\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cytoplasmic signaling partners not yet identified\", \"Ligand identity unknown at this stage\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Discovery that the long 244-residue cytoplasmic domain (initially mis-assigned as short due to splicing) contains SH3-binding and kinase phosphorylation motifs reframed CD6 as a signaling co-receptor rather than a simple adhesion molecule.\",\n      \"evidence\": \"Full-length cDNA isolation, sequence analysis, transfection confirmation\",\n      \"pmids\": [\"7589069\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct cytoplasmic effectors not yet bound\", \"Functional consequence of motifs untested\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Identification of ALCAM/CD166 as the CD6 ligand and mapping the interaction to SRCR domain 3 / the ALCAM N-terminal Ig domain established the molecular basis for CD6-mediated cell adhesion.\",\n      \"evidence\": \"Reciprocal fusion-protein binding, domain-specific constructs, mutagenesis, and stoichiometry determination\",\n      \"pmids\": [\"7760007\", \"7543097\", \"8663238\", \"9054570\", \"8823162\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Affinity/kinetics not yet quantified\", \"Functional role of adhesion in T cell responses not defined\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Showing that TCR/CD3 crosslinking drives CD6 cytoplasmic tyrosine phosphorylation at Y629/Y662 and that this is separable from Ca2+ signaling connected CD6 directly into proximal TCR signaling.\",\n      \"evidence\": \"Anti-phosphotyrosine IP after CD3 crosslinking and chimeric receptor point/truncation mutants with Ca2+ flux readout\",\n      \"pmids\": [\"7678115\", \"9394826\", \"9013954\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Adaptors recruited to phospho-tyrosines unidentified\", \"Link between phosphorylation and downstream transcription unclear\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstration that CD6 associates with the TCR/CD3 complex, localizes to the central SMAC, and that CD6-ALCAM engagement provides costimulation and stabilizes DC–T conjugates positioned CD6 at the heart of the immunological synapse.\",\n      \"evidence\": \"Co-IP, co-capping, FRET, confocal imaging of T-APC conjugates, antibody blocking, and proliferation/reporter assays\",\n      \"pmids\": [\"15294938\", \"16352806\", \"15048703\", \"12473675\", \"12525577\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CD6 is net activating or inhibitory remained unresolved\", \"Itk-CD6 association reported by a single lab\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identifying SLP-76 as a direct phospho-Y662 partner and showing CD6 ligation activates ERK/p38/JNK and AP-1 defined a concrete costimulatory signaling output.\",\n      \"evidence\": \"Phosphopeptide binding with Kd, co-IP from primary T cells, Y662F mutant, MAPK phospho-blot with Src inhibitors and reporter assays\",\n      \"pmids\": [\"16914752\", \"16818773\", \"16034076\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Role of the second tyrosine Y629 not defined\", \"How signaling integrates with TCR proximal machinery unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Genetic and functional dissection of an MS-associated CD6 allele and CD6 knockdown revealed CD6 can attenuate early TCR signaling yet sustain long-term proliferation, exposing its dual regulatory nature.\",\n      \"evidence\": \"Genotype-stratified flow cytometry, exon-specific siRNA, Ca2+ flux, IL-2 ELISA, proliferation assays in Jurkat and primary T cells\",\n      \"pmids\": [\"21956609\", \"21849685\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis reconciling attenuation vs. costimulation not resolved\", \"In vivo relevance of dual signaling untested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Quantitative signalosome MS and splicing studies showed CD6 forms a LAT-independent hub recruiting SLP-76/Vav1/ZAP70 and that SRSF1-controlled exon 5 splicing gates ligand binding and synapse targeting.\",\n      \"evidence\": \"Knock-in affinity-tagged MS in primary T cells, ChIP/RNA-IP, HDAC inhibitor treatment, isoform imaging\",\n      \"pmids\": [\"24584089\", \"24890719\", \"17371992\", \"24945728\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Negative regulators of the hub not yet identified\", \"Trigger linking activation to chromatin acetylation incompletely defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Knockout mouse genetics established T cell-intrinsic roles for CD6 in thymocyte selection, regulatory T cell function, and B1a cell homeostasis, moving CD6 from in vitro signaling into developmental and disease physiology.\",\n      \"evidence\": \"CD6-/- mice with TCR-transgenic crosses, bone marrow chimeras, Treg suppression assays, intestinal I/R model\",\n      \"pmids\": [\"27377588\", \"27909060\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of CD6 control of B1a self-renewal not biochemically resolved\", \"Signaling basis of selection defect unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identification of CD318 as a bona fide second ligand, definition of the bivalent GADS(Y629)/SLP-76(Y662) costimulatory module, and demonstration of CD6's role in T cell survival/Th17 differentiation and migration consolidated CD6 as an autoimmunity-relevant co-receptor and therapeutic target.\",\n      \"evidence\": \"CD318 KO in EAE, adhesion/chemotaxis assays, Y629F/Y662F mutants, CD6-/- T cell transfer and migration assays, anti-CD6 (itolizumab) signaling blockade\",\n      \"pmids\": [\"28760953\", \"28289074\", \"28209777\", \"28672038\", \"15528349\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which domain 1 antibody causes CD6 dephosphorylation not fully resolved\", \"Relative contributions of ALCAM vs. CD318 in disease not dissected\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Comprehensive CRISPR-based signalosome mapping revealed CD6 simultaneously recruits positive (SLP-76, ZAP70, VAV1) and negative (UBASH3A/STS-2) regulators plus constitutive migration-associated partners, providing a unified explanation for CD6's bidirectional control of T cell activation.\",\n      \"evidence\": \"CRISPR/Cas9 knock-in of tagged proteins and quantitative MS in primary mouse T cells compared with LAT and CD5 signalosomes\",\n      \"pmids\": [\"33125054\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How positive vs. negative outputs are balanced contextually unknown\", \"Structural basis of UBASH3A recruitment undetermined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CD6 dynamically switches between amplifying and attenuating TCR signaling in specific T cell subsets and disease contexts, and the in vivo significance of its non-T-cell expression, remain open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the assembled cytoplasmic signalosome\", \"Functional role of CD6 in brain cells uncharacterized\", \"Quantitative balance of ALCAM vs. CD318 signaling in vivo unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [5, 14, 26, 33]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [13, 16, 24, 29]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [12, 23, 30]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [20]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [13, 27, 28, 29]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [16, 23, 30]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [28]}\n    ],\n    \"complexes\": [\"CD6 signalosome\", \"TCR/CD3 complex\"],\n    \"partners\": [\"ALCAM\", \"CD318\", \"SLP-76\", \"GADS\", \"ZAP70\", \"VAV1\", \"UBASH3A\", \"CD5\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}