{"gene":"CIB1","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2004,"finding":"Crystal structure of Ca2+-bound CIB1 determined at 2.0 Å resolution, revealing a compact alpha-helical protein with four EF-hands (last two binding calcium) and a hydrophobic pocket implicated in ligand binding. CIB1 is largely monomeric whether ligand-bound or free, distinguishing it from NCS proteins, and shares structural similarity with calcineurin B and neuronal calcium sensor family proteins.","method":"X-ray crystallography, mutational analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure at 2.0 Å with functional validation via prior mutational analysis; defines a new EF-hand protein family","pmids":["15574431"],"is_preprint":false},{"year":2011,"finding":"Solution structures of Ca2+-CIB1 and Mg2+-CIB1 determined by NMR; EF-hand III is directly involved in binding to the integrin αIIb cytoplasmic domain, and C-terminal helix of Ca2+-CIB1 is displaced upon αIIb binding.","method":"Solution NMR spectroscopy, chemical shift perturbation, nitroxide surface probe","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structure determination with functional validation of binding interface, single lab but multiple orthogonal NMR methods","pmids":["21388953"],"is_preprint":false},{"year":1997,"finding":"CIB1 (referred to as KIP, a novel calcium-binding protein with ~26% identity to calcineurin B) was identified as a binding partner of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) via yeast two-hybrid analysis, satisfying both high genetic and biochemical stringency.","method":"Yeast two-hybrid, biochemical binding assay","journal":"Mutation research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast two-hybrid plus biochemical confirmation, single lab","pmids":["9372844"],"is_preprint":false},{"year":2004,"finding":"CIB1 (KIP) binds directly to the catalytic subunit of telomerase (hTERT) independently of telomerase RNA or telomeric DNA; CIB1 co-localizes with hTERT in the nucleus; overexpression of CIB1 increases endogenous telomerase activity and results in telomere elongation after 60 population doublings.","method":"Yeast two-hybrid, co-immunoprecipitation, immunolocalization, in vitro binding, telomerase activity assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Y2H, Co-IP, in vitro binding, functional telomerase assay) in a single lab","pmids":["15190070"],"is_preprint":false},{"year":2005,"finding":"CIB1 directly and specifically interacts with PAK1 in a calcium-dependent manner, binding within discrete regions surrounding the PAK1 inhibitory switch domain; this interaction activates PAK1 both in vitro and in vivo. CIB1 overexpression decreases cell migration on fibronectin via a PAK1- and LIM kinase-dependent increase in cofilin phosphorylation. RNAi-mediated depletion of CIB1 increases cell migration and reduces adhesion-induced PAK1 activation and cofilin phosphorylation.","method":"In vitro kinase assay, co-immunoprecipitation, RNAi knockdown, cell migration assay, western blotting","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, in vitro and in vivo kinase activation, loss-of-function (RNAi) and gain-of-function with defined cellular phenotype and pathway placement","pmids":["16061695"],"is_preprint":false},{"year":2006,"finding":"CIB1 is an endogenous inhibitor of agonist-induced αIIbβ3 integrin activation in platelets; overexpression in megakaryocytes blocks agonist-induced αIIbβ3 activation, while RNAi reduction of CIB1 enhances activation. CIB1 appears to inhibit integrin activation by competing with talin for binding to the αIIb tail.","method":"Overexpression in megakaryocytes, RNAi knockdown, integrin activation assay, competitive binding","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — bidirectional genetic manipulation (OE and KD) with defined molecular mechanism (competition with talin), replicated with multiple approaches in one study","pmids":["16418530"],"is_preprint":false},{"year":2006,"finding":"CIB1 is essential for spermatogenesis in mice; Cib1-/- males are sterile due to disruption of haploid phase of spermatogenesis with increased germ cell apoptosis and loss of elongated spermatids. Cib1-/- testes show increased Cdc2/Cdk1 mRNA and protein. Cib1-/- MEFs show slower growth rate, suggesting CIB1 regulates cell cycle.","method":"Homologous recombination knockout, histology, Western blotting, RT-PCR, MEF proliferation assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean knockout mouse model with specific phenotypic readouts and molecular correlates","pmids":["16982698"],"is_preprint":false},{"year":2006,"finding":"CIB1 binds to all mammalian InsP3R isoforms in a calcium-sensitive manner dependent on its two functional EF-hands; CIB1 activates InsP3R channel gating in the absence of InsP3 in vitro, but overexpression of CIB1 attenuates InsP3R-dependent Ca2+ signaling in cells; pre-exposure to CIB1 in vitro reduces channels available for subsequent InsP3 stimulation.","method":"Pull-down, patch-clamp electrophysiology, Ca2+ imaging, overexpression","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro channel reconstitution plus cellular Ca2+ assays, multiple orthogonal methods in one lab","pmids":["16723353"],"is_preprint":false},{"year":2007,"finding":"CIB1 and CaBP1 bind to the IQ motifs in the myo1c regulatory domain, competing with calmodulin for binding; both proteins co-localize with myo1c in vivo and binding is enhanced in the presence of calcium.","method":"Pull-down experiments, fluorescence microscopy co-localization, competitive binding assays","journal":"Journal of muscle research and cell motility","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — pull-down and colocalization, single lab, two orthogonal methods","pmids":["17994197"],"is_preprint":false},{"year":2007,"finding":"CIB1 regulates endothelial cell migration, proliferation, and tubule formation; loss of CIB1 (shRNA or knockout) decreases PAK1 activation, ERK1/2 activation, and MMP-2 expression. CIB1-/- mice show reduced growth factor-induced microvessel sprouting, impaired ischemia-induced retinal angiogenesis, and reduced hindlimb adaptive angiogenesis with decreased PAK1 activation.","method":"shRNA knockdown, CIB1-/- mice, ex vivo organ culture, in vivo Matrigel plugs, Western blotting","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple in vitro and in vivo models with defined signaling pathway (PAK1-ERK1/2-MMP2) and consistent phenotype","pmids":["17975111"],"is_preprint":false},{"year":2008,"finding":"CIB1 acts as a general inhibitor of InsP3-dependent Ca2+ release in vivo; stable and transient shRNA depletion of CIB1 increases Ca2+ responses to InsP3-generating ligands (ATP, UTP, carbachol), while overexpression has the opposite effect; this is dependent on ER thapsigargin-sensitive Ca2+ stores and likely mediated via InsP3 receptor interaction.","method":"shRNA depletion, overexpression, FURA-2 Ca2+ imaging","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional manipulation (KD and OE) with functional readout, single lab","pmids":["18627437"],"is_preprint":false},{"year":2009,"finding":"CIB1 binds to ASK1 and negatively regulates ASK1-mediated stress signaling: CIB1 interferes with TRAF2 recruitment to ASK1 and inhibits ASK1 autophosphorylation on Thr-838, thereby blocking ASK1 activation. Ca2+ influx reverses the inhibitory effect of CIB1 on ASK1 activation. CIB1 mitigates apoptotic cell death induced by TNF-α in MCF7 cells or 6-OHDA in dopaminergic cells.","method":"Co-immunoprecipitation, in vitro kinase assay, Ca2+ manipulation, cell death assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, in vitro kinase inhibition assay, mechanistic mutant (Thr-838), Ca2+-dependent reversal, functional cell death readout","pmids":["19805025"],"is_preprint":false},{"year":2009,"finding":"CIB1 deficiency (genetic knockout) impairs in vivo thrombosis: Cib1-/- mice show increased tail bleeding time, rebleeding, delayed carotid artery occlusion, and unstable thrombus formation. Outside-in signaling-dependent β3 tyrosine phosphorylation is significantly reduced in Cib1-/- platelets; platelet spreading on fibrinogen is impaired but filopodia formation is unaffected. Inside-out signaling (agonist-induced aggregation and fibrinogen binding) is unaffected.","method":"Cib1-/- knockout mice, tail bleeding assay, FeCl3-induced carotid thrombosis, platelet spreading assay, Western blotting","journal":"Journal of thrombosis and haemostasis","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean knockout model, multiple in vivo and in vitro assays, specific mechanistic assignment to outside-in signaling pathway","pmids":["19691476"],"is_preprint":false},{"year":2010,"finding":"CIB1 is a regulator of pathological cardiac hypertrophy acting by anchoring calcineurin to the sarcolemma via direct interaction with calcineurin B (identified by yeast two-hybrid). CIB1 localizes primarily to the sarcolemma in mouse and human myocardium, coordinating calcineurin activation with L-type Ca2+ channel. Cib1-/- mice show reduced hypertrophy, fibrosis, and NFAT activity after pressure overload but normal physiological hypertrophy; cardiac-specific CIB1 overexpression enhances hypertrophic response in a Ppp3cb (calcineurin Aβ)-dependent manner.","method":"Yeast two-hybrid, immunolocalization, Cib1-/- knockout mice, inducible transgenic overexpression, pressure overload and exercise models, NFAT reporter assay","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — yeast two-hybrid plus multiple in vivo genetic models (KO and transgenic OE), epistasis with calcineurin Aβ null mice, defined pathway and phenotype","pmids":["20639889"],"is_preprint":false},{"year":2011,"finding":"CIB1 constitutively interacts with PLK3 (polo-like kinase 3) in vitro and in vivo independently of intracellular Ca2+; CIB1 binding inhibits PLK3 kinase activity in vitro and in vivo in a Ca2+-dependent manner, suggesting CIB1 is a regulatory subunit of PLK3.","method":"Co-immunoprecipitation, in vitro kinase assay, Ca2+ manipulation","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro kinase assay plus in vivo co-IP with Ca2+-dependence shown, single lab","pmids":["20473878"],"is_preprint":false},{"year":2012,"finding":"CIB1 depletion in neuroblastoma and breast cancer cells promotes non-apoptotic, caspase-independent cell death requiring nuclear GAPDH accumulation. CIB1 depletion disrupts PI3K/AKT and Ras/MEK/ERK signaling synergistically; AKT inhibition alone maximally induced GAPDH nuclear accumulation while MEK/ERK inhibition had no effect alone; concurrent GAPDH nuclear accumulation and ERK inhibition were required to induce DNA damage response and subsequent cell death.","method":"RNAi depletion, pharmacological inhibitors, immunoblotting, immunofluorescence, cell death assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and pharmacological dissection of two pathways, single lab, pathway epistasis established","pmids":["22964641"],"is_preprint":false},{"year":2013,"finding":"CIB1 interacts with multiple α-integrin cytoplasmic tails beyond αIIb via a conserved hydrophobic binding pocket; novel in vivo interactions with other integrin complexes confirmed by co-immunoprecipitation; isothermal titration calorimetry shows binding is driven by hydrophobic interactions.","method":"Co-immunoprecipitation, solid-phase competitive binding assay, isothermal titration calorimetry, all-atom replica exchange discrete molecular dynamics","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, competitive binding, ITC), single lab","pmids":["24011356"],"is_preprint":false},{"year":2014,"finding":"CIB1 (KIP) interacts with TRF2 and DNA-PKcs at telomeres; CIB1 is required for the association between TRF2 and DNA-PKcs; CIB1 binding to TRF2 enhances TRF2 telomere-binding activity; depletion of CIB1 induces DNA damage foci at telomeres, growth arrest, cellular senescence, and altered cell cycle distribution.","method":"Co-immunoprecipitation, chromatin immunoprecipitation, immunolocalization, telomere dysfunction assay, flow cytometry","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods establishing protein complex and functional consequence, single lab","pmids":["25012820"],"is_preprint":false},{"year":2016,"finding":"CIB1 facilitates agonist-induced plasma membrane localization of sphingosine kinase 1 (SK1) via a Ca2+-myristoyl switch mechanism; CIB1 overexpression alone drives SK1 to the plasma membrane, enhances membrane-associated SK1 enzymatic activity, and is sufficient to drive neoplastic transformation in an SK1-dependent manner. CIB1 inhibition also blocks neoplastic growth induced by oncogenic Ras.","method":"Subcellular fractionation, enzymatic activity assay, transformation assay, shRNA knockdown, overexpression","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with functional consequence (SK1 activity and transformation), genetic epistasis with SK1, single lab","pmids":["27941888"],"is_preprint":false},{"year":2017,"finding":"CIB1 binds specifically to the catalytic domain of type III CD38 (cytosol-facing orientation) as shown by yeast two-hybrid, immunoprecipitation, ELISA, and bimolecular fluorescence complementation; the N-terminus of CIB1 is the interacting domain. shRNA knockdown and CRISPR knockout of CIB1 demonstrate a direct correlation between cellular cADPR levels and CIB1 levels, establishing CIB1 as a modulator of type III CD38 activity.","method":"Yeast two-hybrid, co-immunoprecipitation, ELISA, bimolecular fluorescence complementation, shRNA knockdown, CRISPR knockout, cADPR quantification","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal binding assays plus genetic loss-of-function (shRNA and CRISPR) with direct functional readout (cADPR levels)","pmids":["28720704"],"is_preprint":false},{"year":2018,"finding":"CIB1 forms a complex with EVER1 (TMC6) and EVER2 (TMC8) in keratinocytes; CIB1 is not expressed in EVER1- or EVER2-deficient cells. CIB1 interacts with HPV E5 (α-HPV16) and E8 (γ-HPV4) proteins, suggesting a role as a restriction factor against HPVs. Loss-of-function CIB1 mutations in humans cause epidermodysplasia verruciformis with selective susceptibility to β-HPVs.","method":"Co-immunoprecipitation, immunofluorescence, Western blotting in patient-derived and control keratinocytes, patient genetic analysis","journal":"The Journal of experimental medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP of complex plus human loss-of-function genetics with specific infectious phenotype, single lab","pmids":["30068544"],"is_preprint":false},{"year":2019,"finding":"In resting platelets, CIB1 associates with ASK1 at low Ca2+ concentrations and inhibits ASK1 activation; agonist-induced increase in intracellular Ca2+ causes dissociation of CIB1 from ASK1, allowing ASK1 dimerization via N-terminal coiled-coil domains, TRAF6 recruitment, and autophosphorylation of ASK1 Thr838, resulting in full p38 MAPK activation. Genetic ablation of Cib1 augments agonist-induced Ask1/p38 activation.","method":"Co-immunoprecipitation, kinase assay, Ca2+ chelation/ionophore experiments, Cib1-/- mice, Western blotting","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — Ca2+-dependent co-IP dissociation, phosphorylation site identified, genetic knockout confirmation, multiple agonists tested","pmids":["31530712"],"is_preprint":false},{"year":2020,"finding":"CHIP (an E3 ubiquitin ligase) interacts with CIB1 and promotes its polyubiquitination and proteasomal degradation; lysine residues K10 and K65 of CIB1 are the ubiquitinated sites. CHIP-mediated CIB1 downregulation suppresses EMT, migration, and metastasis of lung adenocarcinoma cells.","method":"Mass spectrometry, co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis, in vitro and in vivo metastasis assays","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 1 / Moderate — ubiquitination assay with mutagenesis identifying specific sites (K10/K65), co-IP of E3-substrate complex, functional rescue experiments","pmids":["33082516"],"is_preprint":false},{"year":2020,"finding":"TMC6 and TMC8 form a protein complex in mouse and human T cells and additionally interact with CIB1 to form TMC6-TMC8-CIB1 trimers; TMC6 and TMC8 protect CIB1 from ubiquitination and proteasomal degradation; reciprocally, CIB1 is needed for stabilizing TMC6 and TMC8 levels.","method":"Co-immunoprecipitation, mass spectrometry, Western blotting, TMC6 and TMC8 knockout mice","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mass spectrometry plus co-IP and knockout genetic models, single lab","pmids":["32917726"],"is_preprint":false},{"year":2024,"finding":"USP14 (a deubiquitinase) directly interacts with and stabilizes CIB1 by reversing K48-linked proteolytic ubiquitination at K24, facilitating the CIB1-PAK1-ERK1/2 signaling axis; USP14 silencing attenuates lenvatinib resistance; adeno-associated virus-mediated CIB1 transduction promotes lenvatinib resistance while CIB1 knockdown resensitizes tumors to lenvatinib.","method":"Co-immunoprecipitation, ubiquitination assay with site identification, in vitro and in vivo xenograft models, AAV transduction","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — deubiquitinase-substrate interaction with specific site (K24), in vivo genetic and pharmacological validation, single lab","pmids":["38993552"],"is_preprint":false}],"current_model":"CIB1 is a ubiquitous 22-kDa EF-hand Ca2+-binding protein that, through a conserved hydrophobic binding cleft, interacts with diverse partners including the platelet αIIb integrin cytoplasmic tail (competitively inhibiting talin-mediated αIIbβ3 activation), PAK1 (activating it in a Ca2+-dependent manner to regulate cell migration via LIM kinase/cofilin), PLK3 (inhibiting its kinase activity in a Ca2+-dependent manner), ASK1 (inhibiting its activation at low Ca2+ by blocking TRAF2 recruitment and Thr838 autophosphorylation, with Ca2+ influx releasing this inhibition), calcineurin B (anchoring calcineurin to the sarcolemma to regulate NFAT-dependent pathological cardiac hypertrophy), all InsP3R isoforms (activating channel gating in the absence of InsP3 yet attenuating net cellular Ca2+ signaling upon overexpression), the telomerase catalytic subunit hTERT (increasing telomerase activity and telomere length), TRF2 and DNA-PKcs at telomeres, type III CD38 (modulating cADPR synthesis), and sphingosine kinase 1 (facilitating its plasma membrane localization via a Ca2+-myristoyl switch); post-translationally, CIB1 is polyubiquitinated by the E3 ligase CHIP at K10/K65 for proteasomal degradation, and stabilized by the deubiquitinase USP14 at K24, while EVER1/TMC6 and EVER2/TMC8 form a trimeric complex with CIB1 that mutually stabilizes all three proteins."},"narrative":{"mechanistic_narrative":"CIB1 is a ubiquitous EF-hand Ca2+-binding protein with a compact alpha-helical fold and a hydrophobic ligand-binding cleft that functions as a Ca2+-regulated adaptor and regulatory subunit for a broad set of partners controlling cell adhesion, migration, kinase signaling, and Ca2+ homeostasis [PMID:15574431, PMID:21388953]. At the platelet membrane it binds the αIIb integrin cytoplasmic tail and competes with talin to restrain agonist-induced αIIbβ3 activation, and in vivo CIB1 loss specifically impairs outside-in signaling, β3 tyrosine phosphorylation, and stable thrombus formation [PMID:16418530, PMID:19691476]; its integrin recognition extends to other α-integrin tails through the same hydrophobic pocket [PMID:24011356]. CIB1 activates PAK1 in a Ca2+-dependent manner to drive LIM kinase/cofilin-mediated control of cell migration, a PAK1–ERK1/2–MMP2 axis that is required for endothelial migration, proliferation, and angiogenesis in vitro and in CIB1-deficient mice [PMID:16061695, PMID:17975111]. It is a Ca2+-gated regulator of stress and cell-cycle kinases, inhibiting ASK1 activation at low Ca2+ by blocking TRAF recruitment and Thr838 autophosphorylation until Ca2+ influx releases the brake to permit p38 activation [PMID:19805025, PMID:31530712], and acting as a regulatory subunit that inhibits PLK3 [PMID:20473878]. CIB1 also tunes intracellular Ca2+ signaling by binding all InsP3R isoforms and attenuating InsP3-dependent Ca2+ release in cells [PMID:16723353, PMID:18627437], and it anchors calcineurin B at the sarcolemma to promote NFAT-dependent pathological cardiac hypertrophy [PMID:20639889]. Additional roles include facilitating Ca2+-myristoyl-switch–dependent plasma-membrane localization of sphingosine kinase 1 to drive neoplastic transformation [PMID:27941888] and supporting survival signaling through PI3K/AKT and Ras/MEK/ERK, with CIB1 depletion triggering caspase-independent death via nuclear GAPDH accumulation [PMID:22964641]. CIB1 abundance is controlled by ubiquitin turnover: the E3 ligase CHIP polyubiquitinates it at K10/K65 for degradation [PMID:33082516], while the deubiquitinase USP14 stabilizes it at K24 to sustain CIB1–PAK1–ERK1/2 signaling [PMID:38993552], and it is mutually stabilized within a TMC6/EVER1–TMC8/EVER2–CIB1 trimeric complex [PMID:32917726]. Loss-of-function CIB1 mutations cause epidermodysplasia verruciformis with selective susceptibility to β-HPVs [PMID:30068544].","teleology":[{"year":1997,"claim":"Established the first physical partner of this novel calcineurin B-like Ca2+-binding protein, linking it to DNA-PKcs and hinting at a nuclear/genome-maintenance role.","evidence":"Yeast two-hybrid plus biochemical binding assay identifying CIB1 (KIP) as a DNA-PKcs partner","pmids":["9372844"],"confidence":"Medium","gaps":["No functional consequence of the interaction shown","Binding interface not mapped","Single-lab Y2H-based discovery"]},{"year":2004,"claim":"Defined CIB1 as a monomeric four-EF-hand protein with a hydrophobic ligand pocket, providing the structural basis for its promiscuous partner binding and distinguishing it from NCS proteins.","evidence":"X-ray crystallography of Ca2+-bound CIB1 at 2.0 Å with mutational analysis; later NMR of Ca2+/Mg2+ forms mapping the αIIb interface","pmids":["15574431","21388953"],"confidence":"High","gaps":["Structures of CIB1 bound to most named partners not solved","Conformational basis for Ca2+ vs Mg2+ switching only partially defined"]},{"year":2004,"claim":"Showed CIB1 can act in the nucleus to enhance telomerase activity and telomere length, the first functional output assigned to the protein.","evidence":"Y2H, co-IP, in vitro binding, immunolocalization, and telomerase activity assay with hTERT","pmids":["15190070"],"confidence":"Medium","gaps":["Mechanism by which CIB1 increases telomerase activity unresolved","Ca2+-dependence of the hTERT interaction not addressed"]},{"year":2005,"claim":"Identified CIB1 as a Ca2+-dependent PAK1 activator coupling it to LIM kinase/cofilin and cell migration, establishing a cytoskeletal signaling role.","evidence":"In vitro kinase assays, reciprocal co-IP, RNAi loss-of-function and overexpression with migration phenotypes","pmids":["16061695"],"confidence":"High","gaps":["Structural basis of PAK1 inhibitory-switch engagement not solved","How Ca2+ gates activation mechanistically unclear"]},{"year":2006,"claim":"Placed CIB1 as a negative regulator of integrin αIIbβ3 activation via competition with talin, and a genetic requirement for spermatogenesis and cell-cycle control.","evidence":"Megakaryocyte overexpression/RNAi with integrin activation assays; Cib1-/- knockout mice with testis histology and MEF proliferation","pmids":["16418530","16982698"],"confidence":"High","gaps":["Direct structural proof of talin competition at the αIIb tail not provided","Molecular link between CIB1 and Cdc2/Cdk1 in germ cells undefined"]},{"year":2006,"claim":"Revealed CIB1 as a Ca2+-sensitive InsP3R-binding protein with paradoxical activity—activating channel gating in vitro yet attenuating cellular Ca2+ signaling—implicating it in Ca2+ homeostasis.","evidence":"Pull-downs, single-channel patch clamp, and Ca2+ imaging with overexpression; later in vivo shRNA/overexpression FURA-2 imaging","pmids":["16723353","18627437"],"confidence":"High","gaps":["Reconciliation of in vitro activation vs cellular attenuation not fully resolved","InsP3R-binding site not mapped"]},{"year":2009,"claim":"Defined CIB1 as a Ca2+-gated brake on ASK1 stress signaling, blocking TRAF2 recruitment and Thr838 autophosphorylation, with Ca2+ influx relieving inhibition.","evidence":"Co-IP, in vitro kinase assays, mechanistic Thr838 mutant, Ca2+ manipulation, and cell death assays; later confirmed in Cib1-/- platelets with p38 readout","pmids":["19805025","31530712"],"confidence":"High","gaps":["Discrepancy in adaptor identity (TRAF2 vs TRAF6) across systems","Stoichiometry of the Ca2+-driven dissociation not quantified"]},{"year":2009,"claim":"Showed CIB1 is required in vivo for thrombosis, assigning its platelet function specifically to outside-in αIIbβ3 signaling.","evidence":"Cib1-/- mice with bleeding, FeCl3 carotid thrombosis, platelet spreading assays, and β3 phosphorylation immunoblotting","pmids":["19691476"],"confidence":"High","gaps":["Direct connection between CIB1 and β3 tyrosine phosphorylation machinery not established"]},{"year":2010,"claim":"Established CIB1 as a sarcolemmal anchor for calcineurin B that drives NFAT-dependent pathological cardiac hypertrophy.","evidence":"Y2H, immunolocalization, Cib1-/- and inducible cardiac-overexpression mice, pressure-overload models, NFAT reporter, epistasis with calcineurin Aβ-null mice","pmids":["20639889"],"confidence":"High","gaps":["How CIB1 selectively couples calcineurin to L-type Ca2+ channels mechanistically unclear"]},{"year":2011,"claim":"Identified CIB1 as a constitutive, Ca2+-dependent inhibitory regulatory subunit of PLK3.","evidence":"Co-IP in vitro and in vivo with in vitro kinase assays and Ca2+ manipulation","pmids":["20473878"],"confidence":"Medium","gaps":["Cellular and physiological consequence of PLK3 inhibition not established","Single-lab finding"]},{"year":2014,"claim":"Connected CIB1 to telomere protection, showing it bridges TRF2 and DNA-PKcs and that its loss provokes telomere damage and senescence.","evidence":"Co-IP, ChIP, immunolocalization, telomere dysfunction assays, and flow cytometry","pmids":["25012820"],"confidence":"Medium","gaps":["Whether telomeric and DNA-PKcs roles are direct or scaffold-mediated unresolved","Single-lab study"]},{"year":2016,"claim":"Showed CIB1 promotes oncogenic transformation by recruiting sphingosine kinase 1 to the plasma membrane through a Ca2+-myristoyl switch.","evidence":"Subcellular fractionation, enzymatic activity assays, transformation assays, shRNA/overexpression, and SK1 epistasis","pmids":["27941888"],"confidence":"Medium","gaps":["Structural detail of the Ca2+-myristoyl switch with SK1 not defined","Single-lab finding"]},{"year":2017,"claim":"Identified CIB1 as a modulator of type III CD38, with cellular cADPR levels tracking CIB1 abundance.","evidence":"Y2H, co-IP, ELISA, BiFC, shRNA and CRISPR knockout with cADPR quantification","pmids":["28720704"],"confidence":"High","gaps":["Mechanism by which CIB1 binding alters CD38 catalysis not defined"]},{"year":2018,"claim":"Linked CIB1 to antiviral keratinocyte biology and human disease, identifying it as part of an EVER1/EVER2 complex and a restriction factor whose loss causes epidermodysplasia verruciformis.","evidence":"Co-IP, immunofluorescence, Western blotting in patient and control keratinocytes, HPV E5/E8 interaction, and patient genetics","pmids":["30068544"],"confidence":"Medium","gaps":["Mechanism of β-HPV restriction by the EVER1/EVER2/CIB1 complex not defined","Single-lab finding"]},{"year":2020,"claim":"Defined the ubiquitin-controlled turnover of CIB1, identifying CHIP-mediated degradation at K10/K65 and mutual stabilization within the TMC6/TMC8/CIB1 trimer.","evidence":"Mass spectrometry, co-IP, ubiquitination assays with site-directed mutagenesis, metastasis assays, and TMC6/TMC8 knockout mice","pmids":["33082516","32917726"],"confidence":"High","gaps":["Signals regulating CHIP-CIB1 engagement unknown","Whether trimer stabilization competes with CHIP not tested"]},{"year":2024,"claim":"Showed USP14 stabilizes CIB1 by removing K48-linked ubiquitin at K24 to sustain CIB1-PAK1-ERK1/2 signaling and drug resistance.","evidence":"Co-IP, ubiquitination assays with site identification, xenografts, and AAV transduction with lenvatinib resistance readouts","pmids":["38993552"],"confidence":"Medium","gaps":["How USP14 and CHIP balance is regulated unknown","Single-lab finding"]},{"year":null,"claim":"It remains unresolved how a single small EF-hand adaptor selects among its many partners in a given cell, and what determines which Ca2+-gated output dominates physiologically.","evidence":"No single study reconciles the partner repertoire or competitive hierarchy","pmids":[],"confidence":"Low","gaps":["No quantitative affinity/competition ranking across partners","Tissue-specific partner usage undefined","Most CIB1-partner co-structures unsolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[4,11,14,21]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,7,11,14,16]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[13,17,18,23]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[0,7,21]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[5,13,18]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3,17]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[11,19]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,11,13,21]},{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[5,12]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[22,23,24]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[11,15]}],"complexes":["TMC6/EVER1-TMC8/EVER2-CIB1 trimer","TRF2-DNA-PKcs telomere complex"],"partners":["PAK1","ASK1","PLK3","ITGA2B","PPP3R1","ITPR1","CD38","SPHK1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q99828","full_name":"Calcium and integrin-binding protein 1","aliases":["Calcium- and integrin-binding protein","CIBP","Calmyrin","DNA-PKcs-interacting protein","Kinase-interacting protein","KIP","SNK-interacting protein 2-28","SIP2-28"],"length_aa":191,"mass_kda":21.7,"function":"Calcium-binding protein that plays a role in the regulation of numerous cellular processes, such as cell differentiation, cell division, cell proliferation, cell migration, thrombosis, angiogenesis, cardiac hypertrophy and apoptosis. Involved in bone marrow megakaryocyte differentiation by negatively regulating thrombopoietin-mediated signaling pathway. Participates in the endomitotic cell cycle of megakaryocyte, a form of mitosis in which both karyokinesis and cytokinesis are interrupted. Plays a role in integrin signaling by negatively regulating alpha-IIb/beta3 activation in thrombin-stimulated megakaryocytes preventing platelet aggregation. Up-regulates PTK2/FAK1 activity, and is also needed for the recruitment of PTK2/FAK1 to focal adhesions; it thus appears to play an important role in focal adhesion formation. Positively regulates cell migration on fibronectin in a CDC42-dependent manner, the effect being negatively regulated by PAK1. Functions as a negative regulator of stress activated MAP kinase (MAPK) signaling pathways. Down-regulates inositol 1,4,5-trisphosphate receptor-dependent calcium signaling. Involved in sphingosine kinase SPHK1 translocation to the plasma membrane in a N-myristoylation-dependent manner preventing TNF-induced apoptosis. Regulates serine/threonine-protein kinase PLK3 activity for proper completion of cell division progression. Plays a role in microtubule (MT) dynamics during neuronal development; disrupts the MT depolymerization activity of STMN2 attenuating NGF-induced neurite outgrowth and the MT reorganization at the edge of lamellipodia. Promotes cardiomyocyte hypertrophy via activation of the calcineurin/NFAT signaling pathway. Stimulates calcineurin PPP3R1 activity by mediating its anchoring to the sarcolemma. In ischemia-induced (pathological or adaptive) angiogenesis, stimulates endothelial cell proliferation, migration and microvessel formation by activating the PAK1 and ERK1/ERK2 signaling pathway. Also promotes cancer cell survival and proliferation. May regulate cell cycle and differentiation of spermatogenic germ cells, and/or differentiation of supporting Sertoli cells. Forms a complex with TMC6/EVER1 and TMC8/EVER2 in lymphocytes and keratynocytes where CIB1 stabilizes TMC6 and TMC8 levels and reciprocally (PubMed:30068544, PubMed:32917726) Acts as a restriction factor that promotes keratinocyte-intrinsic immunity to human beta-papillomaviruses (HPVs) Plays a regulatory role in angiogenesis and tumor growth by mediating PKD/PRKD2-induced vascular endothelial growth factor A (VEGFA) secretion","subcellular_location":"Cytoplasm, perinuclear region; Golgi apparatus, trans-Golgi network","url":"https://www.uniprot.org/uniprotkb/Q99828/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CIB1","classification":"Not 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TMC6","url":"https://www.omim.org/entry/605828"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Plasma membrane","reliability":"Supported"},{"location":"Nuclear bodies","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CIB1"},"hgnc":{"alias_symbol":["SIP2-28","CIB","KIP"],"prev_symbol":[]},"alphafold":{"accession":"Q99828","domains":[{"cath_id":"1.10.238.10","chopping":"10-97","consensus_level":"high","plddt":79.3522,"start":10,"end":97},{"cath_id":"1.10.238.10","chopping":"104-186","consensus_level":"high","plddt":76.6295,"start":104,"end":186}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99828","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q99828-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q99828-F1-predicted_aligned_error_v6.png","plddt_mean":75.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CIB1","jax_strain_url":"https://www.jax.org/strain/search?query=CIB1"},"sequence":{"accession":"Q99828","fasta_url":"https://rest.uniprot.org/uniprotkb/Q99828.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q99828/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99828"}},"corpus_meta":[{"pmid":"7649471","id":"PMC_7649471","title":"Kip/Cip 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Ol-KIP, a cyclin-dependent kinase inhibitor, in embryonic and adult medaka (Oryzias latipes) central nervous system.","date":"2001","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/11747078","citation_count":16,"is_preprint":false},{"pmid":"31530712","id":"PMC_31530712","title":"Calcium-induced dissociation of CIB1 from ASK1 regulates agonist-induced activation of the p38 MAPK pathway in platelets.","date":"2019","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/31530712","citation_count":16,"is_preprint":false},{"pmid":"11408920","id":"PMC_11408920","title":"Expression of second class of KIP protein p57KIP2 in human colorectal carcinoma.","date":"2001","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/11408920","citation_count":15,"is_preprint":false},{"pmid":"21857112","id":"PMC_21857112","title":"Proteomic identification of CIB1 as a potential diagnostic factor in hepatocellular carcinoma.","date":"2011","source":"Journal of biosciences","url":"https://pubmed.ncbi.nlm.nih.gov/21857112","citation_count":15,"is_preprint":false},{"pmid":"12114790","id":"PMC_12114790","title":"TGFB, TGFB Receptors, Ki-67, and p27(Kip)l Expression in Papillary Thyroid Carcinomas.","date":"1997","source":"Endocrine pathology","url":"https://pubmed.ncbi.nlm.nih.gov/12114790","citation_count":15,"is_preprint":false},{"pmid":"24464679","id":"PMC_24464679","title":"Calcium- and integrin-binding protein-1 is down-regulated in the sperm of patients with oligoasthenozoospermia : CIB1 expression in patients with oligoasthenozoospermia.","date":"2014","source":"Journal of assisted reproduction and genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24464679","citation_count":14,"is_preprint":false},{"pmid":"21575583","id":"PMC_21575583","title":"The role of the LH subdomain in the function of the Cip/Kip cyclin-dependent kinase regulators.","date":"2011","source":"Biophysical journal","url":"https://pubmed.ncbi.nlm.nih.gov/21575583","citation_count":14,"is_preprint":false},{"pmid":"11063124","id":"PMC_11063124","title":"P16Ink4a tumor suppressor function in lung cancer cells involves cyclin-dependent kinase 2 inhibition by Cip/Kip protein redistribution.","date":"2000","source":"Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/11063124","citation_count":14,"is_preprint":false},{"pmid":"32917726","id":"PMC_32917726","title":"Expression of a TMC6-TMC8-CIB1 heterotrimeric complex in lymphocytes is regulated by each of the components.","date":"2020","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/32917726","citation_count":13,"is_preprint":false},{"pmid":"33258952","id":"PMC_33258952","title":"The CIB1 transcription factor regulates light- and heat-inducible cell elongation via a two-step HLH/bHLH system.","date":"2021","source":"Journal of experimental botany","url":"https://pubmed.ncbi.nlm.nih.gov/33258952","citation_count":13,"is_preprint":false},{"pmid":"28293892","id":"PMC_28293892","title":"Light-Regulated Protein Kinases Based on the CRY2-CIB1 System.","date":"2017","source":"Methods in molecular biology (Clifton, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/28293892","citation_count":13,"is_preprint":false},{"pmid":"11891212","id":"PMC_11891212","title":"Pituitary hyperplasia in glycoprotein hormone alpha subunit-, p18(INK4C)-, and p27(kip-1)-null mice: analysis of proteins influencing p27(kip-1) ubiquitin degradation.","date":"2002","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/11891212","citation_count":13,"is_preprint":false},{"pmid":"27093436","id":"PMC_27093436","title":"Unfolded Protein Response (UPR) Regulator Cib1 Controls Expression of Genes Encoding Secreted Virulence Factors in Ustilago 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CIB1 is largely monomeric whether ligand-bound or free, distinguishing it from NCS proteins, and shares structural similarity with calcineurin B and neuronal calcium sensor family proteins.\",\n      \"method\": \"X-ray crystallography, mutational analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure at 2.0 Å with functional validation via prior mutational analysis; defines a new EF-hand protein family\",\n      \"pmids\": [\"15574431\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Solution structures of Ca2+-CIB1 and Mg2+-CIB1 determined by NMR; EF-hand III is directly involved in binding to the integrin αIIb cytoplasmic domain, and C-terminal helix of Ca2+-CIB1 is displaced upon αIIb binding.\",\n      \"method\": \"Solution NMR spectroscopy, chemical shift perturbation, nitroxide surface probe\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structure determination with functional validation of binding interface, single lab but multiple orthogonal NMR methods\",\n      \"pmids\": [\"21388953\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"CIB1 (referred to as KIP, a novel calcium-binding protein with ~26% identity to calcineurin B) was identified as a binding partner of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) via yeast two-hybrid analysis, satisfying both high genetic and biochemical stringency.\",\n      \"method\": \"Yeast two-hybrid, biochemical binding assay\",\n      \"journal\": \"Mutation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — yeast two-hybrid plus biochemical confirmation, single lab\",\n      \"pmids\": [\"9372844\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CIB1 (KIP) binds directly to the catalytic subunit of telomerase (hTERT) independently of telomerase RNA or telomeric DNA; CIB1 co-localizes with hTERT in the nucleus; overexpression of CIB1 increases endogenous telomerase activity and results in telomere elongation after 60 population doublings.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, immunolocalization, in vitro binding, telomerase activity assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Y2H, Co-IP, in vitro binding, functional telomerase assay) in a single lab\",\n      \"pmids\": [\"15190070\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CIB1 directly and specifically interacts with PAK1 in a calcium-dependent manner, binding within discrete regions surrounding the PAK1 inhibitory switch domain; this interaction activates PAK1 both in vitro and in vivo. CIB1 overexpression decreases cell migration on fibronectin via a PAK1- and LIM kinase-dependent increase in cofilin phosphorylation. RNAi-mediated depletion of CIB1 increases cell migration and reduces adhesion-induced PAK1 activation and cofilin phosphorylation.\",\n      \"method\": \"In vitro kinase assay, co-immunoprecipitation, RNAi knockdown, cell migration assay, western blotting\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, in vitro and in vivo kinase activation, loss-of-function (RNAi) and gain-of-function with defined cellular phenotype and pathway placement\",\n      \"pmids\": [\"16061695\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CIB1 is an endogenous inhibitor of agonist-induced αIIbβ3 integrin activation in platelets; overexpression in megakaryocytes blocks agonist-induced αIIbβ3 activation, while RNAi reduction of CIB1 enhances activation. CIB1 appears to inhibit integrin activation by competing with talin for binding to the αIIb tail.\",\n      \"method\": \"Overexpression in megakaryocytes, RNAi knockdown, integrin activation assay, competitive binding\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — bidirectional genetic manipulation (OE and KD) with defined molecular mechanism (competition with talin), replicated with multiple approaches in one study\",\n      \"pmids\": [\"16418530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CIB1 is essential for spermatogenesis in mice; Cib1-/- males are sterile due to disruption of haploid phase of spermatogenesis with increased germ cell apoptosis and loss of elongated spermatids. Cib1-/- testes show increased Cdc2/Cdk1 mRNA and protein. Cib1-/- MEFs show slower growth rate, suggesting CIB1 regulates cell cycle.\",\n      \"method\": \"Homologous recombination knockout, histology, Western blotting, RT-PCR, MEF proliferation assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean knockout mouse model with specific phenotypic readouts and molecular correlates\",\n      \"pmids\": [\"16982698\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CIB1 binds to all mammalian InsP3R isoforms in a calcium-sensitive manner dependent on its two functional EF-hands; CIB1 activates InsP3R channel gating in the absence of InsP3 in vitro, but overexpression of CIB1 attenuates InsP3R-dependent Ca2+ signaling in cells; pre-exposure to CIB1 in vitro reduces channels available for subsequent InsP3 stimulation.\",\n      \"method\": \"Pull-down, patch-clamp electrophysiology, Ca2+ imaging, overexpression\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro channel reconstitution plus cellular Ca2+ assays, multiple orthogonal methods in one lab\",\n      \"pmids\": [\"16723353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CIB1 and CaBP1 bind to the IQ motifs in the myo1c regulatory domain, competing with calmodulin for binding; both proteins co-localize with myo1c in vivo and binding is enhanced in the presence of calcium.\",\n      \"method\": \"Pull-down experiments, fluorescence microscopy co-localization, competitive binding assays\",\n      \"journal\": \"Journal of muscle research and cell motility\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — pull-down and colocalization, single lab, two orthogonal methods\",\n      \"pmids\": [\"17994197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CIB1 regulates endothelial cell migration, proliferation, and tubule formation; loss of CIB1 (shRNA or knockout) decreases PAK1 activation, ERK1/2 activation, and MMP-2 expression. CIB1-/- mice show reduced growth factor-induced microvessel sprouting, impaired ischemia-induced retinal angiogenesis, and reduced hindlimb adaptive angiogenesis with decreased PAK1 activation.\",\n      \"method\": \"shRNA knockdown, CIB1-/- mice, ex vivo organ culture, in vivo Matrigel plugs, Western blotting\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple in vitro and in vivo models with defined signaling pathway (PAK1-ERK1/2-MMP2) and consistent phenotype\",\n      \"pmids\": [\"17975111\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CIB1 acts as a general inhibitor of InsP3-dependent Ca2+ release in vivo; stable and transient shRNA depletion of CIB1 increases Ca2+ responses to InsP3-generating ligands (ATP, UTP, carbachol), while overexpression has the opposite effect; this is dependent on ER thapsigargin-sensitive Ca2+ stores and likely mediated via InsP3 receptor interaction.\",\n      \"method\": \"shRNA depletion, overexpression, FURA-2 Ca2+ imaging\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional manipulation (KD and OE) with functional readout, single lab\",\n      \"pmids\": [\"18627437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CIB1 binds to ASK1 and negatively regulates ASK1-mediated stress signaling: CIB1 interferes with TRAF2 recruitment to ASK1 and inhibits ASK1 autophosphorylation on Thr-838, thereby blocking ASK1 activation. Ca2+ influx reverses the inhibitory effect of CIB1 on ASK1 activation. CIB1 mitigates apoptotic cell death induced by TNF-α in MCF7 cells or 6-OHDA in dopaminergic cells.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, Ca2+ manipulation, cell death 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 — Co-IP, in vitro kinase inhibition assay, mechanistic mutant (Thr-838), Ca2+-dependent reversal, functional cell death readout\",\n      \"pmids\": [\"19805025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CIB1 deficiency (genetic knockout) impairs in vivo thrombosis: Cib1-/- mice show increased tail bleeding time, rebleeding, delayed carotid artery occlusion, and unstable thrombus formation. Outside-in signaling-dependent β3 tyrosine phosphorylation is significantly reduced in Cib1-/- platelets; platelet spreading on fibrinogen is impaired but filopodia formation is unaffected. Inside-out signaling (agonist-induced aggregation and fibrinogen binding) is unaffected.\",\n      \"method\": \"Cib1-/- knockout mice, tail bleeding assay, FeCl3-induced carotid thrombosis, platelet spreading assay, Western blotting\",\n      \"journal\": \"Journal of thrombosis and haemostasis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean knockout model, multiple in vivo and in vitro assays, specific mechanistic assignment to outside-in signaling pathway\",\n      \"pmids\": [\"19691476\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CIB1 is a regulator of pathological cardiac hypertrophy acting by anchoring calcineurin to the sarcolemma via direct interaction with calcineurin B (identified by yeast two-hybrid). CIB1 localizes primarily to the sarcolemma in mouse and human myocardium, coordinating calcineurin activation with L-type Ca2+ channel. Cib1-/- mice show reduced hypertrophy, fibrosis, and NFAT activity after pressure overload but normal physiological hypertrophy; cardiac-specific CIB1 overexpression enhances hypertrophic response in a Ppp3cb (calcineurin Aβ)-dependent manner.\",\n      \"method\": \"Yeast two-hybrid, immunolocalization, Cib1-/- knockout mice, inducible transgenic overexpression, pressure overload and exercise models, NFAT reporter assay\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — yeast two-hybrid plus multiple in vivo genetic models (KO and transgenic OE), epistasis with calcineurin Aβ null mice, defined pathway and phenotype\",\n      \"pmids\": [\"20639889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CIB1 constitutively interacts with PLK3 (polo-like kinase 3) in vitro and in vivo independently of intracellular Ca2+; CIB1 binding inhibits PLK3 kinase activity in vitro and in vivo in a Ca2+-dependent manner, suggesting CIB1 is a regulatory subunit of PLK3.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, Ca2+ manipulation\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro kinase assay plus in vivo co-IP with Ca2+-dependence shown, single lab\",\n      \"pmids\": [\"20473878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CIB1 depletion in neuroblastoma and breast cancer cells promotes non-apoptotic, caspase-independent cell death requiring nuclear GAPDH accumulation. CIB1 depletion disrupts PI3K/AKT and Ras/MEK/ERK signaling synergistically; AKT inhibition alone maximally induced GAPDH nuclear accumulation while MEK/ERK inhibition had no effect alone; concurrent GAPDH nuclear accumulation and ERK inhibition were required to induce DNA damage response and subsequent cell death.\",\n      \"method\": \"RNAi depletion, pharmacological inhibitors, immunoblotting, immunofluorescence, cell death assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and pharmacological dissection of two pathways, single lab, pathway epistasis established\",\n      \"pmids\": [\"22964641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CIB1 interacts with multiple α-integrin cytoplasmic tails beyond αIIb via a conserved hydrophobic binding pocket; novel in vivo interactions with other integrin complexes confirmed by co-immunoprecipitation; isothermal titration calorimetry shows binding is driven by hydrophobic interactions.\",\n      \"method\": \"Co-immunoprecipitation, solid-phase competitive binding assay, isothermal titration calorimetry, all-atom replica exchange discrete molecular dynamics\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, competitive binding, ITC), single lab\",\n      \"pmids\": [\"24011356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CIB1 (KIP) interacts with TRF2 and DNA-PKcs at telomeres; CIB1 is required for the association between TRF2 and DNA-PKcs; CIB1 binding to TRF2 enhances TRF2 telomere-binding activity; depletion of CIB1 induces DNA damage foci at telomeres, growth arrest, cellular senescence, and altered cell cycle distribution.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation, immunolocalization, telomere dysfunction assay, flow cytometry\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods establishing protein complex and functional consequence, single lab\",\n      \"pmids\": [\"25012820\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CIB1 facilitates agonist-induced plasma membrane localization of sphingosine kinase 1 (SK1) via a Ca2+-myristoyl switch mechanism; CIB1 overexpression alone drives SK1 to the plasma membrane, enhances membrane-associated SK1 enzymatic activity, and is sufficient to drive neoplastic transformation in an SK1-dependent manner. CIB1 inhibition also blocks neoplastic growth induced by oncogenic Ras.\",\n      \"method\": \"Subcellular fractionation, enzymatic activity assay, transformation assay, shRNA knockdown, overexpression\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with functional consequence (SK1 activity and transformation), genetic epistasis with SK1, single lab\",\n      \"pmids\": [\"27941888\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CIB1 binds specifically to the catalytic domain of type III CD38 (cytosol-facing orientation) as shown by yeast two-hybrid, immunoprecipitation, ELISA, and bimolecular fluorescence complementation; the N-terminus of CIB1 is the interacting domain. shRNA knockdown and CRISPR knockout of CIB1 demonstrate a direct correlation between cellular cADPR levels and CIB1 levels, establishing CIB1 as a modulator of type III CD38 activity.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, ELISA, bimolecular fluorescence complementation, shRNA knockdown, CRISPR knockout, cADPR quantification\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal binding assays plus genetic loss-of-function (shRNA and CRISPR) with direct functional readout (cADPR levels)\",\n      \"pmids\": [\"28720704\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CIB1 forms a complex with EVER1 (TMC6) and EVER2 (TMC8) in keratinocytes; CIB1 is not expressed in EVER1- or EVER2-deficient cells. CIB1 interacts with HPV E5 (α-HPV16) and E8 (γ-HPV4) proteins, suggesting a role as a restriction factor against HPVs. Loss-of-function CIB1 mutations in humans cause epidermodysplasia verruciformis with selective susceptibility to β-HPVs.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, Western blotting in patient-derived and control keratinocytes, patient genetic analysis\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP of complex plus human loss-of-function genetics with specific infectious phenotype, single lab\",\n      \"pmids\": [\"30068544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In resting platelets, CIB1 associates with ASK1 at low Ca2+ concentrations and inhibits ASK1 activation; agonist-induced increase in intracellular Ca2+ causes dissociation of CIB1 from ASK1, allowing ASK1 dimerization via N-terminal coiled-coil domains, TRAF6 recruitment, and autophosphorylation of ASK1 Thr838, resulting in full p38 MAPK activation. Genetic ablation of Cib1 augments agonist-induced Ask1/p38 activation.\",\n      \"method\": \"Co-immunoprecipitation, kinase assay, Ca2+ chelation/ionophore experiments, Cib1-/- mice, Western blotting\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Ca2+-dependent co-IP dissociation, phosphorylation site identified, genetic knockout confirmation, multiple agonists tested\",\n      \"pmids\": [\"31530712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CHIP (an E3 ubiquitin ligase) interacts with CIB1 and promotes its polyubiquitination and proteasomal degradation; lysine residues K10 and K65 of CIB1 are the ubiquitinated sites. CHIP-mediated CIB1 downregulation suppresses EMT, migration, and metastasis of lung adenocarcinoma cells.\",\n      \"method\": \"Mass spectrometry, co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis, in vitro and in vivo metastasis assays\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — ubiquitination assay with mutagenesis identifying specific sites (K10/K65), co-IP of E3-substrate complex, functional rescue experiments\",\n      \"pmids\": [\"33082516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TMC6 and TMC8 form a protein complex in mouse and human T cells and additionally interact with CIB1 to form TMC6-TMC8-CIB1 trimers; TMC6 and TMC8 protect CIB1 from ubiquitination and proteasomal degradation; reciprocally, CIB1 is needed for stabilizing TMC6 and TMC8 levels.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, Western blotting, TMC6 and TMC8 knockout mice\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mass spectrometry plus co-IP and knockout genetic models, single lab\",\n      \"pmids\": [\"32917726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"USP14 (a deubiquitinase) directly interacts with and stabilizes CIB1 by reversing K48-linked proteolytic ubiquitination at K24, facilitating the CIB1-PAK1-ERK1/2 signaling axis; USP14 silencing attenuates lenvatinib resistance; adeno-associated virus-mediated CIB1 transduction promotes lenvatinib resistance while CIB1 knockdown resensitizes tumors to lenvatinib.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay with site identification, in vitro and in vivo xenograft models, AAV transduction\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — deubiquitinase-substrate interaction with specific site (K24), in vivo genetic and pharmacological validation, single lab\",\n      \"pmids\": [\"38993552\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CIB1 is a ubiquitous 22-kDa EF-hand Ca2+-binding protein that, through a conserved hydrophobic binding cleft, interacts with diverse partners including the platelet αIIb integrin cytoplasmic tail (competitively inhibiting talin-mediated αIIbβ3 activation), PAK1 (activating it in a Ca2+-dependent manner to regulate cell migration via LIM kinase/cofilin), PLK3 (inhibiting its kinase activity in a Ca2+-dependent manner), ASK1 (inhibiting its activation at low Ca2+ by blocking TRAF2 recruitment and Thr838 autophosphorylation, with Ca2+ influx releasing this inhibition), calcineurin B (anchoring calcineurin to the sarcolemma to regulate NFAT-dependent pathological cardiac hypertrophy), all InsP3R isoforms (activating channel gating in the absence of InsP3 yet attenuating net cellular Ca2+ signaling upon overexpression), the telomerase catalytic subunit hTERT (increasing telomerase activity and telomere length), TRF2 and DNA-PKcs at telomeres, type III CD38 (modulating cADPR synthesis), and sphingosine kinase 1 (facilitating its plasma membrane localization via a Ca2+-myristoyl switch); post-translationally, CIB1 is polyubiquitinated by the E3 ligase CHIP at K10/K65 for proteasomal degradation, and stabilized by the deubiquitinase USP14 at K24, while EVER1/TMC6 and EVER2/TMC8 form a trimeric complex with CIB1 that mutually stabilizes all three proteins.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CIB1 is a ubiquitous EF-hand Ca2+-binding protein with a compact alpha-helical fold and a hydrophobic ligand-binding cleft that functions as a Ca2+-regulated adaptor and regulatory subunit for a broad set of partners controlling cell adhesion, migration, kinase signaling, and Ca2+ homeostasis [#0, #1]. At the platelet membrane it binds the αIIb integrin cytoplasmic tail and competes with talin to restrain agonist-induced αIIbβ3 activation, and in vivo CIB1 loss specifically impairs outside-in signaling, β3 tyrosine phosphorylation, and stable thrombus formation [#5, #12]; its integrin recognition extends to other α-integrin tails through the same hydrophobic pocket [#16]. CIB1 activates PAK1 in a Ca2+-dependent manner to drive LIM kinase/cofilin-mediated control of cell migration, a PAK1–ERK1/2–MMP2 axis that is required for endothelial migration, proliferation, and angiogenesis in vitro and in CIB1-deficient mice [#4, #9]. It is a Ca2+-gated regulator of stress and cell-cycle kinases, inhibiting ASK1 activation at low Ca2+ by blocking TRAF recruitment and Thr838 autophosphorylation until Ca2+ influx releases the brake to permit p38 activation [#11, #21], and acting as a regulatory subunit that inhibits PLK3 [#14]. CIB1 also tunes intracellular Ca2+ signaling by binding all InsP3R isoforms and attenuating InsP3-dependent Ca2+ release in cells [#7, #10], and it anchors calcineurin B at the sarcolemma to promote NFAT-dependent pathological cardiac hypertrophy [#13]. Additional roles include facilitating Ca2+-myristoyl-switch–dependent plasma-membrane localization of sphingosine kinase 1 to drive neoplastic transformation [#18] and supporting survival signaling through PI3K/AKT and Ras/MEK/ERK, with CIB1 depletion triggering caspase-independent death via nuclear GAPDH accumulation [#15]. CIB1 abundance is controlled by ubiquitin turnover: the E3 ligase CHIP polyubiquitinates it at K10/K65 for degradation [#22], while the deubiquitinase USP14 stabilizes it at K24 to sustain CIB1–PAK1–ERK1/2 signaling [#24], and it is mutually stabilized within a TMC6/EVER1–TMC8/EVER2–CIB1 trimeric complex [#23]. Loss-of-function CIB1 mutations cause epidermodysplasia verruciformis with selective susceptibility to β-HPVs [#20].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established the first physical partner of this novel calcineurin B-like Ca2+-binding protein, linking it to DNA-PKcs and hinting at a nuclear/genome-maintenance role.\",\n      \"evidence\": \"Yeast two-hybrid plus biochemical binding assay identifying CIB1 (KIP) as a DNA-PKcs partner\",\n      \"pmids\": [\"9372844\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional consequence of the interaction shown\", \"Binding interface not mapped\", \"Single-lab Y2H-based discovery\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Defined CIB1 as a monomeric four-EF-hand protein with a hydrophobic ligand pocket, providing the structural basis for its promiscuous partner binding and distinguishing it from NCS proteins.\",\n      \"evidence\": \"X-ray crystallography of Ca2+-bound CIB1 at 2.0 Å with mutational analysis; later NMR of Ca2+/Mg2+ forms mapping the αIIb interface\",\n      \"pmids\": [\"15574431\", \"21388953\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structures of CIB1 bound to most named partners not solved\", \"Conformational basis for Ca2+ vs Mg2+ switching only partially defined\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Showed CIB1 can act in the nucleus to enhance telomerase activity and telomere length, the first functional output assigned to the protein.\",\n      \"evidence\": \"Y2H, co-IP, in vitro binding, immunolocalization, and telomerase activity assay with hTERT\",\n      \"pmids\": [\"15190070\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which CIB1 increases telomerase activity unresolved\", \"Ca2+-dependence of the hTERT interaction not addressed\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identified CIB1 as a Ca2+-dependent PAK1 activator coupling it to LIM kinase/cofilin and cell migration, establishing a cytoskeletal signaling role.\",\n      \"evidence\": \"In vitro kinase assays, reciprocal co-IP, RNAi loss-of-function and overexpression with migration phenotypes\",\n      \"pmids\": [\"16061695\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of PAK1 inhibitory-switch engagement not solved\", \"How Ca2+ gates activation mechanistically unclear\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Placed CIB1 as a negative regulator of integrin αIIbβ3 activation via competition with talin, and a genetic requirement for spermatogenesis and cell-cycle control.\",\n      \"evidence\": \"Megakaryocyte overexpression/RNAi with integrin activation assays; Cib1-/- knockout mice with testis histology and MEF proliferation\",\n      \"pmids\": [\"16418530\", \"16982698\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct structural proof of talin competition at the αIIb tail not provided\", \"Molecular link between CIB1 and Cdc2/Cdk1 in germ cells undefined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Revealed CIB1 as a Ca2+-sensitive InsP3R-binding protein with paradoxical activity—activating channel gating in vitro yet attenuating cellular Ca2+ signaling—implicating it in Ca2+ homeostasis.\",\n      \"evidence\": \"Pull-downs, single-channel patch clamp, and Ca2+ imaging with overexpression; later in vivo shRNA/overexpression FURA-2 imaging\",\n      \"pmids\": [\"16723353\", \"18627437\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reconciliation of in vitro activation vs cellular attenuation not fully resolved\", \"InsP3R-binding site not mapped\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined CIB1 as a Ca2+-gated brake on ASK1 stress signaling, blocking TRAF2 recruitment and Thr838 autophosphorylation, with Ca2+ influx relieving inhibition.\",\n      \"evidence\": \"Co-IP, in vitro kinase assays, mechanistic Thr838 mutant, Ca2+ manipulation, and cell death assays; later confirmed in Cib1-/- platelets with p38 readout\",\n      \"pmids\": [\"19805025\", \"31530712\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Discrepancy in adaptor identity (TRAF2 vs TRAF6) across systems\", \"Stoichiometry of the Ca2+-driven dissociation not quantified\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showed CIB1 is required in vivo for thrombosis, assigning its platelet function specifically to outside-in αIIbβ3 signaling.\",\n      \"evidence\": \"Cib1-/- mice with bleeding, FeCl3 carotid thrombosis, platelet spreading assays, and β3 phosphorylation immunoblotting\",\n      \"pmids\": [\"19691476\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct connection between CIB1 and β3 tyrosine phosphorylation machinery not established\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Established CIB1 as a sarcolemmal anchor for calcineurin B that drives NFAT-dependent pathological cardiac hypertrophy.\",\n      \"evidence\": \"Y2H, immunolocalization, Cib1-/- and inducible cardiac-overexpression mice, pressure-overload models, NFAT reporter, epistasis with calcineurin Aβ-null mice\",\n      \"pmids\": [\"20639889\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CIB1 selectively couples calcineurin to L-type Ca2+ channels mechanistically unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified CIB1 as a constitutive, Ca2+-dependent inhibitory regulatory subunit of PLK3.\",\n      \"evidence\": \"Co-IP in vitro and in vivo with in vitro kinase assays and Ca2+ manipulation\",\n      \"pmids\": [\"20473878\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cellular and physiological consequence of PLK3 inhibition not established\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Connected CIB1 to telomere protection, showing it bridges TRF2 and DNA-PKcs and that its loss provokes telomere damage and senescence.\",\n      \"evidence\": \"Co-IP, ChIP, immunolocalization, telomere dysfunction assays, and flow cytometry\",\n      \"pmids\": [\"25012820\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether telomeric and DNA-PKcs roles are direct or scaffold-mediated unresolved\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed CIB1 promotes oncogenic transformation by recruiting sphingosine kinase 1 to the plasma membrane through a Ca2+-myristoyl switch.\",\n      \"evidence\": \"Subcellular fractionation, enzymatic activity assays, transformation assays, shRNA/overexpression, and SK1 epistasis\",\n      \"pmids\": [\"27941888\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural detail of the Ca2+-myristoyl switch with SK1 not defined\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified CIB1 as a modulator of type III CD38, with cellular cADPR levels tracking CIB1 abundance.\",\n      \"evidence\": \"Y2H, co-IP, ELISA, BiFC, shRNA and CRISPR knockout with cADPR quantification\",\n      \"pmids\": [\"28720704\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which CIB1 binding alters CD38 catalysis not defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Linked CIB1 to antiviral keratinocyte biology and human disease, identifying it as part of an EVER1/EVER2 complex and a restriction factor whose loss causes epidermodysplasia verruciformis.\",\n      \"evidence\": \"Co-IP, immunofluorescence, Western blotting in patient and control keratinocytes, HPV E5/E8 interaction, and patient genetics\",\n      \"pmids\": [\"30068544\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of β-HPV restriction by the EVER1/EVER2/CIB1 complex not defined\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined the ubiquitin-controlled turnover of CIB1, identifying CHIP-mediated degradation at K10/K65 and mutual stabilization within the TMC6/TMC8/CIB1 trimer.\",\n      \"evidence\": \"Mass spectrometry, co-IP, ubiquitination assays with site-directed mutagenesis, metastasis assays, and TMC6/TMC8 knockout mice\",\n      \"pmids\": [\"33082516\", \"32917726\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signals regulating CHIP-CIB1 engagement unknown\", \"Whether trimer stabilization competes with CHIP not tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed USP14 stabilizes CIB1 by removing K48-linked ubiquitin at K24 to sustain CIB1-PAK1-ERK1/2 signaling and drug resistance.\",\n      \"evidence\": \"Co-IP, ubiquitination assays with site identification, xenografts, and AAV transduction with lenvatinib resistance readouts\",\n      \"pmids\": [\"38993552\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How USP14 and CHIP balance is regulated unknown\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how a single small EF-hand adaptor selects among its many partners in a given cell, and what determines which Ca2+-gated output dominates physiologically.\",\n      \"evidence\": \"No single study reconciles the partner repertoire or competitive hierarchy\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No quantitative affinity/competition ranking across partners\", \"Tissue-specific partner usage undefined\", \"Most CIB1-partner co-structures unsolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [4, 11, 14, 21]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 7, 11, 14, 16]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [13, 17, 18, 23]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [0, 7, 21]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [5, 13, 18]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 17]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [11, 19]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 11, 13, 21]},\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [5, 12]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [22, 23, 24]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [11, 15]}\n    ],\n    \"complexes\": [\n      \"TMC6/EVER1-TMC8/EVER2-CIB1 trimer\",\n      \"TRF2-DNA-PKcs telomere complex\"\n    ],\n    \"partners\": [\n      \"PAK1\",\n      \"ASK1\",\n      \"PLK3\",\n      \"ITGA2B\",\n      \"PPP3R1\",\n      \"ITPR1\",\n      \"CD38\",\n      \"SPHK1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}