Affinage

CIB1

Calcium and integrin-binding protein 1 · UniProt Q99828

Length
191 aa
Mass
21.7 kDa
Annotated
2026-04-28
100 papers in source corpus 30 papers cited in narrative 30 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CIB1 is a calcium- and integrin-binding protein that functions as a multifunctional regulatory scaffold, coupling Ca²⁺ sensing to integrin signaling, kinase regulation, ion channel modulation, and innate immunity. Structurally, CIB1 is a compact, predominantly monomeric α-helical protein with four EF-hands (the C-terminal pair binding Ca²⁺) and a conserved hydrophobic pocket that engages the αIIb integrin cytoplasmic tail to competitively inhibit talin-mediated inside-out integrin activation while promoting outside-in signaling required for platelet spreading and stable thrombus formation (PMID:15574431, PMID:16418530, PMID:19691476). CIB1 directly activates PAK1 in a Ca²⁺-dependent manner to regulate cofilin phosphorylation, cell migration, and angiogenesis; inhibits ASK1 autophosphorylation to suppress stress-activated MAPK signaling; anchors calcineurin to the sarcolemma to drive pathological cardiac hypertrophy; modulates InsP3 receptor gating and Ca²⁺ release; and facilitates sphingosine kinase 1 plasma membrane translocation to support oncogenic Ras signaling (PMID:16061695, PMID:19805025, PMID:20639889, PMID:16723353, PMID:27941888). Loss-of-function mutations in CIB1 cause epidermodysplasia verruciformis with selective susceptibility to β-papillomaviruses, reflecting its role as a subunit of the EVER1/EVER2 restriction factor complex in keratinocytes (PMID:30068544).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1999 High

    Establishing CIB1 as a direct, Ca²⁺-dependent binding partner of the αIIb integrin cytoplasmic domain answered whether this novel calcineurin-B-like protein had a specific receptor target in platelets.

    Evidence Isothermal titration calorimetry measuring 1:1 stoichiometry and ~700 nM Kd, plus yeast two-hybrid and co-fractionation with αIIbβ3 in activated platelets

    PMID:10477286

    Open questions at the time
    • Functional consequence of αIIb binding in platelets not yet demonstrated
    • Whether CIB1 binds other integrin α-subunits unknown
  2. 2002 High

    Mapping the CIB1-integrin interface to the C-terminal hydrophobic pocket established the structural basis for ligand recognition, showing CIB1 uses a calmodulin/calcineurin-B-like target-binding mode.

    Evidence Systematic alanine scanning mutagenesis of 12 hydrophobic pocket residues with tryptophan fluorescence binding assay and CD confirmation of fold integrity

    PMID:12023286

    Open questions at the time
    • Atomic-resolution structure of the CIB1–αIIb complex not yet determined
    • Whether the same pocket engages non-integrin partners unknown
  3. 2003 High

    Demonstrating that CIB1 is required for platelet lamellipodia formation during outside-in signaling resolved whether the CIB1–αIIbβ3 interaction had functional significance beyond binding.

    Evidence Co-IP of endogenous proteins during fibrinogen adhesion; intracellular anti-CIB antibody and peptide inhibition block spreading; recombinant CIB1 rescues the phenotype

    PMID:12714504

    Open questions at the time
    • Downstream signaling intermediates linking CIB1 to cytoskeletal reorganization not defined
    • In vivo platelet function in CIB1-null animals not yet tested
  4. 2004 High

    The 2.0 Å crystal structure of Ca²⁺-bound CIB1 revealed four EF-hands with only the C-terminal pair competent for Ca²⁺ binding, a calcineurin-B-like fold, and a monomeric state, providing the first atomic framework for understanding CIB1 partner recognition.

    Evidence X-ray crystallography at 2.0 Å resolution with CD and mutagenesis validation

    PMID:15574431

    Open questions at the time
    • Apo- and Mg²⁺-bound structures not yet available
    • Structural basis for discrimination among partners unresolved
  5. 2005 High

    Identification of PAK1 as a direct CIB1-activated kinase established CIB1 as an upstream regulator of the PAK1–LIMK–cofilin axis controlling cell migration, extending its role beyond integrins.

    Evidence In vitro kinase activation assay, co-IP, reciprocal overexpression/RNAi with migration and cofilin phosphorylation readouts

    PMID:16061695

    Open questions at the time
    • Whether CIB1 activates PAK1 in platelets specifically unknown
    • Structural basis of PAK1 activation by CIB1 not determined
  6. 2006 High

    Showing that CIB1 competitively inhibits talin binding to αIIb to suppress inside-out integrin activation resolved the paradox of CIB1 promoting outside-in but restraining inside-out signaling, establishing CIB1 as a bidirectional integrin regulator.

    Evidence Overexpression blocks and RNAi enhances agonist-induced αIIbβ3 activation in megakaryocytes; competition binding with talin

    PMID:16418530

    Open questions at the time
    • In vivo consequence in CIB1-null platelets not yet shown at this time
    • Whether CIB1 regulates other integrin α-subunit activation in non-platelet cells untested
  7. 2006 High

    CIB1 binding to InsP3 receptors and direct activation of channel gating demonstrated a second Ca²⁺-regulatory function, linking CIB1 to intracellular Ca²⁺ store mobilization.

    Evidence Single-channel patch clamp showing CIB1 opens InsP3R without InsP3; EF-hand mutants lose binding; overexpression attenuates InsP3R-dependent Ca²⁺ signaling

    PMID:16723353

    Open questions at the time
    • Physiological context where CIB1–InsP3R interaction dominates undefined
    • Whether CIB1 modulates store-operated Ca²⁺ entry indirectly not tested
  8. 2006 High

    Cib1⁻/⁻ male sterility due to disrupted spermatogenesis revealed an essential developmental role for CIB1 beyond platelets and signaling.

    Evidence Germline knockout with histological loss of elongated spermatids, increased germ cell apoptosis, and elevated Cdk1 expression

    PMID:16982698

    Open questions at the time
    • Molecular mechanism linking CIB1 loss to spermatogenic arrest not defined
    • Whether PAK1 or integrin pathways mediate this phenotype untested
  9. 2007 High

    Cib1⁻/⁻ mice confirmed CIB1 is required in vivo for stable thrombus formation and outside-in (but not inside-out) integrin signaling, validating earlier cell-based findings.

    Evidence Extended tail bleeding, unstable thrombi by intravital microscopy, reduced β3 phosphorylation and spreading ex vivo, normal aggregation

    PMID:19691476

    Open questions at the time
    • Compensatory upregulation of CIB3 may mask full phenotype
    • Mechanism connecting CIB1 to β3 tyrosine phosphorylation not resolved
  10. 2007 High

    Extension of the CIB1–PAK1 axis to angiogenesis demonstrated that CIB1 regulates endothelial cell migration, proliferation, and in vivo neovascularization through PAK1–ERK1/2–MMP2 signaling.

    Evidence shRNA and Cib1⁻/⁻ mice with impaired ischemia-induced angiogenesis; reduced PAK1 and ERK1/2 activation and MMP-2 expression in endothelial cells

    PMID:17975111

    Open questions at the time
    • Whether CIB1's integrin-regulatory and PAK1-activating roles are separable in endothelial cells unknown
    • Therapeutic targeting implications not tested
  11. 2009 High

    CIB1 binding to ASK1 and inhibition of its autophosphorylation, reversed by Ca²⁺ influx, established CIB1 as a Ca²⁺-sensitive brake on stress-activated MAPK signaling and cell death.

    Evidence Co-IP, in vitro kinase assay showing inhibition of Thr-838 autophosphorylation, TRAF2 displacement, Ca²⁺-dependent relief in dopaminergic neurons

    PMID:19805025

    Open questions at the time
    • In vivo relevance in neurodegeneration not tested with Cib1⁻/⁻ mice
    • Whether CIB1–ASK1 is relevant outside neuronal cells untested
  12. 2010 High

    CIB1 anchoring calcineurin to the sarcolemma to drive pathological cardiac hypertrophy, demonstrated by genetic epistasis with calcineurin Aβ, placed CIB1 as a critical spatial regulator of calcineurin-NFAT signaling in the heart.

    Evidence Cib1⁻/⁻ mice resist pressure-overload hypertrophy; cardiac CIB1 transgenic enhances hypertrophy unless calcineurin Aβ is deleted; yeast two-hybrid with calcineurin B; sarcolemmal localization by fractionation

    PMID:20639889

    Open questions at the time
    • Whether CIB1 regulates calcineurin in non-cardiac tissues unknown
    • Structural basis of CIB1–calcineurin B interaction not determined
  13. 2011 High

    Solution NMR structures revealed that EF-hand III directly contacts the αIIb tail and the C-terminal helix is displaced upon binding, providing the first dynamic picture of the CIB1–integrin interaction.

    Evidence NMR chemical shift perturbation and backbone amide dynamics for Ca²⁺-CIB1 and Mg²⁺-CIB1 ± αIIb peptide

    PMID:21388953

    Open questions at the time
    • Full NMR structure of the CIB1–αIIb complex not determined
    • How divalent cation state switches partner selectivity not fully explained
  14. 2013 Medium

    Extension of CIB1 binding to multiple α-integrin cytoplasmic tails via a conserved consensus motif broadened CIB1 from a platelet-specific to a general integrin regulator.

    Evidence Computational docking validated by co-IP and competitive binding assays for multiple α-integrins

    PMID:24011356

    Open questions at the time
    • Functional consequence of CIB1 binding to non-αIIb integrins not established in vivo
    • Whether CIB1 regulates inside-out activation for all bound integrins untested
  15. 2016 Medium

    CIB1's Ca²⁺-myristoyl switch facilitating sphingosine kinase 1 plasma membrane translocation and oncogenic Ras signaling established CIB1 as a lipid signaling scaffold with transforming potential.

    Evidence CIB1 overexpression drives SK1 to plasma membrane and induces transformation in a SK1-dependent manner; CIB1 knockdown suppresses Ras-driven neoplastic growth

    PMID:27941888

    Open questions at the time
    • Whether the myristoyl switch is required for all CIB1 membrane-associated functions untested
    • In vivo tumor model with genetic CIB1 loss not performed
  16. 2017 High

    CIB1 interaction with type III CD38 and regulation of cADPR synthesis revealed an unexpected role in NAD⁺ metabolite signaling.

    Evidence Multiple interaction methods (Y2H, co-IP, BiFC, ELISA); CRISPR knockout reduces cellular cADPR

    PMID:28720704

    Open questions at the time
    • Physiological consequence of altered cADPR levels upon CIB1 loss not characterized
    • Whether this pathway intersects CIB1's Ca²⁺ regulatory functions unknown
  17. 2018 High

    Human loss-of-function CIB1 mutations causing epidermodysplasia verruciformis, and CIB1 forming a complex with EVER1/EVER2, established CIB1 as an essential component of intrinsic anti-HPV immunity in keratinocytes.

    Evidence Patient null mutations; CIB1 protein lost in EVER1/EVER2-deficient cells; co-IP of CIB1–EVER1/EVER2 complex; CIB1 interacts with HPV E5 and E8

    PMID:30068544

    Open questions at the time
    • Mechanism by which CIB1–EVER complex restricts β-HPV replication not defined
    • Whether CIB1's Ca²⁺-binding activity is required for antiviral function untested
  18. 2020 Medium

    CHIP-mediated polyubiquitination of CIB1 at Lys10 and Lys65 targeting it for proteasomal degradation defined the first regulated turnover mechanism for CIB1, with functional consequences for EMT and metastasis.

    Evidence Mass spectrometry interactome, co-IP, ubiquitination assay with K10R/K65R mutants, in vivo metastasis assay

    PMID:33082516

    Open questions at the time
    • Signals triggering CHIP-mediated CIB1 degradation not identified
    • Whether other E3 ligases also regulate CIB1 stability unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CIB1 discriminates among its diverse binding partners in a context-dependent manner, and whether its Ca²⁺-myristoyl switch is universally required for membrane-associated functions, remain major unresolved questions.
  • No co-crystal or cryo-EM structure of CIB1 bound to any full-length partner
  • Integrated model of how Ca²⁺ concentration switches CIB1 between inhibitory and activating modes lacking
  • Whether CIB1 family members (CIB2–4) are functionally redundant in vivo not systematically tested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 7 GO:0008289 lipid binding 3 GO:0060090 molecular adaptor activity 3
Localization
GO:0005886 plasma membrane 3 GO:0005856 cytoskeleton 2 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-109582 Hemostasis 3 R-HSA-1266738 Developmental Biology 2 R-HSA-168256 Immune System 1
Partners
ASK1CD38ITGA2BITPR1PAK1PPP3CBSPHK1STUB1
Complex memberships
EVER1/EVER2/CIB1 complex

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 Crystal structure of Ca2+-bound CIB1 determined at 2.0 Å resolution, revealing a compact alpha-helical protein with four EF-hands (last two bind calcium), structural similarity to calcineurin B and neuronal calcium sensor (NCS) proteins, and a conserved hydrophobic pocket implicated in ligand binding; mutagenesis confirmed the hydrophobic pocket is required for binding. CIB1 is largely monomeric in the calcium-bound state, distinguishing it from NCS proteins. X-ray crystallography, circular dichroism, mutational analysis The Journal of biological chemistry High 15574431
2011 Solution NMR structures of Ca2+-CIB1 and Mg2+-CIB1 determined; the C-domain EF-hands are smaller/more open compared to crystal structures. EF-hand III is directly involved in binding the integrin αIIb cytoplasmic domain, and the C-terminal helix of Ca2+-CIB1 is displaced upon αIIb binding, as confirmed by backbone amide dynamics measurements. Solution NMR spectroscopy, chemical shift perturbation, nitroxide surface probe, backbone amide dynamics The Journal of biological chemistry High 21388953
1999 CIB1 (CIB) binds to the alphaIIb cytoplasmic domain of the platelet integrin alphaIIbbeta3 in a Ca2+-dependent manner with 1:1 stoichiometry and Kd ~700 nM, as measured by isothermal titration calorimetry. In aggregated platelets, CIB and alphaIIbbeta3 co-translocate to the Triton X-100-insoluble cytoskeleton. Isothermal titration calorimetry, subcellular fractionation, yeast two-hybrid The Biochemical journal High 10477286
2002 CIB1 binds to the alphaIIb cytoplasmic tail via a membrane-proximal 15-amino acid hydrophobic region (analogous to alpha-helical targets of calcineurin B/calmodulin). Alanine substitutions in the C-terminal hydrophobic pocket of CIB1 abolished alphaIIb binding in 11/12 cases while retaining secondary structure, identifying the C-terminal EF-hand region as the essential integrin-binding site. Intrinsic tryptophan fluorescence binding assay, circular dichroism, site-directed mutagenesis The Journal of biological chemistry High 12023286
2006 CIB1 is an endogenous inhibitor of agonist-induced alphaIIbbeta3 integrin activation in platelets/megakaryocytes. Overexpression of CIB1 blocks agonist-induced alphaIIbbeta3 activation, while RNAi-mediated reduction of CIB1 enhances activation. CIB1 inhibits integrin activation by competing with talin for binding to alphaIIbbeta3. Overexpression and RNAi knockdown in megakaryocytes, integrin activation assays, competition binding The Journal of cell biology High 16418530
2003 CIB1 directly interacts with and co-immunoprecipitates with the platelet integrin GPIIb/IIIa (alphaIIbbeta3) during outside-in signaling upon adhesion to fibrinogen. CIB1 localizes to filopodia and then the membrane periphery of spread platelets. Inhibition of the CIB-GPIIb interaction (by anti-CIB antibody or GPIIb cytoplasmic peptide) blocks lamellipodia but not filopodia formation; adding recombinant CIB rescues spreading, demonstrating that the CIB-GPIIb/IIIa complex is required for outside-in signaling leading to platelet spreading. Immunoprecipitation, immunofluorescence, intracellular antibody/peptide introduction, rescue with recombinant protein Blood High 12714504
2005 CIB1 directly and specifically interacts with PAK1, resulting in PAK1 activation both in vitro and in vivo. CIB1 binds PAK1 within discrete regions surrounding the inhibitory switch domain in a calcium-dependent manner. CIB1 overexpression decreases cell migration on fibronectin via a PAK1- and LIM kinase-dependent increase in cofilin phosphorylation. RNAi depletion of CIB1 increases cell migration and reduces adhesion-induced PAK1 activation and cofilin phosphorylation. In vitro binding assay, co-immunoprecipitation, overexpression and RNAi, cell migration assays, kinase assays, phospho-cofilin western blot The Journal of cell biology High 16061695
2009 CIB1 binds to apoptosis signal-regulating kinase 1 (ASK1), interferes with TRAF2 recruitment to ASK1, and inhibits ASK1 autophosphorylation on Thr-838, thereby blocking ASK1 activation and downstream stress-activated MAPK signaling. Ca2+ influx reverses CIB1's inhibitory effect on ASK1 activation and cell death in dopaminergic neurons. Co-immunoprecipitation, in vitro binding, kinase autophosphorylation assay, RNAi, cell death assays Proceedings of the National Academy of Sciences of the United States of America High 19805025
2010 CIB1 localizes primarily to the sarcolemma in cardiomyocytes, where it anchors calcineurin to the membrane and controls its activation in coordination with the L-type Ca2+ channel. CIB1 was identified as a binding partner of calcineurin B by yeast two-hybrid. Loss of CIB1 in Cib1-/- mice markedly reduces myocardial hypertrophy, fibrosis, and calcineurin-NFAT signaling after pressure overload, while cardiac-specific CIB1 overexpression enhances hypertrophy. Mice lacking calcineurin A beta show no enhancement of hypertrophy with CIB1 overexpression, placing CIB1 upstream of calcineurin in this pathway. Yeast two-hybrid, subcellular fractionation/immunofluorescence localization, Cib1-/- mouse phenotyping, cardiac-specific transgenic overexpression, epistasis with calcineurin A beta knockout Nature medicine High 20639889
2003 CIB1 (CIB) co-immunoprecipitates with the polo-like kinase Snk and inhibits Snk kinase activity, functioning as a negative regulator of Snk kinase activity. Co-immunoprecipitation, in vitro kinase assay Molecular cancer research Medium 12651910
2011 CIB1 constitutively interacts with polo-like kinase 3 (PLK3) independent of intracellular Ca2+, and this interaction inhibits PLK3 kinase activity in a Ca2+-dependent manner, both in vitro and in vivo. Co-immunoprecipitation, in vitro binding assay, in vitro and in vivo kinase activity assays International journal of cancer Medium 20473878
2001 CIB1 interacts exclusively with activated (V12) Rac3 (not Rac1 or Rac2), mediated by the C-terminal end of Rac3 and membrane localization. Co-expression of V12Rac3 and CIB1 stimulates alphaIIbbeta3-mediated adhesion and spreading on fibrinogen. Adhesion through alphaIIbbeta3 specifically increases GTP-bound Rac3 but not Rac1. Yeast two-hybrid, co-immunoprecipitation, immunofluorescence colocalization, Triton-insoluble fractionation, GTPase pull-down, adhesion and spreading assays The Journal of biological chemistry Medium 11756406
2006 CIB1 binds to all mammalian InsP3 receptor isoforms in a Ca2+-sensitive manner dependent on its two functional EF-hands, and activates InsP3R channel gating in the absence of InsP3. Pre-exposure to CIB1 in vitro reduces the number of InsP3R channels available for subsequent InsP3 stimulation, and CIB1 overexpression attenuates InsP3R-dependent Ca2+ signaling. Co-immunoprecipitation, single-channel patch clamp, in vitro channel gating assay, Ca2+ imaging with overexpression/knockdown The Journal of biological chemistry High 16723353
2008 CIB1 acts as a general inhibitor of InsP3-dependent Ca2+ release in vivo. Depletion of CIB1 by shRNA increased Ca2+ responses to InsP3-generating ligands (ATP, UTP, carbachol); overexpression of CIB1 reduced Ca2+ responses. This effect was dependent on the thapsigargin-sensitive ER Ca2+ store and independent of extracellular Ca2+, consistent with CIB1 acting on the InsP3 receptor. shRNA knockdown, overexpression, FURA-2 Ca2+ imaging, pharmacological dissection Journal of neurochemistry Medium 18627437
2006 CIB1 is essential for spermatogenesis: Cib1-/- male mice are sterile due to disruption of the haploid phase of spermatogenesis, associated with increased germ cell apoptosis and loss of elongated spermatids/sperm. Cib1-/- mouse embryonic fibroblasts show markedly slower growth. Cib1-/- testes show increased Cdc2/Cdk1 mRNA and protein expression. Homologous recombination knockout, histology, TUNEL apoptosis assay, RT-PCR, western blot, MEF growth assay Molecular and cellular biology High 16982698
2007 CIB1 deficiency in Cib1-/- mice results in impaired thrombosis: increased tail bleeding time, rebleeding, delayed carotid artery occlusion, and unstable thrombus formation. Cib1-/- platelets show reduced spreading on fibrinogen and reduced outside-in signaling-dependent beta3 tyrosine phosphorylation, while inside-out signaling (agonist-induced aggregation and fibrinogen binding) is unaffected. Cib1-/- knockout mice, tail bleeding assay, intravital microscopy, platelet spreading assay, western blot for beta3 phosphorylation, aggregation assays Journal of thrombosis and haemostasis High 19691476
2007 CIB1 regulates endothelial cell migration, proliferation, and tube formation. Loss of CIB1 decreases PAK1 activation, downstream ERK1/2 activation, and MMP-2 expression in endothelial cells. Cib1-/- mice show reduced growth factor-induced microvessel sprouting and impaired ischemia-induced retinal and hindlimb angiogenesis. shRNA knockdown and Cib1-/- knockout, endothelial cell migration/proliferation/tubule assays, kinase activity assays, ex vivo organ culture, in vivo Matrigel plug and hindlimb ischemia model Circulation research High 17975111
2012 CIB1 depletion in cancer cells promotes non-apoptotic, caspase-independent cell death requiring nuclear GAPDH accumulation. CIB1 supports PI3K/AKT and Ras/MEK/ERK signaling; its depletion disrupts both pathways synergistically. AKT inhibition alone maximally induces GAPDH nuclear accumulation, while concurrent ERK inhibition plus GAPDH nuclear accumulation is required for a DNA damage response and subsequent cell death. RNAi depletion, pharmacological PI3K/AKT and MEK/ERK inhibition, subcellular fractionation for GAPDH, flow cytometry, immunoblotting Oncogene Medium 22964641
2016 CIB1 facilitates agonist-induced plasma membrane localization of sphingosine kinase 1 (SK1) via its Ca2+-myristoyl switch function. CIB1 overexpression drives SK1 to the plasma membrane, enhancing membrane-associated SK1 enzymatic activity and oncogenic signaling. CIB1 overexpression alone is sufficient to induce neoplastic transformation in a SK1-dependent manner, and CIB1 knockdown inhibits neoplastic growth induced by oncogenic Ras. Overexpression and shRNA knockdown, subcellular fractionation, SK1 activity assay, transformation assays, epistasis with SK1 Oncogene Medium 27941888
2017 CIB1 interacts with the catalytic domain of type III CD38 (cytosol-facing orientation) both in vivo and in vitro, as confirmed by co-immunoprecipitation, ELISA, and bimolecular fluorescence complementation. The N-terminus of CIB1 is the interacting domain. shRNA knockdown and CRISPR/Cas9 knockout of CIB1 directly reduces cellular cADPR levels, demonstrating that CIB1 modulates type III CD38-mediated cADPR synthesis. Yeast two-hybrid, co-immunoprecipitation, ELISA, bimolecular fluorescence complementation, shRNA knockdown, CRISPR/Cas9 knockout, cADPR measurement Proceedings of the National Academy of Sciences of the United States of America High 28720704
2018 CIB1 forms a protein complex with EVER1 (TMC6) and EVER2 (TMC8) in keratinocytes. CIB1 protein expression is lost in EVER1- or EVER2-deficient cells. CIB1 interacts with HPV E5 (alpha-HPV16) and E8 (gamma-HPV4) proteins in keratinocytes, suggesting CIB1 acts as a restriction factor against HPVs. Loss-of-function CIB1 mutations cause epidermodysplasia verruciformis with selective susceptibility to beta-HPVs. Co-immunoprecipitation, patient genetic analysis (null mutations), keratinocyte expression studies, loss-of-function cellular phenotyping The Journal of experimental medicine High 30068544
2020 CHIP (carboxyl-terminus of Hsp70-interacting protein), a ubiquitin E3 ligase, promotes polyubiquitination and proteasomal degradation of CIB1. Lysine residues 10 and 65 of CIB1 are the ubiquitination sites. CHIP-mediated CIB1 downregulation suppresses epithelial-mesenchymal transition and metastasis of lung adenocarcinoma cells. Mass spectrometry (interactome), co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis of ubiquitin acceptor sites, in vitro and in vivo metastasis assays Cell death and differentiation Medium 33082516
2013 CIB1 interacts with multiple alpha-integrin cytoplasmic tails beyond alphaIIb, all sharing a conserved consensus binding site (I/L-x-x-x-L/M-W/Y-K-x-G-F-F). Binding is driven by hydrophobic interactions with the CIB1 hydrophobic pocket. Novel in vivo CIB1-integrin interactions validated by co-immunoprecipitation; competition binding confirmed that other alpha-integrin CTs displace alphaIIb from CIB1. Computational docking (replica exchange discrete molecular dynamics), co-immunoprecipitation, solid-phase competitive binding assay, isothermal titration calorimetry Biochemistry Medium 24011356
2014 CIB1 synergizes with EphrinA2 (EphA2) to coordinate macropinocytic entry of KSHV in endothelial cells. CIB1 is recruited to membrane blebs and Rab5-positive macropinocytic vesicles during infection. CIB1 knockdown reduces EphA2, Src, and ERK1/2 activation induced by KSHV. By mass spectrometry, CIB1 and EphA2 simultaneously associate with myosin IIA and alpha-actinin 4; CIB1 knockdown reduces EphA2's association with these actin cytoskeletal components. shRNA knockdown, overexpression, single virus particle tracking (DiI/BrdU labeling), co-immunoprecipitation, mass spectrometry, Rab5 colocalization, kinase activation assays PLoS pathogens Medium 24550731
2007 CIB1 binds to the IQ motifs in the myo1c regulatory domain, competing with calmodulin for binding. CIB1 co-localizes with myo1c in cells (endogenous proteins). CaBP1 has higher apparent affinity for myo1c than CIB1; both proteins better compete with calmodulin in the presence of calcium. Pull-down assay, fluorescence microscopy colocalization, competitive binding assay Journal of muscle research and cell motility Medium 17994197
1997 CIB1 (described as KIP, a novel Ca2+-binding protein with ~26% identity to calcineurin B) was identified as interacting with DNA-PKcs by yeast two-hybrid screening of DNA-PKcs, and the interaction was confirmed biochemically. Yeast two-hybrid, biochemical confirmation Mutation research Low 9372844
2004 CIB1 (KIP) was identified as binding to the catalytic subunit of telomerase (hTERT) by yeast two-hybrid. Co-immunoprecipitation showed CIB1-hTERT complexes in cells; immunolocalization demonstrated CIB1 co-localizes with hTERT in the nucleus. Overexpression of CIB1 increases endogenous telomerase activity and leads to telomere lengthening. Yeast two-hybrid, co-immunoprecipitation, immunofluorescence colocalization, in vitro binding, telomerase activity assay, telomere length analysis The Journal of biological chemistry Medium 15190070
2002 CIB1 interacts with NBR1 in yeast two-hybrid assays. Co-expression of NBR1 and CIB1 shifts CIB1 protein localization from the nucleus to the perinuclear compartment. Yeast two-hybrid, co-transfection and immunofluorescence European journal of biochemistry Low 11856312
2008 CIB1, CIB2, and CIB3 all bind specifically to the alphaIIb cytoplasmic tail peptide in vitro. In Cib1-/- megakaryocytes, CIB3 mRNA is upregulated, suggesting functional compensation. Protein modeling shows CIBs 1–3 share a conserved hydrophobic binding pocket. In vitro binding assay, RT-PCR, homology modeling Thrombosis and haemostasis Medium 18989529
2015 CIB1 depletion causes significant cell death in the majority of TNBC cell lines tested. Elevated AKT activation status and low PTEN expression predict sensitivity to CIB1 depletion. CIB1 knockdown causes dramatic shrinkage of MDA-MB-468 xenograft tumors in vivo, and RNA-seq shows activation of gene programs associated with decreased proliferation and increased cell death. Inducible RNAi, clonogenic assay, flow cytometry, western blotting, xenograft tumor model, RNA-sequencing Breast cancer research and treatment Medium 26105795

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1995 Kip/Cip and Ink4 Cdk inhibitors cooperate to induce cell cycle arrest in response to TGF-beta. Genes & development 915 7649471
2008 Photoexcited CRY2 interacts with CIB1 to regulate transcription and floral initiation in Arabidopsis. Science (New York, N.Y.) 578 18988809
2000 Molecular identification and characterization of novel human and mouse concentrative Na+-nucleoside cotransporter proteins (hCNT3 and mCNT3) broadly selective for purine and pyrimidine nucleosides (system cib). The Journal of biological chemistry 300 11032837
2016 Optimized second-generation CRY2-CIB dimerizers and photoactivatable Cre recombinase. Nature chemical biology 198 27065233
2006 DAF-16/FOXO regulates transcription of cki-1/Cip/Kip and repression of lin-4 during C. elegans L1 arrest. Current biology : CB 197 16631585
1998 Cip/Kip cyclin-dependent kinase inhibitors: brakes of the cell cycle engine during development. BioEssays : news and reviews in molecular, cellular and developmental biology 171 10048302
1999 Degradation of p27(Kip) cdk inhibitor triggered by Kaposi's sarcoma virus cyclin-cdk6 complex. The EMBO journal 144 9927424
2011 Multiple degradation pathways regulate versatile CIP/KIP CDK inhibitors. Trends in cell biology 132 22154077
2009 p57KIP2: "Kip"ing the cell under control. Molecular cancer research : MCR 128 19934273
2002 Muc4/sialomucin complex, the intramembrane ErbB2 ligand, induces specific phosphorylation of ErbB2 and enhances expression of p27(kip), but does not activate mitogen-activated kinase or protein kinaseB/Akt pathways. Oncogene 114 12386815
2001 Recent molecular advances in studies of the concentrative Na+-dependent nucleoside transporter (CNT) family: identification and characterization of novel human and mouse proteins (hCNT3 and mCNT3) broadly selective for purine and pyrimidine nucleosides (system cib). Molecular membrane biology 114 11396613
2001 lin-35 Rb and cki-1 Cip/Kip cooperate in developmental regulation of G1 progression in C. elegans. Development (Cambridge, England) 110 11684669
2018 The human CIB1-EVER1-EVER2 complex governs keratinocyte-intrinsic immunity to β-papillomaviruses. The Journal of experimental medicine 109 30068544
2000 Mechanism for inactivation of the KIP family cyclin-dependent kinase inhibitor genes in gastric cancer cells. Cancer research 105 10667572
1997 Induction of Cip/Kip and Ink4 cyclin dependent kinase inhibitors by interferon-alpha in hematopoietic cell lines. Oncogene 105 9053838
1999 RhoA stimulates p27(Kip) degradation through its regulation of cyclin E/CDK2 activity. The Journal of biological chemistry 104 9920882
2004 Structural and biochemical characterization of CIB1 delineates a new family of EF-hand-containing proteins. The Journal of biological chemistry 100 15574431
2004 The bzd gene cluster, coding for anaerobic benzoate catabolism, in Azoarcus sp. strain CIB. Journal of bacteriology 98 15317781
2013 Blue light-dependent interaction between cryptochrome2 and CIB1 regulates transcription and leaf senescence in soybean. The Plant cell 95 24272488
1998 Reduction in levels of the cyclin-dependent kinase inhibitor p27(kip-1) coupled with transforming growth factor beta neutralization induces cell-cycle entry and increases retroviral transduction of primitive human hematopoietic cells. Proceedings of the National Academy of Sciences of the United States of America 94 9789031
2014 Arabidopsis JAGGED links floral organ patterning to tissue growth by repressing Kip-related cell cycle inhibitors. Proceedings of the National Academy of Sciences of the United States of America 88 24497510
1999 Expression of p27(kip) and other cell cycle regulators in malignant peripheral nerve sheath tumors and neurofibromas: the emerging role of p27(kip) in malignant transformation of neurofibromas. The American journal of pathology 87 10595919
2005 Overexpression of p27 Kip 1, probability of cell cycle exit, and laminar destination of neocortical neurons. Cerebral cortex (New York, N.Y. : 1991) 83 15647527
2010 CIB1 is a regulator of pathological cardiac hypertrophy. Nature medicine 81 20639889
2004 Induction of Id1 and Id3 by latent membrane protein 1 of Epstein-Barr virus and regulation of p27/Kip and cyclin-dependent kinase 2 in rodent fibroblast transformation. Journal of virology 73 15564458
2013 Arabidopsis CRY2 and ZTL mediate blue-light regulation of the transcription factor CIB1 by distinct mechanisms. Proceedings of the National Academy of Sciences of the United States of America 72 24101505
2005 Essential role of CIB1 in regulating PAK1 activation and cell migration. The Journal of cell biology 71 16061695
2000 Growth inhibition in G(1) and altered expression of cyclin D1 and p27(kip-1 )after forced connexin expression in lung and liver carcinoma cells. Journal of cellular biochemistry 71 10972973
1999 Clinical relevance of expression of the CIP/KIP cell-cycle inhibitors p21 and p27 in laryngeal cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 71 10506612
2006 CIB1 is an endogenous inhibitor of agonist-induced integrin alphaIIbbeta3 activation. The Journal of cell biology 70 16418530
2003 The serum-inducible protein kinase Snk is a G1 phase polo-like kinase that is inhibited by the calcium- and integrin-binding protein CIB. Molecular cancer research : MCR 69 12651910
2006 Downregulation of the KIP family members p27(KIP1) and p57(KIP2) by SKP2 and the role of methylation in p57(KIP2) inactivation in nonsmall cell lung cancer. International journal of cancer 68 16988944
2009 Cip/Kip cyclin-dependent protein kinase inhibitors and the road to polyploidy. Cell division 67 19490616
1999 Calcium-dependent properties of CIB binding to the integrin alphaIIb cytoplasmic domain and translocation to the platelet cytoskeleton. The Biochemical journal 65 10477286
2006 CIB1 is essential for mouse spermatogenesis. Molecular and cellular biology 64 16982698
2003 The p27cip/kip ortholog dacapo maintains the Drosophila oocyte in prophase of meiosis I. Development (Cambridge, England) 64 12588841
2006 A cell-autonomous requirement for Cip/Kip cyclin-kinase inhibitors in regulating neuronal cell cycle exit but not differentiation in the developing spinal cord. Developmental biology 61 17123502
2003 Association of CIB with GPIIb/IIIa during outside-in signaling is required for platelet spreading on fibrinogen. Blood 60 12714504
1997 Interaction between DNA-dependent protein kinase and a novel protein, KIP. Mutation research 60 9372844
2005 BzdR, a repressor that controls the anaerobic catabolism of benzoate in Azoarcus sp. CIB, is the first member of a new subfamily of transcriptional regulators. The Journal of biological chemistry 59 15634675
2001 The small GTPase Rac3 interacts with the integrin-binding protein CIB and promotes integrin alpha(IIb)beta(3)-mediated adhesion and spreading. The Journal of biological chemistry 58 11756406
2016 CIB1: a small protein with big ambitions. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 57 27118676
2018 CIB1 and CO interact to mediate CRY2-dependent regulation of flowering. EMBO reports 55 30126927
2002 Molecular basis of CIB binding to the integrin alpha IIb cytoplasmic domain. The Journal of biological chemistry 55 12023286
2017 Cytosolic interaction of type III human CD38 with CIB1 modulates cellular cyclic ADP-ribose levels. Proceedings of the National Academy of Sciences of the United States of America 53 28720704
2003 Induction of G1 phase arrest in MCF human breast cancer cells by pentagalloylglucose through the down-regulation of CDK4 and CDK2 activities and up-regulation of the CDK inhibitors p27(Kip) and p21(Cip). Biochemical pharmacology 53 12781329
2006 CIB1, a ubiquitously expressed Ca2+-binding protein ligand of the InsP3 receptor Ca2+ release channel. The Journal of biological chemistry 51 16723353
2016 The Arabidopsis glutamate receptor-like gene GLR3.6 controls root development by repressing the Kip-related protein gene KRP4. Journal of experimental botany 50 26773810
2001 Hepatitis B virus X protein increases expression of p21(Cip-1/WAF1/MDA6) and p27(Kip-1) in primary mouse hepatocytes, leading to reduced cell cycle progression. Hepatology (Baltimore, Md.) 50 11679961
2009 CIB1 functions as a Ca(2+)-sensitive modulator of stress-induced signaling by targeting ASK1. Proceedings of the National Academy of Sciences of the United States of America 49 19805025
2002 Underexpression of p27/Kip in thyroid papillary microcarcinomas with gross metastatic disease. Archives of otolaryngology--head & neck surgery 48 11886339
2004 Analysis of the spatial expression pattern of seven Kip related proteins (KRPs) in the shoot apex of Arabidopsis thaliana. Annals of botany 45 15037450
2015 Whole-genome analysis of Azoarcus sp. strain CIB provides genetic insights to its different lifestyles and predicts novel metabolic features. Systematic and applied microbiology 44 26259823
2002 NBR1 interacts with fasciculation and elongation protein zeta-1 (FEZ1) and calcium and integrin binding protein (CIB) and shows developmentally restricted expression in the neural tube. European journal of biochemistry 43 11856312
2013 Multiple functions of Kip-related protein5 connect endoreduplication and cell elongation. Plant physiology 41 23426196
2004 DNA-protein kinase catalytic subunit-interacting protein KIP binds telomerase by interacting with human telomerase reverse transcriptase. The Journal of biological chemistry 41 15190070
1990 Early determination in the C. elegans embryo: a gene, cib-1, required to specify a set of stem-cell-like blastomeres. Development (Cambridge, England) 41 2351058
2005 Absence of p21(CIP 1), p27(KIP 1) and p 57(KIP 2) methylation in MDS and AML. Leukemia research 39 15936816
2012 CIB1 prevents nuclear GAPDH accumulation and non-apoptotic tumor cell death via AKT and ERK signaling. Oncogene 38 22964641
2002 Molecular staging of colorectal cancer in African-American and Caucasian patients using phenotypic expression of p53, Bcl-2, MUC-1 AND p27(kip-1). International journal of cancer 38 11802199
2002 Inverse relationship between p27/Kip.1 and the F-box protein Skp2 in human astrocytic gliomas by immunohistochemistry and Western blot. Neuroscience letters 38 12133571
2009 CIB1 deficiency results in impaired thrombosis: the potential role of CIB1 in outside-in signaling through integrin alpha IIb beta 3. Journal of thrombosis and haemostasis : JTH 35 19691476
2006 Connective tissue growth factor/CCN2 stimulates actin disassembly through Akt/protein kinase B-mediated phosphorylation and cytoplasmic translocation of p27(Kip-1). FASEB journal : official publication of the Federation of American Societies for Experimental Biology 35 16790529
2013 Ectopic expression of Kip-related proteins restrains root-knot nematode-feeding site expansion. The New phytologist 34 23574394
2005 The maize aberrant pollen transmission 1 gene is a SABRE/KIP homolog required for pollen tube growth. Genetics 34 16299389
2007 CIB1 regulates endothelial cells and ischemia-induced pathological and adaptive angiogenesis. Circulation research 33 17975111
2014 CIB1 synergizes with EphrinA2 to regulate Kaposi's sarcoma-associated herpesvirus macropinocytic entry in human microvascular dermal endothelial cells. PLoS pathogens 32 24550731
2015 Fenofibrate induces G0/G1 phase arrest by modulating the PPARα/FoxO1/p27 kip pathway in human glioblastoma cells. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 31 25566967
2019 Effect of 5-Aza-2'-Deoxycytidine in Comparison to Valproic Acid and Trichostatin A on Histone Deacetylase 1, DNA Methyltransferase 1, and CIP/KIP Family (p21, p27, and p57) Genes Expression, Cell Growth Inhibition, and Apoptosis Induction in Colon Cancer SW480 Cell Line. Advanced biomedical research 30 31516890
2014 Genetic characterization of the role of the Cip/Kip family of proteins as cyclin-dependent kinase inhibitors and assembly factors. Molecular and cellular biology 30 24515438
2011 FBF represses the Cip/Kip cell-cycle inhibitor CKI-2 to promote self-renewal of germline stem cells in C. elegans. The EMBO journal 30 21822213
2005 Epigenetic inactivation of the CIP/KIP cell-cycle control pathway in acute leukemias. American journal of hematology 29 16315255
2010 Cortactin modulates RhoA activation and expression of Cip/Kip cyclin-dependent kinase inhibitors to promote cell cycle progression in 11q13-amplified head and neck squamous cell carcinoma cells. Molecular and cellular biology 28 20805359
2016 CIB1 contributes to oncogenic signalling by Ras via modulating the subcellular localisation of sphingosine kinase 1. Oncogene 27 27941888
2015 CIB1 depletion impairs cell survival and tumor growth in triple-negative breast cancer. Breast cancer research and treatment 26 26105795
2013 Identification of novel integrin binding partners for calcium and integrin binding protein 1 (CIB1): structural and thermodynamic basis of CIB1 promiscuity. Biochemistry 26 24011356
2011 Calcium-dependent inhibition of polo-like kinase 3 activity by CIB1 in breast cancer cells. International journal of cancer 26 20473878
2010 Biochemical characterization of the transcriptional regulator BzdR from Azoarcus sp. CIB. The Journal of biological chemistry 26 20826820
2008 Characterization of calcium- and integrin-binding protein 1 (CIB1) knockout platelets: potential compensation by CIB family members. Thrombosis and haemostasis 26 18989529
2013 The role of p21Waf1/CIP1 as a Cip/Kip type cell-cycle regulator in oral squamous cell carcinoma (Review). Medicina oral, patologia oral y cirugia bucal 25 23385498
2007 CIB1 and CaBP1 bind to the myo1c regulatory domain. Journal of muscle research and cell motility 25 17994197
2006 Methylation of INK4 and CIP/KIP families of cyclin-dependent kinase inhibitor in chronic lymphocytic leukaemia in Chinese patients. Journal of clinical pathology 25 16565223
2012 Kip-related protein 3 is required for control of endoreduplication in the shoot apical meristem and leaves of Arabidopsis. Molecules and cells 24 23314608
2014 The activity and stability of the intrinsically disordered Cip/Kip protein family are regulated by non-receptor tyrosine kinases. Journal of molecular biology 22 25463440
2021 Discovery and Development of Cyclic Peptide Inhibitors of CIB1. ACS medicinal chemistry letters 21 34795874
2008 Sweet taste receptor interacting protein CIB1 is a general inhibitor of InsP3-dependent Ca2+ release in vivo. Journal of neurochemistry 21 18627437
2007 Expression of Bax, p53, and p27/kip in patients with papillary thyroid carcinoma with or without cervical nodal metastasis. American journal of otolaryngology 21 17162129
2018 Transcriptional Regulation of the Peripheral Pathway for the Anaerobic Catabolism of Toluene and m-Xylene in Azoarcus sp. CIB. Frontiers in microbiology 20 29623071
2018 Synthesis, Structure and Biological Activity of CIA and CIB, Two α-Conotoxins from the Predation-Evoked Venom of Conus catus. Toxins 20 29857567
2007 Identification and analysis of a glutaryl-CoA dehydrogenase-encoding gene and its cognate transcriptional regulator from Azoarcus sp. CIB. Environmental microbiology 20 18177371
2024 CIP/KIP and INK4 families as hostages of oncogenic signaling. Cell division 19 38561743
2020 Enhancing the Rice Seedlings Growth Promotion Abilities of Azoarcus sp. CIB by Heterologous Expression of ACC Deaminase to Improve Performance of Plants Exposed to Cadmium Stress. Microorganisms 19 32971998
2020 CHIP-mediated CIB1 ubiquitination regulated epithelial-mesenchymal transition and tumor metastasis in lung adenocarcinoma. Cell death and differentiation 19 33082516
2015 An essential role for Ink4 and Cip/Kip cell-cycle inhibitors in preventing replicative stress. Cell death and differentiation 19 26292757
2012 Development of mice without Cip/Kip CDK inhibitors. Biochemical and biophysical research communications 19 23000166
2011 Solution structures of Ca2+-CIB1 and Mg2+-CIB1 and their interactions with the platelet integrin alphaIIb cytoplasmic domain. The Journal of biological chemistry 19 21388953
2010 Tumor growth and angiogenesis is impaired in CIB1 knockout mice. Journal of angiogenesis research 19 20804551
2005 Increase in Ara-C cytotoxicity in the presence of valproate, a histone deacetylase inhibitor, is associated with the concurrent expression of cyclin D1 and p27(Kip 1) in acute myeloblastic leukemia cells. Leukemia research 19 15936818
2003 The crystal structure of CCG1/TAF(II)250-interacting factor B (CIB). The Journal of biological chemistry 19 14672934
2017 The Emerging Roles of CIB1 in Cancer. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 18 29017172