Affinage

BIK

Bcl-2-interacting killer · UniProt Q13323

Length
160 aa
Mass
18.0 kDa
Annotated
2026-04-28
100 papers in source corpus 32 papers cited in narrative 32 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

BIK is a BH3-only pro-apoptotic member of the BCL-2 family that functions as a sentinel at the endoplasmic reticulum to initiate the intrinsic mitochondrial apoptotic pathway. Anchored to the ER membrane via its C-terminal transmembrane domain with its bulk facing the cytosol, BIK uses its BH3 domain to bind and neutralize anti-apoptotic BCL-2, BCL-XL, and MCL-1, thereby liberating BAK and enabling BAX activation; it also disrupts BCL-2/IP3R complexes to trigger ER Ca²⁺ release, promotes DRP1-dependent mitochondrial cristae remodeling, and facilitates mitochondrial Ca²⁺ uptake at ER–mitochondria contact sites through a DAPk1-dependent mechanism (PMID:7478623, PMID:11884414, PMID:15791210, PMID:28986568, PMID:36603764). BIK is activated by casein kinase IIα phosphorylation at Thr33/Ser35 during S/G2/M phase, transcriptionally induced by p53, Smad, and Star-PAP/PKCδ signaling, sequestered by ER chaperone GRP78/BiP, and targeted for proteasomal degradation via ERK1/2-mediated Thr124 phosphorylation and the Cul5-ASB11 E3 ligase under the IRE1α-XBP1s adaptive UPR (PMID:11084041, PMID:34741311, PMID:22388352, PMID:31387940, PMID:17440086, PMID:19136942). Beyond apoptosis, BIK interacts with proteasome subunits RPN1/RPN2 via the BCL-2 BH4 domain to enhance nuclear proteasomal degradation of NF-κB p65, suppressing inflammation; accordingly, Bik-deficient female mice develop spontaneous emphysema with low-grade inflammation (PMID:38113109).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1995 High

    Identification of BIK as a BH3-domain-containing pro-apoptotic protein that physically engages anti-apoptotic BCL-2 family members established it as a death-promoting antagonist of survival proteins.

    Evidence Yeast two-hybrid, co-immunoprecipitation, and apoptosis assays in transfected cells

    PMID:7478623 PMID:8816500

    Open questions at the time
    • Mechanism of death induction beyond heterodimerization was unknown
    • Subcellular site of action unresolved
    • Endogenous regulation of BIK expression and turnover not addressed
  2. 1997 High

    Mapping the BH3 domain as necessary for BCL-2/BCL-XL binding but insufficient for apoptosis revealed that a C-terminal region (beyond residue 120) provides an additional required function, later shown to be the ER-targeting transmembrane anchor.

    Evidence Deletion mutagenesis with yeast two-hybrid and functional apoptosis assays

    PMID:9082997 PMID:9305912

    Open questions at the time
    • Nature of the C-terminal contribution (membrane anchor vs. protein interaction) was unresolved
    • Downstream effectors were not identified
  3. 2000 High

    Discovery that phosphorylation at Thr33/Ser35 by a casein kinase II-related enzyme activates BIK's pro-apoptotic function established the first post-translational activation mechanism for BIK.

    Evidence Phosphorylation mapping, site-directed mutagenesis, partial kinase purification from HeLa extracts

    PMID:11084041

    Open questions at the time
    • Identity of the kinase was only partial (CKII-related)
    • Cell-cycle context of phosphorylation was unknown
    • Relationship between phosphorylation and BCL-2 binding was unclear
  4. 2002 High

    Localization of BIK to the ER membrane—with retention of full apoptotic activity when ER-restricted—fundamentally redefined BIK as an ER-resident initiator of mitochondrial apoptosis, distinct from mitochondria-localized BH3-only proteins.

    Evidence Subcellular fractionation, chimeric ER-anchor constructs, in vitro reconstitution with ER and cytosol, p53-induction studies

    PMID:11884414 PMID:11971188

    Open questions at the time
    • Signal transmitted from ER to mitochondria was unidentified
    • Whether Ca²⁺ was involved was unknown
  5. 2003 High

    Demonstration that BIK-induced apoptosis is entirely BAX-dependent—even in BAK-expressing cells—positioned BIK as an indirect activator that de-represses effector proteins rather than directly permeabilizing membranes.

    Evidence Conditional adenoviral BIK expression in BAX-deficient cells with BAX re-expression rescue

    PMID:12853473

    Open questions at the time
    • How BIK signals to BAX from the ER was mechanistically undefined
    • Role of BAK at the ER was not yet explored
  6. 2005 High

    Multiple studies converged to show that ER-localized BIK triggers Ca²⁺ release from ER stores, recruits DRP1 for mitochondrial cristae remodeling, and cooperates with BAX/BAK for cytochrome c release—establishing the ER-to-mitochondria Ca²⁺ signaling axis as the core BIK mechanism; in parallel, Bik/Bim double-knockout mice revealed a physiological role in spermatogenesis upstream of Bax.

    Evidence Live imaging, DRP1 dominant-negative/siRNA, Ca²⁺ assays, BAX/BAK DKO cells, Bik/Bim DKO mice with histology

    PMID:15767553 PMID:15791210 PMID:15809295 PMID:16270031

    Open questions at the time
    • Identity of the ER Ca²⁺ channel involved was not determined
    • Precise mechanism of DRP1 recruitment was unclear
    • Whether BIK directly engages BAK at the ER was unknown
  7. 2007 High

    BIK was shown to displace BAK from MCL-1/BCL-XL sequestration, while GRP78/BiP was identified as an ER-resident inhibitor that sequesters BIK independently of the BH3 domain—revealing dual layers of BIK regulation at the ER.

    Evidence Co-immunoprecipitation of MCL-1/BAK complexes after BIK expression; GRP78 overexpression/siRNA with apoptosis readouts; BH3-mutant mapping

    PMID:17403773 PMID:17440086 PMID:18025305

    Open questions at the time
    • BIK's inability to displace MCL-1 from BAK (unlike PUMA) left the MCL-1 neutralization mechanism incomplete
    • GRP78 binding site on BIK was unmapped
  8. 2008 High

    BIK was found to interact with phospho-ERK1/2 via its BH3 domain and suppress ERK nuclear translocation, revealing a non-canonical signaling function; separately, RHBDD1 rhomboid protease was identified as cleaving BIK in its transmembrane domain to attenuate apoptosis.

    Evidence Co-IP with BH3 mutant control and bik−/− cells for ERK; RHBDD1 active-site mutagenesis with apoptosis assays

    PMID:18953687 PMID:18981230

    Open questions at the time
    • Physiological contexts for RHBDD1-mediated BIK cleavage were not defined
    • Whether ERK sequestration and apoptosis induction are separable functions was unclear
  9. 2009 High

    Identification of direct Smad-binding elements in the BIK promoter established TGF-β as a transcriptional inducer of BIK, adding to the p53/E2F axis and explaining BIK's role in TGF-β-induced B-cell apoptosis.

    Evidence ChIP showing Smad binding to BIK promoter, promoter-reporter assays, BIK shRNA rescue

    PMID:19136942

    Open questions at the time
    • Whether other Smad family members differentially regulate BIK was not tested
    • Integration of multiple transcriptional inputs was not modeled
  10. 2012 High

    Two degradation-regulation mechanisms were defined: ERK1/2-mediated Thr124 phosphorylation drives Lys33 ubiquitylation and proteasomal degradation of BIK (explaining Src/Ras oncogene resistance), while Star-PAP/PKCδ/PI4,5P2 nuclear signaling controls BIK mRNA 3′ end processing after DNA damage.

    Evidence Phosphosite mutagenesis with ubiquitylation assays in v-Src-transformed cells; siRNA/co-IP of Star-PAP complex with mRNA processing assays

    PMID:22244330 PMID:22388352

    Open questions at the time
    • The E3 ligase mediating Thr124-dependent ubiquitylation was not identified in this study
    • Whether Star-PAP regulation extends to other BH3-only genes was unknown
  11. 2017 High

    BIK was shown to form a complex with DAPk1, ERK1/2, and BAK at the ER, disrupt BCL-2/IP3R interactions to release ER Ca²⁺, and increase ER–mitochondria contact sites for mitochondrial Ca²⁺ uptake—providing a complete mechanistic pathway from ER perturbation to mitochondrial engagement.

    Evidence Co-IP, IP3R interaction assays, ER–mitochondria contact imaging, BH3 peptide experiments, Ca²⁺ flux measurements, in vivo allergen/smoke models

    PMID:28986568

    Open questions at the time
    • Structural basis of BIK–DAPk1 interaction was not resolved
    • Stoichiometry and dynamics of the quaternary complex were undefined
  12. 2019 High

    Identification of Cul5-ASB11 as the E3 ligase targeting BIK, activated by the IRE1α-XBP1s adaptive UPR and involving p97/VCP extraction, explained how ER stress initially suppresses BIK to allow adaptation, while genotoxic stress downregulates this axis to stabilize BIK.

    Evidence Co-IP, ubiquitination assays, IRE1α inhibitor, XBP1s and ASB11 knockdown, p97/VCP interaction assays

    PMID:31387940

    Open questions at the time
    • Whether Cul5-ASB11 also mediates the ERK-Thr124-dependent degradation was not tested
    • Recognition determinants on BIK for ASB11 binding were unmapped
  13. 2021 High

    CKIIα was confirmed as the activating kinase for BIK, and its expression restricted to G2/M phase explained why BIK kills specifically dividing (S/G2/M) cells—linking BIK activation to cell-cycle progression.

    Evidence FUCCI cell-cycle tracking, co-IP/proteomics identifying CKIIα, phosphomutant BIK in transgenic mouse airway epithelial cells

    PMID:34741311

    Open questions at the time
    • Whether CKIIα phosphorylation creates a binding interface for downstream effectors was unknown
    • Cell-type generality beyond airway epithelia was not established
  14. 2023 High

    Three major advances: FLIM-FRET confirmed direct BIK interaction with mitochondria-localized BCL-XL/BCL-2 at MAMs; TMEM215-BiP was identified as a ternary complex restraining BIK; and BIK's interaction with RPN1/RPN2 proteasome subunits via BCL-2 BH4 domain was shown to promote nuclear proteasomal degradation of NF-κB p65, revealing a non-apoptotic anti-inflammatory function (Bik−/− female mice develop spontaneous emphysema).

    Evidence FLIM-FRET with chimeric constructs; IP-MS for TMEM215-BiP-BIK; co-IP/proteasome assays and bik−/− mice with lung pathology

    PMID:36603764 PMID:37750320 PMID:38113109

    Open questions at the time
    • Structural basis for BIK–RPN1/RPN2 interaction is unresolved
    • Sex-specific mechanism of emphysema in Bik−/− mice is unexplained
    • Whether BIK's proteasomal function operates in tissues beyond lung is unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include the structural basis of BIK's multivalent interactions at ER–mitochondria contact sites, how its apoptotic and non-apoptotic (proteasomal/anti-inflammatory) functions are partitioned in different cell types, and whether BIK loss contributes to human disease.
  • No high-resolution structure of BIK in complex with any partner
  • Human genetic disease associations via causative mutations are absent
  • Relative contributions of CKIIα activation vs. Cul5-ASB11 degradation in setting BIK protein levels in vivo are unquantified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 7
Localization
GO:0005783 endoplasmic reticulum 6 GO:0005739 mitochondrion 1
Pathway
R-HSA-5357801 Programmed Cell Death 10 R-HSA-162582 Signal Transduction 3 R-HSA-8953897 Cellular responses to stimuli 2
Partners
ASB11BAK1BCL2BCL2L1DAPK1HSPA5MCL1PSMD1

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 BIK (Bcl-2-interacting killer) was identified as a novel pro-apoptotic protein containing a BH3 domain that physically interacts with anti-apoptotic proteins BCL-2, BCL-XL, EBV-BHRF1, and adenovirus E1B-19 kDa; its death-promoting activity can be suppressed by co-expression of these anti-apoptotic proteins. Yeast two-hybrid, co-immunoprecipitation, transient transfection apoptosis assays Oncogene High 7478623
1996 BIK (Nbk) was cloned via yeast two-hybrid screen for E1B 19K interactors; it contains BH3 but not BH1/BH2, interacts with BCL-2 and E1B 19K in vitro and in vivo, co-localizes with cytoplasmic and nuclear membranes, antagonizes E1B 19K-mediated inhibition of apoptosis, and induces apoptosis independently of BAX. Yeast two-hybrid, in vitro binding assay, immunoprecipitation, co-localization, transient transfection apoptosis assays Molecular and cellular biology High 8816500
1997 The BH3 domain of BIK (residues 57–74) is the core heterodimerization domain required for interaction with BCL-2 and BCL-XL, but heterodimerization alone is insufficient for cell death; C-terminal sequences beyond residue 120 are additionally required for efficient apoptotic activity. Deletion mutagenesis, yeast two-hybrid, immunoprecipitation, functional apoptosis assays The Journal of biological chemistry High 9305912
1997 BIK and BAK induce apoptosis downstream of the CrmA block but upstream of the IAP (inhibitor of apoptosis) block, placing BIK in a defined position within the caspase activation cascade. Genetic epistasis using CrmA and IAP expression constructs with apoptosis assays The Journal of biological chemistry Medium 9082997
2000 BIK is phosphorylated at Thr33 and Ser35; mutation of these residues to alanine reduces apoptotic activity without significantly affecting heterodimerization with BCL-2; partial purification suggests BIK is phosphorylated by a casein kinase II-related enzyme. Phosphorylation mapping, site-directed mutagenesis, partial kinase purification from HeLa cell extracts, functional apoptosis assays The Journal of biological chemistry High 11084041
2002 BIK is localized to the endoplasmic reticulum membrane (with bulk of the protein facing the cytosol) and stimulates cytochrome c release from mitochondria and caspase activation from this ER location; restricting BIK to the ER via the cytochrome b5 transmembrane anchor retains its cell death activity; this pathway was reconstituted in vitro requiring ER and cytosol components. Subcellular fractionation, chimeric membrane anchor constructs, in vitro reconstitution, caspase inhibitor treatment, functional apoptosis assays The Journal of biological chemistry High 11884414
2002 BIK/NBK is induced at the mRNA level by oncogenic E1A in a wild-type p53-dependent manner, and by p53 independently; BIK function requires an intact BH3 domain (point mutation abrogates activity); a significant fraction of endogenous BIK associates with the endoplasmic reticulum. DNA microarray, RT-PCR, Western blot, subcellular fractionation, BH3 domain point mutagenesis, apoptosis assays Oncogene High 11971188
2003 BIK (Nbk) induces apoptosis through an entirely BAX-dependent mechanism; BAX-deficient cells are resistant to BIK-induced apoptosis even when BAK is expressed; re-expression of BAX restores sensitivity; BIK interacts with BCL-XL and BCL-2 but not BAX; BIK does not localize to mitochondria, suggesting it acts as an indirect activator of BAX. Conditional adenoviral expression system (Tet-off), BAX-deficient cell lines, BAX re-expression, immunoprecipitation, subcellular localization The EMBO journal High 12853473
2005 ER-localized BIK activates a pathway involving calcium (Ca2+) release from ER stores upstream of BAX/BAK activation; this triggers DRP1 recruitment, mitochondrial fragmentation, and DRP1-dependent remodelling and opening of cristae; BIK can cooperate with NOXA to activate BAX and cause rapid cytochrome c release independently of DRP1 enzymatic activity. Live cell imaging, DRP1 dominant-negative and siRNA, selective membrane permeabilization with digitonin, cytochrome c release assays, BIK ER-restricted constructs The EMBO journal High 15791210
2005 BIK initiates BAX/BAK-dependent Ca2+ release from ER stores upstream of effector caspases; BIK knockdown blocks ER Ca2+ release and mitochondrial apoptosis in human epithelial cells; DRP1 is required for p53-induced mitochondrial fission and cytochrome c release downstream of BIK; p53 overexpression stimulates BAK recruitment to the ER, which is inhibited by BIK siRNA. siRNA knockdown, Ca2+ release assays, BAX/BAK double-knockout BMK cells, cytochrome c release assays, immunoprecipitation The Journal of biological chemistry High 15809295
2005 BIK protein is stabilized from proteasomal degradation by bortezomib, leading to its accumulation; BIK (together with BIM) is required for bortezomib-induced apoptosis, as double knockout of Bik and Bim in MEFs renders cells resistant; BIK acts through the mitochondrial pathway (APAF-1 dependent). Proteasome inhibitor treatment, MEF double-knockout cells, RNA interference, APAF-1-deficient cells, apoptosis assays Molecular cancer therapeutics High 15767553
2007 BIK (NBK) activates BAK-mediated apoptosis in response to protein synthesis inhibition by displacing BAK from sequestration by anti-apoptotic MCL-1 and BCL-XL; BIK- or BAK-deficient cells are resistant to translation inhibition-induced apoptosis. MazF toxin-induced translation inhibition, BIK/BAK-deficient cells, immunoprecipitation to assess MCL-1/BAK and BCL-XL/BAK complexes, genetic rescue experiments Genes & development High 17403773
2007 GRP78/BiP physically interacts with BIK at the ER; GRP78 overexpression inhibits estrogen starvation-induced BAX activation and apoptosis; GRP78 knockdown sensitizes cells to estrogen starvation-induced apoptosis in a BIK-dependent manner. Co-immunoprecipitation, GRP78 overexpression and siRNA knockdown, BAX activation assays, apoptosis assays Cancer research High 17440086
2007 MCL-1 binding to BAK persists after BIK expression and prevents BIK-induced apoptosis in BAX-deficient cells; PUMA (but not BIK) can disrupt MCL-1-BAK interaction; targeted knockdown of MCL-1 allows BAK activation by BIK, demonstrating that BIK's BAX-dependency is due to MCL-1 inhibiting BAK. Immunoprecipitation, MCL-1 siRNA knockdown, BAX-deficient cell lines, apoptosis assays The Journal of cell biology High 18025305
2008 RHBDD1, a rhomboid serine protease, cleaves BIK at a site in its transmembrane region; residues Gly142 and Ser144 of RHBDD1 are critical for this cleavage; RHBDD1 overexpression reduces BIK-mediated apoptosis while knockdown enhances it. Mutagenesis of RHBDD1 active site, overexpression/knockdown experiments, apoptosis assays Cellular and molecular life sciences Medium 18953687
2008 BIK interacts with phospho-ERK1/2 and suppresses nuclear translocation of activated ERK1/2; this is dependent on a functional BH3 domain (BikL61G mutant does not interact or suppress nuclear pERK1/2); BIK-mediated suppression of nuclear pERK1/2 is required for IFNγ-induced cell death in airway epithelial cells. Co-immunoprecipitation, BH3 domain point mutant (L61G), nuclear/cytosolic fractionation, bik-/- mouse AECs, phospho-ERK inhibition, apoptosis assays The Journal of cell biology High 18981230
2009 TGF-β directly induces BIK transcription via Smad transcription factor complexes binding to a consensus Smad-binding element in the BIK promoter; TGF-β also represses BCL-XL; both effects cooperate to activate the intrinsic apoptotic pathway in B cells. Chromatin immunoprecipitation (ChIP), promoter-reporter assays, Smad-binding element identification, shRNA knockdown of BIK, BCL-XL overexpression Cell death and differentiation High 19136942
2011 GRP78 interacts with BIK independently of the BH3 domain (unlike all other BIK protein interactions); GRP78 and BCL-2 form independent complexes with BIK; increased GRP78 expression decreases BIK binding to BCL-2, releasing BCL-2 from sequestration to suppress apoptosis. Co-immunoprecipitation, BH3 domain mutants, GRP78 overexpression, isolated clonal cell lines, apoptosis assays The Journal of biological chemistry High 21622563
2012 BIK mRNA 3' end processing and expression are controlled by the poly(A) polymerase Star-PAP downstream of DNA damage; nuclear PKCδ associates with the Star-PAP complex and is required for Star-PAP-dependent BIK expression; PIPKIα binds PKCδ and is essential for PKCδ interaction with Star-PAP, with PKCδ activity stimulated by PI4,5P2. siRNA knockdown, co-immunoprecipitation, mRNA 3' end processing assays, kinase activity assays, BIK mRNA 3' UTR analysis Molecular cell High 22244330
2012 Src kinase-dependent resistance to apoptosis operates via Ras-Raf-Mek1/2-Erk1/2 pathway phosphorylation of BIK on Thr124, which drives BIK ubiquitylation on Lys33 and subsequent proteasomal degradation. v-Src transformed fibroblasts, Erk1/2 pathway inhibitors, phosphorylation site mutagenesis (Thr124), ubiquitylation assays, proteasome inhibition, apoptosis assays Cell death and differentiation High 22388352
2014 SQSTM1/p62 knockdown causes cargo loading failure in autophagy, leading to accumulation of NBK/Bik on ER membranes (by blocking autophagic loading and degradation of NBK/Bik), which triggers apoptosis; NBK/Bik knockdown markedly attenuates this apoptosis in vitro and in vivo. shRNA targeting SQSTM1/p62 and NBK/Bik, autophagy flux assays, ER membrane fractionation, xenograft tumor model, apoptosis assays Molecular and cellular biology Medium 25002530
2017 BIK dissociates the BAK/BCL-2 complex to enrich ER-associated BAK; BIK interacts with the kinase domain of DAPk1 to form a BIK-DAPk1-ERK1/2-BAK complex; BIK disrupts BCL-2/IP3R interaction to cause ER Ca2+ release; ER-associated BAK interacts with DAPk1 to increase ER-mitochondria contact sites facilitating mitochondrial Ca2+ uptake; the BIK BH3 helix is sufficient for ER-BAK enrichment and ER Ca2+ release but not for mitochondrial Ca2+ uptake (requires Bak). Co-immunoprecipitation, BAK knockdown, IP3R interaction assays, ER-mitochondria contact site imaging, BIK BH3 peptide experiments, Ca2+ flux assays, allergen/cigarette smoke mouse models Nature communications High 28986568
2017 p53-mediated suppression of BiP expression during prolonged ER stress releases pro-apoptotic BIK from BiP, activating apoptosis; p53 suppresses bip mRNA translation by binding to the first 346-nt of bip mRNA via a p53 trans-suppression domain in the first 7 N-terminal amino acids of p53ΔN40. RNA-protein binding assays, siRNA knockdown of BiP and BIK, co-immunoprecipitation, p53 isoform expression, ER stress induction, apoptosis assays Cell death and differentiation High 28622297
2019 The E3 ubiquitin ligase Cul5-ASB11 targets BIK for ubiquitination and degradation; ER stress activates ASB11 via the IRE1α-XBP1s axis during the adaptive UPR, stimulating BIK ubiquitination, interaction with p97/VCP, and proteolysis; genotoxic stress down-regulates this axis, stabilizing BIK to promote apoptosis. Co-immunoprecipitation, ubiquitination assays, IRE1α inhibitor, XBP1s overexpression/knockdown, ASB11 knockdown, p97/VCP interaction assays, apoptosis assays The Journal of cell biology High 31387940
2021 Casein kinase IIα (CKIIα) phosphorylates and activates BIK to kill cells specifically in S/G2/M phase of the cell cycle; CKIIα is expressed only during G2/M phase; BIK phosphorylation at Thr33/Ser35 is required for activity even in quiescent cells; BIK localizes to and is only detected in green-fluorescent (S/G2/M) cells as shown by fluorescent cell cycle indicators. Fluorescent ubiquitin cell cycle indicators (FUCCI), co-immunoprecipitation, proteomics, BIK phosphorylation mutants, transgenic mouse airway epithelial cells, allergen exposure model Journal of cellular physiology High 34741311
2023 BIK is detected at both ER and mitochondria-associated ER membranes (MAMs); BIK binds directly to mitochondria-localized BCL-XL and BCL-2 in a BH3-domain-dependent manner as shown by FLIM-FRET microscopy; BIK or its binding partners relocalize at ER-mitochondria contact sites to initiate mitochondrial outer membrane permeabilization. FLIM-FRET microscopy, chimeric mitochondria-localized BCL-XL/BCL-2 mutants, BAX/BAK double-knockout BMK cells, BH3-domain mutants, co-localization in MCF-7 and BMK cells The Journal of biological chemistry High 36603764
2023 BIK interacts with the BH4 domain of BCL-2 and with proteasome subunits RPN1 and RPN2 to enhance proteasomal degradation of nuclear proteins, suppressing NF-κB nuclear p65; BIK deficiency increases nuclear p65 and causes low-grade inflammation and spontaneous emphysema in female mice. Co-immunoprecipitation, proteasomal degradation assays, transgenic BIK airway expression, bik-/- mice, nuclear fractionation, NF-κB p65 quantification The Journal of clinical investigation High 38113109
2023 TMEM215 forms a complex with BiP and facilitates BiP interaction with BIK; TMEM215 knockdown triggers BIK-dependent apoptosis associated with increased mitochondria-associated ER membrane contacts and mitochondrial calcium influx; blocking IP3R or MCU abrogates TMEM215 knockdown-induced apoptosis. Co-immunoprecipitation-mass spectrometry, BIK siRNA rescue, IP3R/MCU inhibitors, mitochondria-associated ER membrane imaging, EC-specific conditional knockout mice, tumor models Circulation research High 37750320
2016 BIK promotes caspase-dependent cleavage of influenza A virus nucleoprotein and M2 proteins, facilitating cytoplasmic export of viral ribonucleoprotein; bik-/- mouse airway epithelial cells show reduced viral titers, caspase 3 activation, and viral RNA export compared to wild-type cells. bik-/- mouse airway epithelial cells, caspase inhibition, viral protein cleavage assays, viral RNP export assays, in vivo infection model American journal of respiratory cell and molecular biology High 26437021
2014 HCV NS5B RNA-dependent RNA polymerase induces BIK expression; BIK co-localizes and co-immunoprecipitates with NS5B, suggesting BIK interacts with the HCV replication complex; BIK depletion significantly suppresses viral RNA replication and release. PCR array, co-immunoprecipitation, immunofluorescence co-localization, BIK siRNA knockdown, viral replication assays Virology Medium 25463603
2017 TMEM74, a lysosome transmembrane protein, co-localizes with BIK in subcellular organelles and associates with BIK via the TM domains of TMEM74 and the BH3 domain of BIK; TMEM74 inhibits BIK-induced apoptosis through this direct interaction. Co-immunoprecipitation, fluorescent co-localization, domain mapping with TM-deficient mutants, BIK apoptosis assays with TMEM74 knockdown/overexpression Cellular signalling Medium 28412412
2005 Concomitant loss of both Bik and Bim (but not either alone) arrests spermatogenesis in mice, resulting in infertility and testicular cellularity reduction similar to Bax deficiency; Bik and Bim act upstream of Bax to eliminate supernumerary germ cells during the first wave of spermatogenesis. Bik/Bim double-knockout mice, histological and cell count analyses, genetic epistasis with Bax-deficient mice The EMBO journal High 16270031

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1995 Bik, a novel death-inducing protein shares a distinct sequence motif with Bcl-2 family proteins and interacts with viral and cellular survival-promoting proteins. Oncogene 408 7478623
2005 Endoplasmic reticulum BIK initiates DRP1-regulated remodelling of mitochondrial cristae during apoptosis. The EMBO journal 284 15791210
2007 GRP78/BiP inhibits endoplasmic reticulum BIK and protects human breast cancer cells against estrogen starvation-induced apoptosis. Cancer research 264 17440086
1996 Induction of apoptosis by human Nbk/Bik, a BH3-containing protein that interacts with E1B 19K. Molecular and cellular biology 168 8816500
2005 The proteasome inhibitor bortezomib sensitizes cells to killing by death receptor ligand TRAIL via BH3-only proteins Bik and Bim. Molecular cancer therapeutics 150 15767553
2005 BH3-only BIK regulates BAX,BAK-dependent release of Ca2+ from endoplasmic reticulum stores and mitochondrial apoptosis during stress-induced cell death. The Journal of biological chemistry 149 15809295
2016 LncRNA H19 confers chemoresistance in ERα-positive breast cancer through epigenetic silencing of the pro-apoptotic gene BIK. Oncotarget 124 27845892
2002 BH-3-only BIK functions at the endoplasmic reticulum to stimulate cytochrome c release from mitochondria. The Journal of biological chemistry 123 11884414
2011 Novel mechanism of anti-apoptotic function of 78-kDa glucose-regulated protein (GRP78): endocrine resistance factor in breast cancer, through release of B-cell lymphoma 2 (BCL-2) from BCL-2-interacting killer (BIK). The Journal of biological chemistry 112 21622563
2007 NBK/BIK antagonizes MCL-1 and BCL-XL and activates BAK-mediated apoptosis in response to protein synthesis inhibition. Genes & development 112 17403773
2005 Bik/NBK accumulation correlates with apoptosis-induction by bortezomib (PS-341, Velcade) and other proteasome inhibitors. Oncogene 109 15824729
2003 Induction of cell death by the BH3-only Bcl-2 homolog Nbk/Bik is mediated by an entirely Bax-dependent mitochondrial pathway. The EMBO journal 107 12853473
2002 Induction and endoplasmic reticulum location of BIK/NBK in response to apoptotic signaling by E1A and p53. Oncogene 107 11971188
2008 BIK, the founding member of the BH3-only family proteins: mechanisms of cell death and role in cancer and pathogenic processes. Oncogene 103 19641504
2004 Proapoptotic BH3-only Bcl-2 family member Bik/Blk/Nbk is expressed in hemopoietic and endothelial cells but is redundant for their programmed death. Molecular and cellular biology 99 14749373
2006 Loss of the tissue-specific proapoptotic BH3-only protein Nbk/Bik is a unifying feature of renal cell carcinoma. Cell death and differentiation 85 16322756
2005 Concomitant loss of proapoptotic BH3-only Bcl-2 antagonists Bik and Bim arrests spermatogenesis. The EMBO journal 85 16270031
2009 TGF-beta induces apoptosis in human B cells by transcriptional regulation of BIK and BCL-XL. Cell death and differentiation 77 19136942
2000 Phosphorylation of the pro-apoptotic protein BIK: mapping of phosphorylation sites and effect on apoptosis. The Journal of biological chemistry 74 11084041
2004 The Bik BH3-only protein is induced in estrogen-starved and antiestrogen-exposed breast cancer cells and provokes apoptosis. Proceedings of the National Academy of Sciences of the United States of America 72 14983013
2012 Star-PAP control of BIK expression and apoptosis is regulated by nuclear PIPKIα and PKCδ signaling. Molecular cell 68 22244330
2014 Targeting SQSTM1/p62 induces cargo loading failure and converts autophagy to apoptosis via NBK/Bik. Molecular and cellular biology 67 25002530
2002 Systemic tumor suppression by the proapoptotic gene bik. Cancer research 65 11782349
2008 Bortezomib induces apoptosis via Bim and Bik up-regulation and synergizes with cisplatin in the killing of head and neck squamous cell carcinoma cells. Molecular cancer therapeutics 62 18566236
2007 BH3-only protein BIK induces caspase-independent cell death with autophagic features in Bcl-2 null cells. Oncogene 57 17873911
1997 Functional dissection of the pro-apoptotic protein Bik. Heterodimerization with anti-apoptosis proteins is insufficient for induction of cell death. The Journal of biological chemistry 54 9305912
2005 Proteasome inhibitors-mediated TRAIL resensitization and Bik accumulation. Cancer biology & therapy 53 16082182
1997 Bik and Bak induce apoptosis downstream of CrmA but upstream of inhibitor of apoptosis. The Journal of biological chemistry 51 9082997
2002 The apoptosis promoting Bcl-2 homologues Bak and Nbk/Bik overcome drug resistance in Mdr-1-negative and Mdr-1-overexpressing breast cancer cell lines. Oncogene 50 11803466
2012 Src tyrosine kinase inhibits apoptosis through the Erk1/2- dependent degradation of the death accelerator Bik. Cell death and differentiation 49 22388352
2008 A novel member of the Rhomboid family, RHBDD1, regulates BIK-mediated apoptosis. Cellular and molecular life sciences : CMLS 49 18953687
2018 KLF4, a miR-32-5p targeted gene, promotes cisplatin-induced apoptosis by upregulating BIK expression in prostate cancer. Cell communication and signaling : CCS 48 30176890
2017 p53-mediated suppression of BiP triggers BIK-induced apoptosis during prolonged endoplasmic reticulum stress. Cell death and differentiation 48 28622297
2006 Regulation of expression of BIK proapoptotic protein in human breast cancer cells: p53-dependent induction of BIK mRNA by fulvestrant and proteasomal degradation of BIK protein. Cancer research 48 17047080
2008 The BH3-only protein Bik/Blk/Nbk inhibits nuclear translocation of activated ERK1/2 to mediate IFNgamma-induced cell death. The Journal of cell biology 46 18981230
2003 Enhancement of Bik antitumor effect by Bik mutants. Cancer research 45 14633680
2011 Cigarette smoke suppresses Bik to cause epithelial cell hyperplasia and mucous cell metaplasia. American journal of respiratory and critical care medicine 44 21317312
2003 Mutations of the BIK gene in human peripheral B-cell lymphomas. Genes, chromosomes & cancer 44 12874789
2007 Mcl-1 determines the Bax dependency of Nbk/Bik-induced apoptosis. The Journal of cell biology 43 18025305
1999 Expression of the death gene Bik/Nbk promotes sensitivity to drug-induced apoptosis in corticosteroid-resistant T-cell lymphoma and prevents tumor growth in severe combined immunodeficient mice. Blood 43 10419903
2001 Involvement of Bik, a proapoptotic member of the Bcl-2 family, in surface IgM-mediated B cell apoptosis. Journal of immunology (Baltimore, Md. : 1950) 41 11342619
2009 PAR bZIP-bik is a novel transcriptional pathway that mediates oxidative stress-induced apoptosis in fibroblasts. Cell death and differentiation 37 19219069
2005 Caspase-independent induction of apoptosis in human melanoma cells by the proapoptotic Bcl-2-related protein Nbk / Bik. Oncogene 34 16007125
2001 The pro-apoptotic protein, Bik, exhibits potent antitumor activity that is dependent on its BH3 domain. Molecular cancer therapeutics 33 12467227
2019 HDAC4 Levels Control Sensibility toward Cisplatin in Gastric Cancer via the p53-p73/BIK Pathway. Cancers 32 31703394
2006 Transcriptional activation of the proapoptotic bik gene by E2F proteins in cancer cells. FEBS letters 32 17027756
2017 Plumbagin sensitizes breast cancer cells to tamoxifen-induced cell death through GRP78 inhibition and Bik upregulation. Scientific reports 29 28287102
2016 Osteopontin-stimulated apoptosis in cardiac myocytes involves oxidative stress and mitochondrial death pathway: role of a pro-apoptotic protein BIK. Molecular and cellular biochemistry 28 27262843
2010 BH3-only protein Bik is involved in both apoptosis induction and sensitivity to oxidative stress in multiple myeloma. British journal of cancer 26 21063407
2000 GnRH-Bik/Bax/Bak chimeric proteins target and kill adenocarcinoma cells; the general use of pro-apoptotic proteins of the Bcl-2 family as novel killing components of targeting chimeric proteins. Apoptosis : an international journal on programmed cell death 26 11303912
2019 Upregulation of miR-1306-5p decreases cerebral ischemia/reperfusion injury in vitro by targeting BIK. Bioscience, biotechnology, and biochemistry 25 31460837
2017 Bik reduces hyperplastic cells by increasing Bak and activating DAPk1 to juxtapose ER and mitochondria. Nature communications 25 28986568
2023 TMEM215 Prevents Endothelial Cell Apoptosis in Vessel Regression by Blunting BIK-Regulated ER-to-Mitochondrial Ca Influx. Circulation research 24 37750320
2014 Reversal of Mutant KRAS-Mediated Apoptosis Resistance by Concurrent Noxa/Bik Induction and Bcl-2/Bcl-xL Antagonism in Colon Cancer Cells. Molecular cancer research : MCR 24 25548100
2000 Structural analysis of the human pro-apoptotic gene Bik: chromosomal localization, genomic organization and localization of promoter sequences. Gene 23 10974546
2019 BIK ubiquitination by the E3 ligase Cul5-ASB11 determines cell fate during cellular stress. The Journal of cell biology 21 31387940
2017 Biphasic ROS production, p53 and BIK dictate the mode of cell death in response to DNA damage in colon cancer cells. PloS one 20 28796811
2014 Repression of the proapoptotic cellular BIK/NBK gene by Epstein-Barr virus antagonizes transforming growth factor β1-induced B-cell apoptosis. Journal of virology 19 24554662
2005 Suppression of pancreatic tumor progression by systemic delivery of a pancreatic-cancer-specific promoter driven Bik mutant. Cancer letters 19 15953675
2015 Induction of BCL2-Interacting Killer, BIK, is Mediated for Anti-Cancer Activity of Curcumin in Human Head and Neck Squamous Cell Carcinoma Cells. Journal of Cancer 17 25767602
2012 The proteasome inhibitor MG132 potentiates TRAIL receptor agonist-induced apoptosis by stabilizing tBid and Bik in human head and neck squamous cell carcinoma cells. Experimental cell research 16 22513214
2018 MicroRNA 486-3p directly targets BIK and regulates apoptosis and invasion in colorectal cancer cells. OncoTargets and therapy 15 30584337
2017 Autophagy regulatory molecule, TMEM74, interacts with BIK and inhibits BIK-induced apoptosis. Cellular signalling 15 28412412
2013 BH3-only proteins Noxa, Bik, Bmf, and Bid activate Bax and Bak indirectly when studied in yeast model. FEMS yeast research 15 23991648
2017 BIK is involved in BRAF/MEK inhibitor induced apoptosis in melanoma cell lines. Cancer letters 14 28720543
2017 Activation of Casein Kinase II by Gallic Acid Induces BIK-BAX/BAK-Mediated ER Ca++-ROS-Dependent Apoptosis of Human Oral Cancer Cells. Frontiers in physiology 14 29033852
2013 Suppression of the death gene BIK is a critical factor for resistance to tamoxifen in MCF-7 breast cancer cells. International journal of oncology 14 24100375
2017 Blocking Bcl-2 resolves IL-13-mediated mucous cell hyperplasia in a Bik-dependent manner. The Journal of allergy and clinical immunology 13 28784260
2006 5-Aza-2'-deoxycytidine and depsipeptide synergistically induce expression of BIK (BCL2-interacting killer). Biochemical and biophysical research communications 13 17064661
2021 Long non-coding RNA TUG1 knockdown prevents neurons from death to alleviate acute spinal cord injury via the microRNA-338/BIK axis. Bioengineered 11 34517787
2016 Bik Mediates Caspase-Dependent Cleavage of Viral Proteins to Promote Influenza A Virus Infection. American journal of respiratory cell and molecular biology 11 26437021
2008 The endoplasmic reticulum (ER)-target protein Bik induces Hep3B cells apoptosis by the depletion of the ER Ca2+ stores. Molecular and cellular biochemistry 11 18299962
2006 Mutant Bik expression mediated by the enhanced minimal topoisomerase IIalpha promoter selectively suppressed breast tumors in an animal model. Cancer gene therapy 11 16514421
2015 Bik subcellular localization in response to oxidative stress induced by chemotherapy, in Two different breast cancer cell lines and a Non-tumorigenic epithelial cell line. Journal of applied toxicology : JAT 10 26059411
2012 Neither loss of Bik alone, nor combined loss of Bik and Noxa, accelerate murine lymphoma development or render lymphoma cells resistant to DNA damaging drugs. Cell death & disease 10 22573037
2023 Bik promotes proteasomal degradation to control low-grade inflammation. The Journal of clinical investigation 9 38113109
2018 Biodistribution and Internal Radiation Dosimetry of 99mTc-IDA-D-[c(RGDfK)]2 (BIK-505), a Novel SPECT Radiotracer for the Imaging of Integrin αvβ3 Expression. Cancer biotherapy & radiopharmaceuticals 9 30133309
2007 Apoptosis induced by BIK was decreased with RNA interference of caspase-12. Biochemical and biophysical research communications 9 17574210
2007 Mutant Bik gene transferred by cationic liposome inhibits peritoneal disseminated murine colon cancer. Clinical & experimental metastasis 9 17636408
2023 Endoplasmic reticulum protein BIK binds to and inhibits mitochondria-localized antiapoptotic proteins. The Journal of biological chemistry 8 36603764
2014 Combination of lenalidomide with vitamin D3 induces apoptosis in mantle cell lymphoma via demethylation of BIK. Cell death & disease 8 25165875
2015 Breast cancer cell line MDA-MB-231 miRNA profile expression after BIK interference: BIK involvement in autophagy. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 7 26662110
2014 NS5B induces up-regulation of the BH3-only protein, BIK, essential for the hepatitis C virus RNA replication and viral release. Virology 7 25463603
2012 BIK (NBK) is a mediator of the sensitivity of Fanconi anaemia group C lymphoblastoid cell lines to interstrand DNA cross-linking agents. The Biochemical journal 7 22873408
2014 BikDDA, a mutant of Bik with longer half-life expression protein, can be a novel therapeutic gene for triple-negative breast cancer. PloS one 6 24637719
2009 BAK, BAX, and NBK/BIK proapoptotic gene alterations in Iranian patients with ataxia telangiectasia. Journal of clinical immunology 6 19898928
2024 MyoD1 promotes the transcription of BIK and plays an apoptosis-promoting role in the development of gastric cancer. Cell cycle (Georgetown, Tex.) 5 38701194
2023 Independent role of caspases and Bik in augmenting influenza A virus replication in airway epithelial cells and mice. Virology journal 5 37095508
2022 Copy number amplification-activated long non-coding RNA LINC00662 epigenetically inhibits BIK by interacting with EZH2 to regulate tumorigenesis in non-small cell lung cancer. Journal of Cancer 5 35371316
2015 Involvement of multiple cellular pathways in regulating resistance to tamoxifen in BIK-suppressed MCF-7 cells. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 5 25861752
2016 Low BIK outside-inside-out interactive inflammation immune-induced transcription-dependent apoptosis through FUT3-PMM2-SQSTM1-SFN-ZNF384. Immunologic research 4 26423071
2014 The increase in BIK expression following ERK1/2 pathway inhibition is a consequence of G₁ cell-cycle arrest and not a direct effect on BIK protein stability. The Biochemical journal 4 24527759
2021 Casein kinase II activates Bik to induce death of hyperplastic mucous cells in a cell cycle-dependent manner. Journal of cellular physiology 3 34741311
2018 Does the BCL-2 family member BIK control lung carcinogenesis? Molecular & cellular oncology 3 30250907
2025 BIK polymorphism and proteasome regulation unveil host risk factor for severe influenza. Proceedings of the National Academy of Sciences of the United States of America 2 40627391
2021 Expression of bik cluster and production of bikaverin by Fusarium oxysporum f. sp. lycopersici grown using two alternate nitrogen sources. International microbiology : the official journal of the Spanish Society for Microbiology 2 34455510
2021 Rhomboid domain containing 1 promotes the growth of non-small cell lung cancer through the activation of EGFR and regulation of the BIK-mediated apoptosis. Neoplasma 2 34962825
2025 Confirmation of BIK and SAMHD1 as Prostate Cancer Susceptibility Genes. The Prostate 1 40825105
2024 Reduced Bik expression drives low-grade airway inflammation and increased risk for COPD in females. The Journal of clinical investigation 1 38357926
2009 No association between the Bcl2-interacting killer (BIK) gene and schizophrenia. Neuroscience letters 1 19632297