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Showing BNIP2 — BNIP-2 is a alias.

BNIP2

BCL2/adenovirus E1B 19 kDa protein-interacting protein 2 · UniProt Q12982

Length
314 aa
Mass
36.0 kDa
Annotated
2026-06-09
35 papers in source corpus 15 papers cited in narrative 15 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

BNIP2 is a BCH domain-containing scaffold protein that organizes Rho-family GTPase signaling on intracellular membranes and microtubules to control cell shape, differentiation, and apoptosis (PMID:10799524, PMID:18678706). Through an arginine-patch motif (Arg-235/Arg-238) in its BCH domain it acts as a GAP-like activator of Cdc42, while a distinct motif (288EYV290 / 285VPMEYVGI292) mediates Cdc42 binding and drives cell elongation and membrane protrusions (PMID:10799524, PMID:15652341); FGFR1 phosphorylates BNIP2 on tyrosine residues, abolishing both its Cdc42GAP binding and its GAP-like activity, providing a kinase-controlled switch over this output (PMID:10551883). The BCH domain also engages partner proteins through homophilic and heterophilic BCH-BCH interactions, including with Cdc42GAP (PMID:10954711). BNIP2 binds phosphatidylserine through its CRAL-TRIO domain to localize to the Golgi, endosomes, and mitochondria, and is carried anterogradely along microtubules by kinesin-1, binding both KIF5B and the kinesin light chains via an N-terminal WED motif (PMID:25378581, PMID:25472445). This transport platform is used in distinct contexts: BNIP2 assembles a Cdo–JLP–Cdc42GAP complex that stimulates Cdc42 and p38 MAPK to drive myoblast differentiation, an output requiring KIF5B-mediated transport (PMID:18678706, PMID:25378581); it scaffolds GEF-H1 and RhoA on microtubules so that microtubule disassembly activates RhoA, thereby promoting cell rounding and restraining breast cancer cell migration (PMID:32789168); and it scaffolds LATS1 to phosphorylate and inactivate YAP, coupling RhoA/Myosin II contractility to Hippo signaling during cardiomyoblast differentiation (PMID:35975420). Independently, BNIP2 is a pro-apoptotic substrate cleaved by caspases at its N-terminal EF-hand region and by granzyme B at the IEAD28 motif, generating BCH-containing fragments (PMID:17961507, PMID:20704564, PMID:25208769).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1999 High

    Established that BNIP2 function is under tyrosine-kinase control, linking it to FGFR1 signaling and revealing a regulatory switch over its GTPase-directed activity.

    Evidence In vitro phosphorylation of recombinant BNIP2 by active FGFR1 plus co-IP, pulldown, and GTPase assays in 293T cells

    PMID:10551883

    Open questions at the time
    • Specific phosphorylated tyrosine residues not all mapped
    • Physiological cellular context of FGFR1-BNIP2 regulation not defined
  2. 2000 High

    Defined the molecular basis of BNIP2's GAP-like activity and its self/partner assembly, showing the BCH domain uses separable motifs for Cdc42 stimulation, Cdc42 binding, and BCH-BCH complex formation.

    Evidence GST pulldown, site-directed mutagenesis, in vitro GTPase assays, yeast two-hybrid and co-IP with recombinant BCH domain

    PMID:10799524 PMID:10954711

    Open questions at the time
    • Functional consequence of BNIP2/Cdc42GAP heterocomplex in cells not established
    • No structural model of the BCH-GTPase interface
  3. 2003 Medium

    Extended the BCH-BCH interaction network by showing BNIP2 forms complexes with another BCH-domain RhoGAP, BPGAP1.

    Evidence GST pulldown, co-IP, and fluorescence microscopy

    PMID:12944407

    Open questions at the time
    • Functional output of the BNIP2-BPGAP1 complex unresolved
    • Single-lab, two orthogonal methods only
  4. 2005 High

    Connected BNIP2 to cell morphology, demonstrating that Cdc42 binding via a non-canonical motif drives cell elongation and protrusion formation at the leading edge.

    Evidence Transient and dominant-negative Cdc42 expression, deletion mutagenesis, binding studies, fluorescence microscopy

    PMID:15652341

    Open questions at the time
    • Endogenous role in cell migration not tested here
    • Upstream signals controlling the morphological response unknown
  5. 2007 Medium

    Identified BNIP2 as a caspase substrate, showing apoptotic cleavage at its N-terminal EF-hand region liberates pro-apoptotic BCH-containing fragments.

    Evidence In vitro caspase cleavage with site mapping and cell-based apoptosis assays

    PMID:17961507

    Open questions at the time
    • Effector mechanism of the released fragments not defined
    • Physiological apoptotic trigger not identified
  6. 2008 High

    Revealed BNIP2 as a multi-scaffold for promyogenic signaling, bridging the Cdo receptor, JLP, and Cdc42GAP to activate Cdc42 and p38 MAPK during myoblast differentiation.

    Evidence Reciprocal co-IP with gain/loss-of-function in myoblasts, Cdc42 and p38 activity assays

    PMID:18678706

    Open questions at the time
    • Spatial regulation of the complex not yet resolved
    • How tyrosine phosphorylation intersects with this complex untested
  7. 2008 Medium

    Characterized RhoA regulation by BNIP2 family members, showing BCH-domain proteins can bind specific RhoA conformers and RhoGEF catalytic domains to suppress oncogenic transformation.

    Evidence Co-IP, RhoA pulldown activity assays, knockdown, overexpression, and transformation assays (BNIPXL/BNIP-Salpha)

    PMID:16331259 PMID:18445682

    Open questions at the time
    • Findings concern BNIP2 family members rather than BNIP2 itself
    • Conformer selectivity mechanism not structurally defined
  8. 2010 High

    Established BNIP2 as a granzyme B substrate during NK-cell killing, broadening its pro-apoptotic role to caspase-independent cleavage with subsequent caspase-dependent processing.

    Evidence In vitro granzyme B cleavage, NK killing assay, siRNA knockdown, mutagenesis, immunoprecipitation

    PMID:20704564

    Open questions at the time
    • BNIP2 knockdown did not alter NK killing susceptibility, leaving physiological significance open
    • Downstream apoptotic targets of the fragments unknown
  9. 2014 High

    Defined the membrane-targeting and transport machinery of BNIP2, showing phosphatidylserine binding via CRAL-TRIO and kinesin-1-driven anterograde transport that is required for its promyogenic p38 signaling.

    Evidence Lipid-binding assays, co-IP with KIF5B/KLC, far-Western, live imaging, mutagenesis, organelle markers, p38 and differentiation assays

    PMID:25378581 PMID:25472445

    Open questions at the time
    • Cargo composition delivered by BNIP2-bearing vesicles not fully cataloged
    • Regulation of the WED-KLC interaction unknown
  10. 2014 High

    Refined the granzyme B cleavage determinants, mapping the IEAD28 site and showing extended substrate context governs human vs. mouse cleavage efficiency.

    Evidence In vitro kinetic cleavage assays with cleavage-site mutagenesis

    PMID:25208769

    Open questions at the time
    • In vivo relevance of species-specific cleavage efficiency not addressed
    • Single-lab biochemical study
  11. 2020 High

    Showed BNIP2 transduces microtubule dynamics into RhoA activity by scaffolding GEF-H1 and RhoA, coupling microtubule disassembly to RhoA activation and restraint of cancer cell migration.

    Evidence Reciprocal co-IP, siRNA knockdown, RhoA activation assay, nocodazole treatment, live imaging, migration assays in MDA-MB-231 cells

    PMID:32789168

    Open questions at the time
    • How the same scaffold partitions between Cdc42 and RhoA outputs unresolved
    • In vivo tumor relevance not tested
  12. 2022 High

    Connected BNIP2 to Hippo mechanotransduction, demonstrating it scaffolds LATS1 to inactivate YAP downstream of RhoA/Myosin II contractility to drive cardiomyoblast differentiation.

    Evidence Turbo-ID proximity labeling, super-resolution microscopy, pulldown, YAP phosphorylation assays, knockdown/overexpression, cardiac gene markers

    PMID:35975420

    Open questions at the time
    • Mechanism selecting LATS1 versus other scaffolding partners unclear
    • In vivo cardiac developmental requirement not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How BNIP2 integrates and switches between its distinct outputs — Cdc42-driven morphology, RhoA/GEF-H1 microtubule sensing, LATS1/YAP Hippo signaling, and apoptotic fragment generation — within a single cell remains unresolved.
  • No structural model of the full-length scaffold with its multiple partners
  • Signals that route BNIP2 toward Cdc42 versus RhoA versus apoptotic cleavage unknown
  • In vivo physiological loss-of-function phenotype not characterized in the corpus

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 3 GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 3 GO:0008289 lipid binding 1
Localization
GO:0005768 endosome 2 GO:0005856 cytoskeleton 2 GO:0005739 mitochondrion 1 GO:0005794 Golgi apparatus 1 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1266738 Developmental Biology 2 R-HSA-5357801 Programmed Cell Death 2 R-HSA-9609507 Protein localization 2
Partners
ARHGAP1ARHGEF2CDC42CDONKIF5BLATS1RHOASPAG9

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 BNIP-2 is a substrate of FGF receptor-1 (FGFR1/Flg) tyrosine kinase; FGFR1 phosphorylates BNIP-2 on tyrosine residues both in co-transfected 293T cells and in vitro using recombinant proteins. Tyrosine phosphorylation of BNIP-2 prevents its binding to Cdc42GAP and Cdc42, and abolishes its GAP-like activity toward Cdc42. Co-transfection/capture experiments with kinase-dead mutant in 293T cells; in vitro phosphorylation of bacterially expressed BNIP-2 by active FGFR1; co-immunoprecipitation; GST pulldown; GTPase activity assay The Journal of biological chemistry High 10551883
2000 The BCH domain of BNIP-2 binds Cdc42 and stimulates its GTPase activity via a novel arginine-patch motif (Arg-235, Arg-238). Site-directed mutagenesis of R235K or R238K severely impairs GAP activity without affecting Cdc42 binding. The Cdc42 binding involves residues 288EYV290 and the Switch I and Insert regions of Cdc42. GST pulldown with recombinant BCH domain; site-directed mutagenesis; in vitro GTPase activity assay; deletion studies The Journal of biological chemistry High 10799524
2000 BNIP-2 and Cdc42GAP form homo- and heterocomplexes via their conserved BCH domains. The major BCH-BCH interaction site within BNIP-2 is the region 217RRKMP221, distinct from the arginine-patch required for GAP activity (235RRLRK239) or the Cdc42 binding sequence (288EYV290). GST recombinant protein pulldown; co-immunoprecipitation; yeast two-hybrid assay; deletion mutagenesis; molecular modeling The Journal of biological chemistry High 10954711
2003 BPGAP1, a novel RhoGAP containing a BCH domain, interacts with BCH domain-containing proteins including BNIP-2 via homophilic and heterophilic BCH-BCH interactions, as shown by pulldown and co-immunoprecipitation. BNIP-2's BCH domain mediates formation of these complexes. GST pulldown; co-immunoprecipitation; fluorescence microscopy The Journal of biological chemistry Medium 12944407
2005 BNIP-2 induces cell elongation and membrane protrusions via its BCH domain by binding Cdc42 through a unique motif 285VPMEYVGI292, distinct from canonical CRIB motifs. Dominant-negative Cdc42 completely blocked BNIP-2-induced cell elongation. Subcellular localization of BNIP-2 is to the cytoplasm and concentrated at the leading edge of cellular extensions. Transient expression; dominant-negative GTPase co-expression; deletional mutagenesis; binding studies; fluorescence microscopy Experimental cell research High 15652341
2006 BNIP-Salpha (a BNIP-2 family member) activates RhoA by competing with p50RhoGAP/Cdc42GAP for RhoA binding via overlapping motifs (residues 133-147 and 148-177) in its BCH domain, leading to cell rounding and apoptosis. Only dominant-negative RhoA prevented this effect; BNIP-2's BCH domain interaction with p50RhoGAP involves overlapping regions with its RhoA-binding site. Mutagenesis; co-immunoprecipitation; dominant-negative/constitutively active GTPase expression; cell morphology assays Oncogene Medium 16331259
2008 BNIP-2 interacts with Cdo (a promyogenic cell surface receptor), JLP (a p38 scaffold), and Cdc42GAP, forming a multi-scaffold complex. Cdo-BNIP-2 interaction stimulates Cdc42 activity, which promotes p38alpha/beta MAPK activity and myoblast differentiation. BNIP-2 and JLP are brought together through mutual interaction with Cdo. Co-immunoprecipitation; gain- and loss-of-function experiments in myoblasts; p38 activity assays; Cdc42 activation assays The Journal of cell biology High 18678706
2008 BNIPXL (BNIP2 Extra Long) BCH domain inhibits RhoA activity by binding specific conformers of RhoA (fast-cycling F30L and dominant-negative T19N, but not constitutively active G14V or Q63L) and interacts with the DH-PH catalytic domains of Lbc RhoGEF, suppressing Lbc-induced oncogenic transformation. Knockdown of BNIPXL increases active RhoA levels. Co-immunoprecipitation; RhoA pulldown activity assay; knockdown; overexpression; transformation assay Journal of cell science Medium 18445682
2007 BNIP-2 and BNIP-XL are cleaved by caspases during apoptosis. Caspase cleavage sites on BNIP-2 are located on its N-terminal EF-hand motif. Caspase-mediated cleavage releases the BCH domain or smaller fragments implicated in pro-apoptotic activities. In vitro caspase cleavage assay; identification of cleavage sites by mutagenesis/biochemical analysis; cell-based apoptosis assays Biochemical and biophysical research communications Medium 17961507
2010 BNIP-2 is a substrate of granzyme B during natural killer cell-mediated killing. Granzyme B cleaves recombinant BNIP-2 in vitro at a defined site (bioinformatically identified), and endogenous BNIP-2 is cleaved during NK cell-mediated tumor cell killing in a caspase-independent manner. Full-length BNIP-2 and the truncated granzyme B-cleaved form are both pro-apoptotic and lead to subsequent caspase-dependent cleavage of BNIP-2 at a distinct site. Inhibition of BNIP-2 expression did not affect susceptibility to NK cell killing. In vitro granzyme B cleavage assay; NK cell killing assay; siRNA knockdown; site-directed mutagenesis; immunoprecipitation The Biochemical journal High 20704564
2014 BNIP-2 interacts with kinesin-1 (KIF5B) via its BCH domain, binding both the motor and tail domains of KIF5B. BNIP-2 undergoes microtubule-dependent anterograde transport on endosomes in C2C12 cells; disruption by dominant-negative KIF5B or KIF5B knockdown causes aberrant aggregation of BNIP-2. KIF5B-mediated anterograde transport of BNIP-2 is required for its pro-myogenic effects on p38MAPK activity and myogenic differentiation. Co-immunoprecipitation; far-Western blot; organelle marker co-localization; live cell microscopy; dominant-negative expression; siRNA knockdown; p38 activity assay; differentiation assay Molecular biology of the cell High 25378581
2014 BNIP-2 binds phosphatidylserine via its CRAL-TRIO domain and localizes to Golgi apparatus, early and recycling endosomes, and mitochondria aligned with microtubules. BNIP-2 interacts with kinesin light chains (KLC) through a conserved WED motif in its N-terminal region and is transported by kinesin-1. Vesicular localization requires phosphatidylserine binding; BNIP-2 mutants that do not bind phosphatidylserine fail to induce morphological changes. Lipid-binding assay; co-immunoprecipitation with KLC; live cell imaging; speed measurement; mutagenesis; subcellular fractionation/organelle markers Genes to cells High 25472445
2014 Mouse granzyme B efficiently cleaves BNIP-2 at the IEAD28 tetrapeptide motif in vitro. Extended substrate context beyond P4-P1 positions (particularly P1' and P3' positions) differentially influences cleavage efficiency by human vs. mouse granzyme B. Mutagenesis of P1' (I29>T) yields a 4-fold increase in mouse granzyme B cleavage efficiency. In vitro degradomics/kinetic cleavage assay; mutagenesis of cleavage site residues BMC biochemistry High 25208769
2020 BNIP-2 scaffolds GEF-H1 and RhoA on microtubules, coupling microtubule disassembly to RhoA activation. BNIP-2 binds both RhoA and GEF-H1, and traffics with kinesin-1 on microtubules. Upon nocodazole-induced microtubule disassembly, BNIP-2–GEF-H1 interaction increases. Depletion of BNIP-2 in MDA-MB-231 cells reduces RhoA activity, uncouples RhoA-GEF-H1 interaction, reduces cell rounding, and promotes cell migration. Co-immunoprecipitation; knockdown (siRNA); RhoA activation assay; live cell imaging; nocodazole treatment; migration assay Science advances High 32789168
2022 BNIP-2 promotes cardiomyoblast differentiation by scaffolding LATS1 to phosphorylate and inactivate YAP (causing its cytosolic retention), in a process requiring BNIP-2 activation of cellular contractility via RhoA/Myosin II. Turbo-ID proximity labeling, super-resolution microscopy, and biochemical pulldown data together revealed BNIP-2 as a scaffold integrating RhoA/Myosin II and LATS1/YAP signaling. Turbo-ID proximity labeling; super-resolution microscopy; co-immunoprecipitation/pulldown; YAP phosphorylation assay; knockdown; overexpression; cardiac gene expression (cTnT, Myl2) Advanced science High 35975420

Source papers

Stage 0 corpus · 35 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 A Cdo-Bnip-2-Cdc42 signaling pathway regulates p38alpha/beta MAPK activity and myogenic differentiation. The Journal of cell biology 91 18678706
2011 miR-20a targets BNIP2 and contributes chemotherapeutic resistance in colorectal adenocarcinoma SW480 and SW620 cell lines. Acta biochimica et biophysica Sinica 89 21242194
2007 Characterization of NIP2/centrobin, a novel substrate of Nek2, and its potential role in microtubule stabilization. Journal of cell science 74 17535851
2017 Monodispersed Carbon-Coated Cubic NiP2 Nanoparticles Anchored on Carbon Nanotubes as Ultra-Long-Life Anodes for Reversible Lithium Storage. ACS nano 58 28323408
2006 Brain-specific BNIP-2-homology protein Caytaxin relocalises glutaminase to neurite terminals and reduces glutamate levels. Journal of cell science 55 16899818
2020 Astrocyte-derived exosomes carry microRNA-17-5p to protect neonatal rats from hypoxic-ischemic brain damage via inhibiting BNIP-2 expression. Neurotoxicology 54 33309839
2003 Concerted regulation of cell dynamics by BNIP-2 and Cdc42GAP homology/Sec14p-like, proline-rich, and GTPase-activating protein domains of a novel Rho GTPase-activating protein, BPGAP1. The Journal of biological chemistry 44 12944407
1999 Tyrosine phosphorylation of the Bcl-2-associated protein BNIP-2 by fibroblast growth factor receptor-1 prevents its binding to Cdc42GAP and Cdc42. The Journal of biological chemistry 42 10551883
2000 The BNIP-2 and Cdc42GAP homology domain of BNIP-2 mediates its homophilic association and heterophilic interaction with Cdc42GAP. The Journal of biological chemistry 39 10954711
2008 BNIP2 extra long inhibits RhoA and cellular transformation by Lbc RhoGEF via its BCH domain. Journal of cell science 38 18445682
2001 The BNIP-2 and Cdc42GAP homology/Sec14p-like domain of BNIP-Salpha is a novel apoptosis-inducing sequence. The Journal of biological chemistry 38 11741952
2006 BNIP-Salpha induces cell rounding and apoptosis by displacing p50RhoGAP and facilitating RhoA activation via its unique motifs in the BNIP-2 and Cdc42GAP homology domain. Oncogene 36 16331259
2000 Oestrogen prevention of neural cell death correlates with decreased expression of mRNA for the pro-apoptotic protein nip-2. Journal of neuroendocrinology 33 11069120
2005 BNIP-2 induces cell elongation and membrane protrusions by interacting with Cdc42 via a unique Cdc42-binding motif within its BNIP-2 and Cdc42GAP homology domain. Experimental cell research 32 15652341
2000 Evidence for a novel Cdc42GAP domain at the carboxyl terminus of BNIP-2. The Journal of biological chemistry 32 10799524
2001 Estrogen neuroprotection: the involvement of the Bcl-2 binding protein BNIP2. Brain research. Brain research reviews 30 11744098
2020 BNIP-2 retards breast cancer cell migration by coupling microtubule-mediated GEF-H1 and RhoA activation. Science advances 25 32789168
2010 Centrobin/NIP2 is a microtubule stabilizer whose activity is enhanced by PLK1 phosphorylation during mitosis. The Journal of biological chemistry 24 20511645
2010 The BNIP-2 and Cdc42GAP homology (BCH) domain of p50RhoGAP/Cdc42GAP sequesters RhoA from inactivation by the adjacent GTPase-activating protein domain. Molecular biology of the cell 24 20660160
2003 BNIPL-2, a novel homologue of BNIP-2, interacts with Bcl-2 and Cdc42GAP in apoptosis. Biochemical and biophysical research communications 23 12901880
2012 Functional plasticity of the BNIP-2 and Cdc42GAP Homology (BCH) domain in cell signaling and cell dynamics. FEBS letters 22 22710163
2009 Nip2/centrobin may be a substrate of Nek2 that is required for proper spindle assembly during mitosis in early mouse embryos. Molecular reproduction and development 21 19117032
2012 Cross-species analyses identify the BNIP-2 and Cdc42GAP homology (BCH) domain as a distinct functional subclass of the CRAL_TRIO/Sec14 superfamily. PloS one 20 22479462
2020 The grapevine NIP2;1 aquaporin is a silicon channel. Journal of experimental botany 17 32584998
2007 Cleavage of BNIP-2 and BNIP-XL by caspases. Biochemical and biophysical research communications 17 17961507
2014 KIF5B transports BNIP-2 to regulate p38 mitogen-activated protein kinase activation and myoblast differentiation. Molecular biology of the cell 16 25378581
2010 Nek2 and its substrate, centrobin/Nip2, are required for proper meiotic spindle formation of the mouse oocytes. Zygote (Cambridge, England) 15 20569513
2010 Identification of the BCL2/adenovirus E1B-19K protein-interacting protein 2 (BNIP-2) as a granzyme B target during human natural killer cell-mediated killing. The Biochemical journal 12 20704564
2000 Expression of the estrogen-regulated gene Nip2 during rat brain maturation. International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience 12 10715586
2022 BNIP-2 Activation of Cellular Contractility Inactivates YAP for H9c2 Cardiomyoblast Differentiation. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 11 35975420
2022 Superhydrophilic/Superaerophobic Hierarchical NiP2@MoO2/Co(Ni)MoO4 Core-Shell Array Electrocatalysts for Efficient Hydrogen Production at Large Current Densities. ACS applied materials & interfaces 10 35469395
2009 Pro-apoptotic activity of mBNIP-21 depends on its BNIP-2 and Cdc42GAP homology (BCH) domain and is enhanced by coxsackievirus B3 infection. Cellular microbiology 10 19951366
2009 Centrobin/Nip2 expression in vivo suggests its involvement in cell proliferation. Molecules and cells 6 19533028
2014 Importance of extended protease substrate recognition motifs in steering BNIP-2 cleavage by human and mouse granzymes B. BMC biochemistry 4 25208769
2014 BNIP-2 binds phosphatidylserine, localizes to vesicles, and is transported by kinesin-1. Genes to cells : devoted to molecular & cellular mechanisms 3 25472445

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