Affinage

Showing KRIT1 — CCM1 is a alias.

KRIT1

Krev interaction trapped protein 1 · UniProt O00522

Length
736 aa
Mass
84.3 kDa
Annotated
2026-06-10
100 papers in source corpus 25 papers cited in narrative 24 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KRIT1 (CCM1) is an intracellular scaffold protein that acts as a Rap1 GTPase effector at endothelial cell-cell junctions to maintain vascular barrier integrity, apicobasal polarity, and quiescence (PMID:17954608, PMID:22577140). Its FERM domain binds active Rap1 across an extended surface spanning Rap1 Switch I/II and the F1 and F2 lobes, and is structurally similar to talin (PMID:22577140); the same FERM domain is recruited to junctions by direct binding to the transmembrane receptor HEG1, which also stabilizes KRIT1 protein levels (PMID:33977234, PMID:29364115). At junctions KRIT1 associates with VE-cadherin and is required for adherens-junction organization and coupling to the Par3/PKCζ polarity complex (PMID:20332120). Through its N-terminal NPXY motifs KRIT1 nucleates a CCM signaling unit, binding ICAP-1 and the CCM2 PTB domain to form a CCM1/CCM2/CCM3 ternary complex with CCM2 as the essential core, which in turn links to MEKK3 (PMID:11854171, PMID:16037064, PMID:18300272). Co-crystallography shows KRIT1 binds ICAP1 by a bidentate surface that directly competes with the β1 integrin cytoplasmic tail, making KRIT1 a switch that antagonizes ICAP1-mediated inside-out β1 integrin activation (PMID:23317506, PMID:23918940). Loss of KRIT1 destabilizes junctions and drives pathology through several convergent axes: excessive ROCK1-dependent actin stress fibers and contractility, since KRIT1 normally scaffolds ROCK2 to VE-cadherin while limiting ROCK1 activity (PMID:30030370, PMID:23918940); dissociation of β-catenin from VE-cadherin with nuclear accumulation, increased β-catenin transcription and VEGF-A/VEGFR2 signaling (PMID:20007487, PMID:25320085); elevated ROS via NADPH oxidase (Nox4) and NF-κB, with downstream c-Jun/COX-2 induction (PMID:28811547, PMID:24291398); and derepression of mechanosensitive KLF2/KLF4 and Notch/DLL4 programs that control sprouting and cardiac valve formation (PMID:29364115, PMID:33977234, PMID:20616044). Truncating mutations in KRIT1 cause hereditary cerebral cavernous malformations, and KRIT1 loss is cell-autonomously required for normal endothelial morphogenesis in vivo (PMID:10508515, PMID:10545614, PMID:18469344).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1999 High

    Established the molecular entry point: KRIT1 binds the Ras-family GTPase RAP1A and KRIT1 truncating mutations cause hereditary cavernous angiomas, placing KRIT1 in a Rap1-dependent vascular signaling pathway.

    Evidence Yeast two-hybrid interaction with RAP1A; positional cloning and mutation identification in CCM1 families

    PMID:10508515 PMID:10545614

    Open questions at the time
    • Did not define how Rap1 binding controls KRIT1 function
    • No cellular localization or downstream effector identified
  2. 2002 High

    Identified KRIT1's first molecular interfaces, linking it to integrin signaling via the NPXY motif and to microtubules, beginning to define its scaffolding role.

    Evidence Yeast two-hybrid, GST pulldown with NPXY mutagenesis for ICAP-1; immunofluorescence and Co-IP for microtubule association in endothelial cells

    PMID:11854171 PMID:12140362

    Open questions at the time
    • Functional consequence of ICAP-1 binding for integrin activation not yet shown
    • Microtubule association not independently replicated
    • Did not connect interactions to vascular phenotype
  3. 2005 High

    Assembled the CCM signaling complex, showing KRIT1 bridges CCM2 (via its NPXY/CCM2-PTB interface) and MEKK3 in a ternary complex, with disease mutations disrupting the interaction.

    Evidence Co-IP, FRET, subcellular localization, and disease-associated CCM2 missense mutation analysis

    PMID:16037064

    Open questions at the time
    • Downstream signaling output of the KRIT1/CCM2/MEKK3 complex not resolved
    • Stoichiometry and regulation of complex assembly unclear
  4. 2007 High

    Defined KRIT1 as a Rap1 effector at endothelial junctions, demonstrating Rap1-dependent junctional recruitment via the FERM domain and a requirement for junction stability.

    Evidence Immunofluorescence, Co-IP, FERM domain mapping, and siRNA knockdown with junction/stress-fiber readouts in endothelial cells

    PMID:17290187 PMID:17954608

    Open questions at the time
    • Junctional binding partners not fully enumerated
    • Mechanism linking junctional KRIT1 to actin remodeling not defined
  5. 2008 High

    Established cell-autonomous in vivo requirement for KRIT1 in vascular morphogenesis and refined the CCM complex architecture, while linking KRIT1/ICAP-1 to FAK→ERK proliferation signaling.

    Evidence Zebrafish loss-of-function with chimeric transplantation and EM; CCM2 deletion-mutant Co-IP; siRNA with phospho-FAK/ERK readout across cell types

    PMID:18300272 PMID:18469344 PMID:18812969

    Open questions at the time
    • Molecular cause of endothelial spreading not pinpointed
    • Relationship between proliferation signaling and junction phenotype unclear
  6. 2009 High

    Connected KRIT1 to transcriptional control, showing it acts downstream of Rap1 to restrain nuclear β-catenin signaling and that Krit1 deficiency cooperates with Apc loss in vivo.

    Evidence siRNA, nuclear fractionation, reporter assays, and Krit1(+/-) × Apc(Min/+) mouse epistasis

    PMID:20007487

    Open questions at the time
    • Direct vs indirect effect on β-catenin pool not separated
    • Downstream β-catenin target genes driving pathology not identified
  7. 2010 High

    Broadened the pathway map, showing KRIT1 controls DLL4-Notch sprouting, VE-cadherin/Par-complex polarity, and redox/quiescence programs, and that silencing recapitulates CCM pathology in vivo.

    Evidence siRNA, Notch inhibition, SCID xenograft, VE-cadherin Co-IP/polarity assays, and ROS/SOD2/FoxO1 measurements with KRIT1 reconstitution

    PMID:20332120 PMID:20616044 PMID:20668652

    Open questions at the time
    • Causal hierarchy among Notch, polarity, and ROS axes not established
    • ROS findings from a single lab not independently replicated
  8. 2012 High

    Provided atomic-resolution mechanism for Rap1 recognition, showing the KRIT1 FERM domain engages Rap1 across F1 and F2 lobes and resembles the talin FERM fold.

    Evidence 1.95 Å co-crystal structure of KRIT1 FERM–Rap1 with point mutagenesis

    PMID:22577140

    Open questions at the time
    • Structure does not explain how Rap1 binding drives junctional recruitment
    • Conformational regulation of full-length KRIT1 not captured
  9. 2013 High

    Resolved the integrin switch and the mechanotransduction consequences, showing KRIT1 competes with β1 integrin for ICAP1 and that CCM1/2 loss raises β1 integrin activation, RhoA contractility, and aberrant ECM remodeling.

    Evidence Co-crystal structures of KRIT1–ICAP1 and ICAP1–β1 tail with competition/integrin-activation assays; RNAi, traction microscopy, and CCM knockout mouse ECM analysis

    PMID:23317506 PMID:23918940

    Open questions at the time
    • How junctional Rap1/HEG1 cues are coordinated with the integrin switch not defined
    • Feedback between ECM stiffness and intracellular tension only partially mapped
  10. 2013 Medium

    Linked KRIT1 loss to inflammatory signaling, showing ROS-dependent induction and phosphorylation of c-Jun and its target COX-2, reversible by KRIT1 re-expression or ROS scavenging.

    Evidence Western blot, qPCR, KRIT1 re-expression and ROS scavenging rescue, and human CCM tissue analysis

    PMID:24291398

    Open questions at the time
    • Single-lab finding
    • Mechanism connecting ROS to c-Jun activation not detailed
  11. 2014 Medium

    Identified a KRIT1-specific VEGF axis, showing KRIT1 (but not CCM2) loss elevates nuclear β-catenin and VEGF-A to activate VEGFR2 and increase endothelial permeability in vivo.

    Evidence siRNA, VEGFR2 inhibition, intravital permeability in Krit1(+/-) mice, and migration/barrier assays

    PMID:25320085

    Open questions at the time
    • Why the VEGF axis is KRIT1-specific and CCM2-independent not mechanistically explained
    • Single-lab finding
  12. 2017 Medium

    Defined the redox source and a therapeutic handle, showing KRIT1 loss drives Nox4/NF-κB-dependent ROS and that targeted antioxidants reverse permeability in vivo.

    Evidence siRNA, intravital microscopy with targeted antioxidant enzymes, NF-κB reporter, Nox4 western, and Krit1(+/-) mice

    PMID:28811547

    Open questions at the time
    • Arteriole-vs-venule difference in TNF-α responsiveness unexplained
    • Single-lab finding
  13. 2018 High

    Refined the cytoskeletal mechanism and mechanosensitive transcription control, showing KRIT1 scaffolds ROCK2 to VE-cadherin while limiting ROCK1, and that Krit1/Heg1 damp KLF2a/Notch1b to permit cardiac valve formation.

    Evidence Co-IP, isoform-specific ROCK1/2 knockdown, traction microscopy, and zebrafish genetic rescue/double-mutant analysis

    PMID:29364115 PMID:30030370

    Open questions at the time
    • How KRIT1 selectively partitions ROCK1 vs ROCK2 activity not resolved
    • KLF2a link from mechanosensing in mammalian endothelium not directly tested here
  14. 2020 Medium

    Extended KRIT1 function beyond endothelium, showing stromal-cell KRIT1 loss activates NOX1/inflammatory signaling and drives a paracrine pro-angiogenic program acting on neighboring endothelial cells.

    Evidence Fibroblast KRIT1 siRNA, VEGF/PGE2 ELISA, conditioned-media transfer, MMP2 zymography, and immunofluorescence

    PMID:31917192

    Open questions at the time
    • In vivo relevance of stromal paracrine mechanism not established
    • Single-lab finding
  15. 2021 High

    Validated the HEG1–KRIT1 junctional recruitment interface as druggable, showing direct FERM-domain binding and that pharmacological disruption de-represses KLF4/KLF2 and activates PI3K/Akt.

    Evidence Crystal structure of HKi2–KRIT1 FERM, high-throughput screening, colocalization, transcriptome analysis, and zebrafish klf2a assay

    PMID:33977234

    Open questions at the time
    • Therapeutic consequence of acute HEG1-KRIT1 disruption in CCM disease models not shown
    • Specificity of KLF/Akt response over other junctional pathways unclear
  16. 2022 Medium

    Identified upstream transcriptional/epigenetic regulation of KRIT1, showing NGBR sustains CCM1/CCM2 expression via HBO1-mediated histone H4 acetylation at their promoters.

    Evidence Endothelial-specific Ngbr knockout mice, RNA-seq, ChIP-qPCR, and histone-acetylation westerns

    PMID:35316220

    Open questions at the time
    • Whether NGBR/HBO1 regulation is dynamically used to tune KRIT1 in normal vasculature unclear
    • Single-lab finding

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple downstream axes — integrin/RhoA-ROCK tension, β-catenin/VEGF, ROS/NF-κB, and KLF/Notch derepression — are causally ordered into a single hierarchy from junctional KRIT1 loss remains unresolved.
  • No unified epistasis study ranking the axes
  • Tissue-specific contributions (endothelial vs stromal) not integrated
  • Structure of full-length KRIT1 and its autoregulation not determined

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 2
Localization
GO:0005886 plasma membrane 3 GO:0005634 nucleus 2 GO:0005829 cytosol 2 GO:0005856 cytoskeleton 2
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 3 R-HSA-8953897 Cellular responses to stimuli 2 R-HSA-1474244 Extracellular matrix organization 1
Partners
CCM2HEG1ICAP-1ITGB1MEKK3RAP1AROCK2VE-CADHERIN
Complex memberships
CCM1/CCM2/CCM3 complex

Evidence

Reading pass · 24 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 KRIT1 protein physically interacts with RAP1A (Krev-1/rap1a), a member of the RAS family of GTPases; truncating mutations in CCM1/KRIT1 cause hereditary cavernous angiomas, implicating the RAP1A signal transduction pathway in vasculogenesis/angiogenesis. Yeast two-hybrid interaction (previously established); positional cloning and mutation identification in CCM1 families Nature genetics High 10508515 10545614
2002 KRIT1 colocalizes with microtubules in interphase cells and localizes to spindle pole bodies, mitotic spindle, and microtubule plus ends during mitosis; coimmunoprecipitation confirmed KRIT1 association with microtubules, establishing KRIT1 as a microtubule-associated protein. Immunofluorescence microscopy with anti-KRIT1 antibodies; coimmunoprecipitation from endothelial cells Proceedings of the National Academy of Sciences of the United States of America Medium 12140362
2002 KRIT1 physically interacts with ICAP-1 (integrin cytoplasmic domain-associated protein-1); interaction is mediated by the N-terminal NPXY motif of KRIT1, and mutagenesis of this motif abrogates binding; ICAP-1 is a known β1 integrin cytoplasmic tail binder, suggesting KRIT1 participates in integrin–cytoskeleton signaling. Yeast two-hybrid screen of human fetal brain and HeLa cDNA libraries; GST-KRIT1 pulldown of endogenous ICAP-1 from 293T cells; site-directed mutagenesis of NPXY motif Human molecular genetics High 11854171
2005 KRIT1 (CCM1) interacts with CCM2 (malcavernin/OSM) protein; this interaction is dependent on the phosphotyrosine binding (PTB) domain of CCM2 and the NPXY motif of CCM1; a familial CCM2 missense mutation abrogates this interaction; CCM1 associates with CCM2 and MEKK3 in a ternary complex; CCM2 and ICAP-1 differentially influence CCM1 subcellular localization. Coimmunoprecipitation; fluorescence resonance energy transfer (FRET); subcellular localization assays; analysis of disease-associated CCM2 missense mutation Human molecular genetics High 16037064
2007 KRIT1 is expressed in endothelial cells and localizes to cell-cell junctions via its FERM domain; Rap1 GTPase activity regulates the junctional localization of KRIT1 and its physical association with junctional proteins; siRNA depletion of KRIT1 blocked Rap1-mediated stabilization of endothelial junctions and was associated with increased actin stress fibers, establishing KRIT1 as a Rap1 effector at endothelial junctions. Immunofluorescence localization; coimmunoprecipitation; siRNA knockdown with functional readout (junction stability, actin stress fibers); domain mapping with isolated FERM domain The Journal of cell biology High 17954608
2007 KRIT1 (krit1) interacts with CCM2 (malcavernin) through two of the three NPXY motifs in KRIT1; CCM2 protein shuttles between nucleus and cytoplasm; KRIT1 co-localizes with ICAP-1 in both nucleus and cytoplasm, and KRIT1 depletion causes loss of ICAP-1 from cytoplasm and nucleus, suggesting KRIT1 stabilizes and shuttles ICAP-1. Yeast two-hybrid; coimmunoprecipitation; epitope mapping; immunocytochemistry; siRNA knockdown Neurosurgery Medium 17290187
2008 Loss of ccm1 in zebrafish leads to progressive dilation of major vessels due to cell-autonomous spreading of endothelial cells and thinning of vessel walls, with ultrastructurally normal cell-cell contacts; rescue experiments confirmed cell-autonomous function of ccm1 in endothelial morphogenesis. Zebrafish genetic loss-of-function; chimeric transplantation experiments establishing cell autonomy; electron microscopy Human molecular genetics High 18469344
2009 KRIT1/CCM1, acting downstream of Rap1 GTPase, negatively regulates canonical β-catenin signaling in endothelial cells; KRIT1 depletion causes β-catenin to dissociate from VE-cadherin and accumulate in the nucleus with increased β-catenin-dependent transcription; Rap1 activation inhibits β-catenin transcription in a manner dependent on intact cell-cell junctions and KRIT1; hemizygous Krit1 deficiency in Apc(Min/+) mice increased intestinal polyp burden. siRNA knockdown; nuclear fractionation; transcriptional reporter assays; in vivo Krit1(+/-) × Apc(Min/+) mouse epistasis Disease models & mechanisms High 20007487
2010 CCM1 (KRIT1) induces DLL4-NOTCH signaling in endothelial cells, inhibiting sprouting angiogenesis; CCM1 promotes AKT phosphorylation but reduces ERK phosphorylation; blocking NOTCH activity alleviates CCM1 effects; CCM1 silencing in human endothelial cells transplanted into SCID mice recapitulates CCM pathology. siRNA knockdown; western blotting; NOTCH pharmacological inhibition; SCID mouse xenograft model; ERK/AKT phosphorylation assays Proceedings of the National Academy of Sciences of the United States of America High 20616044
2010 CCM1 (KRIT1) interacts with VE-cadherin and is required for proper adherens junction (AJ) organization and AJ association with the Par polarity complex (Par3 and PKCζ); CCM1 and VE-cadherin control Rap1 concentration at cell-cell junctions; loss of CCM1 leads to loss of endothelial apicobasal polarity and severe alterations in vascular lumen structure. Coimmunoprecipitation; siRNA knockdown; immunofluorescence; PKCζ activation assays; analysis of human CCM1 lesions Journal of cell science High 20332120
2010 KRIT1 loss/down-regulation increases intracellular ROS levels and decreases expression of antioxidant protein SOD2 and transcription factor FoxO1; restoration of KRIT1 expression dose-dependently reduces ROS levels; KRIT1-dependent low ROS levels facilitate downregulation of cyclin D1 for cell quiescence; KRIT1 loss increases susceptibility to oxidative DNA damage and induces Gadd45α and declines mitochondrial metabolism. ROS measurement assays; western blotting; KRIT1 reconstitution in knockout cells; cyclin D1 expression analysis; Gadd45α induction; mitochondrial metabolism assays PloS one Medium 20668652
2012 Crystal structure of KRIT1 FERM domain in complex with Rap1 determined at 1.95 Å; Rap1-KRIT1 interaction spans an extended surface including Rap1 Switch I and II and KRIT1 FERM F1 and F2 lobes; Rap1 binds KRIT1-F1 via a GTPase-ubiquitin-like fold interaction and KRIT1-F2 via a novel interaction; point mutagenesis confirms the interaction surface; KRIT1 FERM domain is structurally similar to talin. Co-crystal structure determination (1.95 Å resolution); point mutagenesis; structural comparison The Journal of biological chemistry High 22577140
2013 KRIT1 functions as a switch for β1 integrin activation by antagonizing ICAP1-mediated inside-out activation; co-crystal structures of KRIT1 with ICAP1 (2.54 Å) and ICAP1 with integrin β1 cytoplasmic tail (3.0 Å) show that KRIT1 binds ICAP1 by a bidentate surface that directly competes with integrin β1; KRIT1 contains an N-terminal Nudix domain in a region previously thought to be unstructured. Co-crystal structure determination (2.54 Å and 3.0 Å); in vitro competition binding assays; integrin activation assay; structural mutagenesis Molecular cell High 23317506
2013 CCM1 (KRIT1)/CCM2 complex interacts with ICAP-1 to regulate β1 integrin activation; CCM1/2 loss results in ICAP-1 destabilization, increased β1 integrin activation, increased RhoA-dependent contractility, and aberrant ECM remodeling; a positive feedback loop between aberrant ECM and internal cellular tension leads to decreased endothelial barrier function. RNAi knockdown; force/traction microscopy; β1 integrin activation assays; immunofluorescence; CCM1/2 knockout mouse ECM analysis The Journal of cell biology High 23918940
2013 KRIT1 loss of function leads to enhanced expression and phosphorylation of c-Jun and induction of its target COX-2 in a ROS-dependent manner; c-Jun upregulation can be reversed by KRIT1 re-expression or ROS scavenging; KRIT1 overexpression prevents forced c-Jun upregulation induced by oxidative stimuli. Western blotting; qPCR; KRIT1 re-expression and ROS scavenging rescue experiments; analysis of human CCM tissues Free radical biology & medicine Medium 24291398
2014 KRIT1 depletion increases nuclear β-catenin signaling and upregulates VEGF-A protein expression; increased VEGF-A activates VEGFR2 leading to altered cytoskeletal organization, migration, barrier function, and in vivo endothelial permeability in KRIT1-deficient animals; loss of KRIT1 but not CCM2 specifically triggers this VEGF signaling axis. siRNA knockdown; western blotting; VEGFR2 inhibition; intravital permeability assay in Krit1(+/-) mice; migration and barrier function assays The Journal of biological chemistry Medium 25320085
2017 KRIT1 depletion increases endothelial ROS production via NADPH oxidase (Nox4 upregulation) and NF-κB-dependent signaling; targeted antioxidant delivery reversed increased permeability in KRIT1-heterozygous mice; rescue of redox state restored TNF-α responsiveness in KRIT1-deficient arterioles but not venules. KRIT1 siRNA; intravital microscopy with targeted antioxidant enzymes; NF-κB reporter assay; Nox4 western blotting; Krit1(+/-) mouse model Scientific reports Medium 28811547
2018 CCM1 (KRIT1) acts as a scaffold promoting ROCK2 interaction with VE-cadherin and limiting ROCK1 kinase activity; loss of CCM1 produces excessive ROCK1-dependent actin stress fibers and destabilizes intercellular junctions; ROCK1 silencing (but not ROCK2) restores adhesive and mechanical homeostasis of CCM1-depleted endothelial monolayers and rescues cardiovascular defects in ccm1 mutant zebrafish; ROCK2 knockdown in wild-type zebrafish generates CCM1-like defects. Co-immunoprecipitation; siRNA knockdown; traction force microscopy; zebrafish genetic rescue experiments; ROCK1/2 isoform-specific knockdown Journal of cell science High 30030370
2018 Zebrafish Krit1 regulates cardiac valve formation by damping mechanosensitive KLF2a expression; HEG1 binding partner stabilizes Krit1 protein levels; Heg1 and Krit1 suppress klf2a and notch1b expression throughout the endocardium; loss of Krit1 results in increased klf2a and notch1b and prevents cardiac valve leaflet formation. Zebrafish genetic loss-of-function; quantitative gene expression analysis; protein level assessment; heg1/krit1 double-mutant analysis eLife Medium 29364115
2021 HEG1 directly binds to KRIT1 FERM domain and recruits it to endothelial junctions; a small-molecule inhibitor (HKi2) occupies the HEG1-binding pocket on KRIT1 FERM, and acute inhibition of HEG1-KRIT1 interaction increases KLF4 and KLF2 expression in endothelial cells and activates PI3K-dependent Akt phosphorylation. Crystal structure of HKi2-KRIT1 FERM complex; high-throughput screening; colocalization assay in CHO cells; RNA transcriptome analysis; pharmacological inhibition with inactive analog control; zebrafish klf2a expression assay FASEB bioAdvances High 33977234
2008 KRIT1 depletion reduces endothelial cell proliferation and decreases phosphorylation along the FAK→ERK/MAPK pathway downstream of β1 integrin; ICAP-1α depletion produces similar effects, suggesting synergistic function; KRIT1 stabilizes ICAP-1 and shuttles it between cytoplasm and nucleus. siRNA knockdown in HeLa, HUVEC, and microvascular endothelial cells; cell counting; phospho-FAK/ERK western blotting; immunocytochemistry Neurosurgery Medium 18812969
2008 An in-frame deletion of CCM2 exon 2 (CCM2:p.P11_K68del) can form a complex with CCM3 but loses the ability to interact with CCM1 and to form a CCM1/CCM2/CCM3 ternary complex, identifying an N-terminal CCM2 domain required for CCM1 binding and establishing full-length CCM2 as the essential core protein in the CCM1/CCM2/CCM3 complex. Cell-based expression; coimmunoprecipitation; functional mutation analysis Human mutation Medium 18300272
2020 KRIT1 loss-of-function in stromal cells (fibroblasts) upregulates NADPH oxidase isoform NOX1 and activates inflammatory pathways, leading to increased production of VEGF and PGE2; conditioned media from KRIT1-null fibroblasts promotes proliferation, migration, MMP2 activation, and VE-cadherin redistribution in wild-type endothelial cells, demonstrating a paracrine pro-angiogenic mechanism. KRIT1 siRNA in fibroblasts; ELISA for VEGF/PGE2; conditioned media transfer to endothelial cells; MMP2 zymography; immunofluorescence Cellular signalling Medium 31917192
2022 NOGOB receptor (NGBR) is required for maintaining CCM1 and CCM2 expression in endothelial cells via HBO1-mediated histone H4 acetylation; ChIP-qPCR demonstrated that NGBR loss impairs binding of HBO1 and acetylated histone H4K5/H4K12 to the CCM1 and CCM2 gene promoters, establishing epigenetic regulation of KRIT1/CCM1 expression. Endothelial-specific Ngbr knockout mice; RNA-sequencing; ChIP-qPCR; western blotting for histone acetylation marks; HBO1 manipulation The Journal of clinical investigation Medium 35316220

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1994 The CaM kinase II hypothesis for the storage of synaptic memory. Trends in neurosciences 421 7530878
2001 Ca(2+)/CaM-dependent kinases: from activation to function. Annual review of pharmacology and toxicology 412 11264466
1999 Truncating mutations in CCM1, encoding KRIT1, cause hereditary cavernous angiomas. Nature genetics 369 10508515
1999 Mutations in the gene encoding KRIT1, a Krev-1/rap1a binding protein, cause cerebral cavernous malformations (CCM1). Human molecular genetics 304 10545614
2019 CaM Kinase: Still Inspiring at 40. Neuron 273 31394063
2007 KRIT-1/CCM1 is a Rap1 effector that regulates endothelial cell cell junctions. The Journal of cell biology 267 17954608
1999 The role of CD146 (Mel-CAM) in biology and pathology. The Journal of pathology 202 10451481
2005 CCM1 and CCM2 protein interactions in cell signaling: implications for cerebral cavernous malformations pathogenesis. Human molecular genetics 200 16037064
2000 CaM-kinases: modulators of synaptic plasticity. Current opinion in neurobiology 190 10851169
2008 Activity-dependent synaptogenesis: regulation by a CaM-kinase kinase/CaM-kinase I/betaPIX signaling complex. Neuron 184 18184567
1999 Expression of Ep-CAM in normal, regenerating, metaplastic, and neoplastic liver. The Journal of pathology 180 10398165
2004 Ecophysiology of Crassulacean Acid Metabolism (CAM). Annals of botany 174 15150072
2010 Cerebral cavernous malformation protein CCM1 inhibits sprouting angiogenesis by activating DELTA-NOTCH signaling. Proceedings of the National Academy of Sciences of the United States of America 165 20616044
2004 Ccm1 is required for arterial morphogenesis: implications for the etiology of human cavernous malformations. Development (Cambridge, England) 160 14993192
2002 KRIT1 association with the integrin-binding protein ICAP-1: a new direction in the elucidation of cerebral cavernous malformations (CCM1) pathogenesis. Human molecular genetics 160 11854171
1994 N-CAM and N-cadherin expression during in vitro chondrogenesis. Experimental cell research 151 7982473
2010 CCM1 regulates vascular-lumen organization by inducing endothelial polarity. Journal of cell science 144 20332120
2000 The regulation of phosphoenolpyruvate carboxylase in CAM plants. Trends in plant science 137 10664617
1986 Differential contributions of Ng-CAM and N-CAM to cell adhesion in different neural regions. The Journal of cell biology 137 3522601
2021 Cancer-secreted exosomal miR-21-5p induces angiogenesis and vascular permeability by targeting KRIT1. Cell death & disease 130 34088891
2005 Biallelic somatic and germ line CCM1 truncating mutations in a cerebral cavernous malformation lesion. Stroke 130 15718512
2001 Ccm1, a regulatory gene controlling the induction of a carbon-concentrating mechanism in Chlamydomonas reinhardtii by sensing CO2 availability. Proceedings of the National Academy of Sciences of the United States of America 119 11287669
2010 KRIT1 regulates the homeostasis of intracellular reactive oxygen species. PloS one 106 20668652
2016 Transcript, protein and metabolite temporal dynamics in the CAM plant Agave. Nature plants 104 27869799
2011 Analysis of CaM-kinase signaling in cells. Cell calcium 102 21529938
2009 Rap1 and its effector KRIT1/CCM1 regulate beta-catenin signaling. Disease models & mechanisms 100 20007487
2006 Derepression of pathological cardiac genes by members of the CaM kinase superfamily. Cardiovascular research 97 17217938
2019 The KN-93 Molecule Inhibits Calcium/Calmodulin-Dependent Protein Kinase II (CaMKII) Activity by Binding to Ca2+/CaM. Journal of molecular biology 95 30753871
2002 KRIT1, a gene mutated in cerebral cavernous malformation, encodes a microtubule-associated protein. Proceedings of the National Academy of Sciences of the United States of America 95 12140362
2004 Loss of p53 sensitizes mice with a mutation in Ccm1 (KRIT1) to development of cerebral vascular malformations. The American journal of pathology 92 15509522
2008 ccm1 cell autonomously regulates endothelial cellular morphogenesis and vascular tubulogenesis in zebrafish. Human molecular genetics 90 18469344
2008 Novel CCM1, CCM2, and CCM3 mutations in patients with cerebral cavernous malformations: in-frame deletion in CCM2 prevents formation of a CCM1/CCM2/CCM3 protein complex. Human mutation 89 18300272
2002 Spectrum and expression analysis of KRIT1 mutations in 121 consecutive and unrelated patients with Cerebral Cavernous Malformations. European journal of human genetics : EJHG 89 12404106
2013 CCM1-ICAP-1 complex controls β1 integrin-dependent endothelial contractility and fibronectin remodeling. The Journal of cell biology 88 23918940
2007 CaM Kinase II-dependent pathophysiological signalling in endothelial cells. Cardiovascular research 88 18006482
1992 Decoding calcium signals by multifunctional CaM kinase. Cell calcium 88 1324121
2007 Depolarization and CaM kinase IV modulate NMDA receptor splicing through two essential RNA elements. PLoS biology 86 17298178
1996 CaM kinase II in long-term potentiation. Neurochemistry international 86 8740440
2008 L1-CAM in cancerous tissues. Expert opinion on biological therapy 85 18847309
1991 Regulation of Cl- channels by multifunctional CaM kinase. Neuron 77 1849722
2013 Mechanism for KRIT1 release of ICAP1-mediated suppression of integrin activation. Molecular cell 72 23317506
2000 Mutations in KRIT1 in familial cerebral cavernous malformations. Neurosurgery 70 10807272
2013 KRIT1 loss of function causes a ROS-dependent upregulation of c-Jun. Free radical biology & medicine 68 24291398
2007 Interaction between krit1 and malcavernin: implications for the pathogenesis of cerebral cavernous malformations. Neurosurgery 66 17290187
1998 CaM kinase II as frequency decoder of Ca2+ oscillations. BioEssays : news and reviews in molecular, cellular and developmental biology 66 9780834
2002 Cerebral cavernous malformations: mutations in Krit1. Neurology 58 11914398
2014 KRIT1 protein depletion modifies endothelial cell behavior via increased vascular endothelial growth factor (VEGF) signaling. The Journal of biological chemistry 57 25320085
1991 C-CAM (cell-CAM 105)--a member of the growing immunoglobulin superfamily of cell adhesion proteins. BioEssays : news and reviews in molecular, cellular and developmental biology 55 1892475
2010 Mutation analysis of CCM1, CCM2 and CCM3 genes in a cohort of Italian patients with cerebral cavernous malformation. Brain pathology (Zurich, Switzerland) 54 21029238
2016 CaM/BAG5/Hsc70 signaling complex dynamically regulates leaf senescence. Scientific reports 53 27539741
2015 L1-CAM and N-CAM: From Adhesion Proteins to Pharmacological Targets. Trends in pharmacological sciences 53 26478212
2005 Nuclear Ca2+ and CaM kinase IV specify hormonal- and Notch-responsiveness. Journal of neurochemistry 53 15773917
2002 Mutation and expression analysis of the KRIT1 gene associated with cerebral cavernous malformations (CCM1). Acta neuropathologica 52 12172908
2018 Heg1 and Ccm1/2 proteins control endocardial mechanosensitivity during zebrafish valvulogenesis. eLife 50 29364115
2017 Up-regulation of NADPH oxidase-mediated redox signaling contributes to the loss of barrier function in KRIT1 deficient endothelium. Scientific reports 50 28811547
2012 Structural basis for small G protein effector interaction of Ras-related protein 1 (Rap1) and adaptor protein Krev interaction trapped 1 (KRIT1). The Journal of biological chemistry 47 22577140
2015 Neurogranin regulates CaM dynamics at dendritic spines. Scientific reports 46 26084473
2005 The shed ectodomain of Nr-CAM stimulates cell proliferation and motility, and confers cell transformation. Cancer research 46 16357171
2018 The CCM1-CCM2 complex controls complementary functions of ROCK1 and ROCK2 that are required for endothelial integrity. Journal of cell science 42 30030370
2009 L1-CAM as a target for treatment of cancer with monoclonal antibodies. Anticancer research 41 20044598
2005 CCM2 expression parallels that of CCM1. Stroke 41 16373645
2002 Krit1/cerebral cavernous malformation 1 mRNA is preferentially expressed in neurons and epithelial cells in embryo and adult. Mechanisms of development 40 12204286
2001 Computational and experimental analyses reveal previously undetected coding exons of the KRIT1 (CCM1) gene. Genomics 40 11161805
1991 Expression of polysialylated N-CAM during rat heart development. Differentiation; research in biological diversity 40 1955110
1997 Cell signalling and CAM-mediated neurite outgrowth. Society of General Physiologists series 39 9210232
2001 Germline mutations in the CCM1 gene, encoding Krit1, cause cerebral cavernous malformations. Annals of neurology 38 11310633
2023 The CAM lineages of planet Earth. Annals of botany 37 37698538
2010 Ccm1 regulates microvascular morphogenesis during angiogenesis. Journal of vascular research 37 20926893
2020 Cadherins, Selectins, and Integrins in CAM-DR in Leukemia. Frontiers in oncology 36 33425742
2017 Hepatic Activation of the FAM3C-HSF1-CaM Pathway Attenuates Hyperglycemia of Obese Diabetic Mice. Diabetes 36 28246289
2008 Krit1 modulates beta 1-integrin-mediated endothelial cell proliferation. Neurosurgery 35 18812969
2014 PTEN/PI3K/Akt/VEGF signaling and the cross talk to KRIT1, CCM2, and PDCD10 proteins in cerebral cavernous malformations. Neurosurgical review 34 25403688
2015 CaM Kinases: From Memories to Addiction. Trends in pharmacological sciences 33 26674562
2019 Understanding trait diversity associated with crassulacean acid metabolism (CAM). Current opinion in plant biology 30 31284077
2019 KRIT1 Deficiency Promotes Aortic Endothelial Dysfunction. International journal of molecular sciences 29 31590384
2022 Gene co-expression reveals the modularity and integration of C4 and CAM in Portulaca. Plant physiology 28 35285495
2020 Ca2+-CaM Dependent Inactivation of RyR2 Underlies Ca2+ Alternans in Intact Heart. Circulation research 28 33375811
2004 CAM and NK Cells. Evidence-based complementary and alternative medicine : eCAM 28 15257322
2015 Activity dependent CAM cleavage and neurotransmission. Frontiers in cellular neuroscience 25 26321910
2018 Grip and slip of L1-CAM on adhesive substrates direct growth cone haptotaxis. Proceedings of the National Academy of Sciences of the United States of America 24 29483251
2011 Cell adhesion molecules in context: CAM function depends on the neighborhood. Cell adhesion & migration 24 20948304
2022 NOGOB receptor deficiency increases cerebrovascular permeability and hemorrhage via impairing histone acetylation-mediated CCM1/2 expression. The Journal of clinical investigation 22 35316220
2013 miR-21 coordinates tumor growth and modulates KRIT1 levels. Biochemical and biophysical research communications 22 23872064
2017 Reduced CaM Kinase II and CaM Kinase IV Activities Underlie Cognitive Deficits in NCKX2 Heterozygous Mice. Molecular neurobiology 20 28547530
2014 Genomic analyses of the CAM plant pineapple. Journal of experimental botany 19 24692645
2020 Biosystems Design to Accelerate C3-to-CAM Progression. Biodesign research 18 37849902
2012 CaM kinase control of AKT and LNCaP cell survival. Journal of cellular biochemistry 18 22173970
2016 Australia lacks stem succulents but is it depauperate in plants with crassulacean acid metabolism (CAM)? Current opinion in plant biology 17 27088716
2022 Proteomic Analysis of Chicken Chorioallantoic Membrane (CAM) during Embryonic Development Provides Functional Insight. BioMed research international 16 35774275
2021 The CAM assay in the study of the metastatic process. Experimental cell research 16 33524363
2021 Inhibition of the HEG1-KRIT1 interaction increases KLF4 and KLF2 expression in endothelial cells. FASEB bioAdvances 16 33977234
2019 CaM kinase II regulates cardiac hemoglobin expression through histone phosphorylation upon sympathetic activation. Proceedings of the National Academy of Sciences of the United States of America 16 31619570
2017 MicroRNA-1185 Induces Endothelial Cell Apoptosis by Targeting UVRAG and KRIT1. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 16 28441650
2017 Novel functions of CCM1 delimit the relationship of PTB/PH domains. Biochimica et biophysica acta. Proteins and proteomics 16 28698152
2016 CRISPR-Cas-Assisted Multiplexing (CAM): Simple Same-Day Multi-Locus Engineering in Yeast. Journal of cellular physiology 16 26991244
2021 KRIT1 Gene in Patients with Cerebral Cavernous Malformations: Clinical Features and Molecular Characterization of Novel Variants. Journal of molecular neuroscience : MN 15 33651268
2020 KRIT1 loss-mediated upregulation of NOX1 in stromal cells promotes paracrine pro-angiogenic responses. Cellular signalling 15 31917192
2003 Mel-CAM (CD146) expression in parotid mucoepidermoid carcinoma. Oral oncology 15 12618200
2003 Extracellular crosstalk: when GDNF meets N-CAM. Cell 15 12837237
2023 Gene duplications facilitate C4-CAM compatibility in common purslane. Plant physiology 14 37587696

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