{"gene":"KRIT1","run_date":"2026-04-28T18:30:27","timeline":{"discoveries":[{"year":1997,"finding":"KRIT1 (Krev Interaction Trapped 1) was identified as a binding partner of Krev-1/Rap1A GTPase via yeast two-hybrid screening of a HeLa cell cDNA library. The protein contains an N-terminal ankyrin repeat domain and a C-terminal domain; it interacts strongly with Krev-1/Rap1A but only weakly with Ras, suggesting specificity for Rap1A signaling.","method":"Yeast two-hybrid screen, domain mapping","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1 — original discovery by two-hybrid with domain mapping, foundational paper replicated by subsequent studies","pmids":["9285558"],"is_preprint":false},{"year":1999,"finding":"Truncating mutations in CCM1, which encodes KRIT1, cause hereditary cerebral cavernous angiomas (CCM1 families), establishing loss-of-function of KRIT1 as the molecular basis of CCM1 disease and implicating the RAP1A signal transduction pathway in vasculogenesis or angiogenesis.","method":"Positional cloning, mutation analysis in CCM1 families","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 — mutation identification in human families, independently replicated","pmids":["10508515"],"is_preprint":false},{"year":2002,"finding":"KRIT1 associates with integrin cytoplasmic domain-associated protein-1 (ICAP-1) via an NPXY motif at the N-terminus of KRIT1; mutagenesis of this NPXY sequence completely abrogates the KRIT1/ICAP-1 interaction, suggesting KRIT1 is involved in integrin-cytoskeleton signaling.","method":"Yeast two-hybrid screening, GST pulldown of endogenous ICAP-1 from 293T cells, site-directed mutagenesis","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1/2 — multiple orthogonal methods including in vitro pulldown and mutagenesis confirming interaction site","pmids":["11854171"],"is_preprint":false},{"year":2002,"finding":"KRIT1 colocalizes with microtubules in endothelial cells during interphase and localizes to spindle pole bodies, mitotic spindle, and microtubule plus ends during mitosis, establishing KRIT1 as a microtubule-associated protein potentially involved in microtubule targeting and endothelial cell shape.","method":"Immunofluorescence microscopy, coimmunoprecipitation with anti-KRIT1 antibodies in endothelial cells","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP and direct imaging, single lab, but orthogonal methods used","pmids":["12140362"],"is_preprint":false},{"year":2007,"finding":"KRIT1 is a Rap1 effector in endothelial cells: KRIT1 is present at cell-cell junctions via its FERM domain, colocalizes and physically associates with junctional proteins, and Rap1 activity regulates junctional localization of KRIT1. KRIT1 depletion by siRNA blocks Rap1-mediated stabilization of endothelial junctions and leads to increased actin stress fibers.","method":"Co-immunoprecipitation, siRNA knockdown, immunofluorescence, Rap1 activation assays in endothelial cells","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, domain mapping, clean KD with defined cellular phenotype, Rap1 manipulation","pmids":["17954608"],"is_preprint":false},{"year":2007,"finding":"KRIT1 interacts with CCM2 (malcavernin) through its NPXY motifs; malcavernin independently binds to two of the three NPXY motifs in KRIT1, and at steady state malcavernin shuttles between nucleus and cytoplasm, with KRIT1 potentially regulating its nuclear localization.","method":"Yeast two-hybrid, in vivo coimmunoprecipitation, epitope mapping, immunocytochemistry","journal":"Neurosurgery","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal Co-IP with epitope mapping, single lab","pmids":["17290187"],"is_preprint":false},{"year":2008,"finding":"Loss of ccm1 in zebrafish embryos leads to severe progressive dilation of major vessels with endothelial cell spreading and thinning of vessel walls despite normal cell-cell contacts; ccm1 function is cell-autonomous in endothelial cells, establishing that CCM1 regulates endothelial cellular morphogenesis.","method":"Zebrafish genetic mutant analysis, mosaic rescue experiments, electron microscopy, cell transplantation","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — genetic loss-of-function in vertebrate model with cell-autonomous rescue, orthogonal morphological analyses","pmids":["18469344"],"is_preprint":false},{"year":2008,"finding":"KRIT1 depletion reduces endothelial cell proliferation and decreases phosphorylation along the β1-integrin/FAK/ERK/MAPK pathway; KRIT1 colocalizes with ICAP-1α in nucleus and cytoplasm and stabilizes/shuttles ICAP-1α, modulating β1-integrin-mediated signal transduction.","method":"siRNA knockdown in HeLa, HUVEC, and microvascular endothelial cells; western blot for pathway phosphorylation; immunocytochemistry","journal":"Neurosurgery","confidence":"Medium","confidence_rationale":"Tier 2 — clean KD with defined signaling phenotype, colocalization, single lab","pmids":["18812969"],"is_preprint":false},{"year":2009,"finding":"KRIT1 and Rap1 are negative regulators of canonical β-catenin signaling; depletion of endothelial KRIT1 causes β-catenin to dissociate from VE-cadherin and accumulate in the nucleus with increased β-catenin-dependent transcription. This effect requires intact cell-cell junctions and KRIT1. Hemizygous Krit1 deficiency in vivo increases intestinal polyps in ApcMin/+ mice.","method":"siRNA knockdown, Rap1 activation, β-catenin reporter assays, ApcMin/+ mouse cross, nuclear fractionation","journal":"Disease models & mechanisms","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods in vitro and in vivo, pathway placement via epistasis and reporter assay","pmids":["20007487"],"is_preprint":false},{"year":2010,"finding":"CCM1/KRIT1 inhibits sprouting angiogenesis by strongly inducing DLL4-NOTCH signaling in endothelial cells, promoting AKT phosphorylation while reducing ERK phosphorylation; blocking NOTCH activity alleviates CCM1 effects. Loss of CCM1 leads to excessive capillary sprouting.","method":"siRNA knockdown in primary human endothelial cells, SCID mouse xenograft model, NOTCH pathway inhibition, phosphorylation assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — pathway rescue by NOTCH inhibition, in vitro and in vivo, multiple orthogonal methods","pmids":["20616044"],"is_preprint":false},{"year":2013,"finding":"Crystal structures of KRIT1 bound to ICAP1 and ICAP1 bound to integrin β1 cytoplasmic tail were solved to 2.54 Å and 3.0 Å resolution. KRIT1 binds ICAP1 via a bidentate surface that directly competes with integrin β1, antagonizing ICAP1-mediated suppression of integrin inside-out activation. KRIT1 also contains an N-terminal Nudix domain previously considered unstructured.","method":"X-ray crystallography (co-crystal structures), competition binding assays, integrin activation functional assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 — crystal structures with functional validation and competition assay, single rigorous study with multiple orthogonal methods","pmids":["23317506"],"is_preprint":false},{"year":2013,"finding":"The CCM1-ICAP-1 complex controls β1 integrin-dependent endothelial contractility and ECM remodeling; loss of CCM1/2 destabilizes ICAP-1, increases β1 integrin activation, and leads to increased RhoA-dependent contractility and aberrant fibronectin remodeling, destabilizing endothelial barrier function via a positive feedback loop between aberrant ECM and cellular tension.","method":"siRNA knockdown, traction force microscopy, β1 integrin activation assays, CCM1/2 mouse models, RhoA activity assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods in vitro and in vivo mouse models, pathway dissection with mechanistic follow-up","pmids":["23918940"],"is_preprint":false},{"year":2014,"finding":"Loss of KRIT1 (but not CCM2) increases nuclear β-catenin signaling and up-regulates VEGF-A protein expression in endothelial cells; increased VEGF-A leads to VEGFR2 activation with consequent altered cytoskeletal organization, migration, barrier function, and in vivo endothelial permeability in KRIT1-deficient animals.","method":"siRNA knockdown, western blot, VEGFR2 signaling assays, β-catenin reporter, in vivo permeability measurements in Krit1+/- mice","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — in vitro and in vivo experiments, pathway dissection, multiple orthogonal methods","pmids":["25320085"],"is_preprint":false},{"year":2017,"finding":"KRIT1 depletion increases endothelial ROS production via NADPH oxidase/Nox4 signaling and NF-κB-dependent promoter activity, directly contributing to loss of barrier function; targeted antioxidant delivery reversed permeability increases in KRIT1 heterozygous mice in vivo.","method":"siRNA knockdown, intravital microscopy in Krit1+/- mice with targeted antioxidant enzymes, Nox4 expression analysis, NF-κB reporter assay","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 — in vitro and in vivo rescue experiments, mechanistic pathway identification, multiple methods","pmids":["28811547"],"is_preprint":false},{"year":2018,"finding":"Zebrafish Krit1 regulates cardiac valve formation; HEG1 expression is induced by blood flow, Heg1 stabilizes Krit1 protein levels, and Heg1/Krit1 dampen mechanosensitive klf2a expression. Loss of Krit1 increases klf2a and notch1b throughout the endocardium and prevents valve leaflet formation.","method":"Zebrafish genetic mutants, morpholino knockdown, blood flow manipulation, in situ hybridization, protein level analysis","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis in zebrafish, mechanosensitive pathway placement, multiple orthogonal methods","pmids":["29364115"],"is_preprint":false},{"year":2018,"finding":"The CCM1-CCM2 complex controls complementary functions of ROCK1 and ROCK2: CCM proteins act as a scaffold promoting ROCK2 interactions with VE-cadherin and limiting ROCK1 kinase activity. Loss of CCM1 produces excessive ROCK1-dependent actin stress fibers; silencing ROCK1 (but not ROCK2) restores endothelial homeostasis and rescues ccm1 mutant zebrafish cardiovascular defects.","method":"siRNA knockdown of CCM1/CCM2 and ROCK isoforms, traction force microscopy, VE-cadherin co-IP, zebrafish ccm1 mutant rescue experiments","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — isoform-specific genetic epistasis in vitro and in zebrafish, Co-IP, mechanistic pathway placement","pmids":["30030370"],"is_preprint":false},{"year":2021,"finding":"HEG1 directly binds to and recruits KRIT1 to endothelial junctions via the KRIT1 FERM domain; a crystal structure of a small-molecule HEG1-KRIT1 inhibitor (HKi2) bound to the KRIT1 FERM domain revealed it occupies the same binding pocket as the HEG1 cytoplasmic tail. Acute inhibition of HEG1-KRIT1 interaction increases KLF4 and KLF2 expression and activates Akt signaling in endothelial cells.","method":"High-throughput screening, crystal structure of inhibitor-KRIT1 FERM complex, in vitro colocalization assay, endothelial cell reporter assays, zebrafish klf2a expression analysis","journal":"FASEB bioAdvances","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with functional validation in vitro and in vivo, multiple orthogonal methods","pmids":["33977234"],"is_preprint":false},{"year":2017,"finding":"CCM1/KRIT1 contains three NPXY motifs that interact with a spectrum of PTB and PH domain-containing proteins; the KRIT1 F3 lobe of the FERM domain acts as a functional PH domain to interact with NPXY motifs, and KRIT1 can form oligomers through intermolecular interaction between its F3 FERM lobe and an NPXY motif. Twenty-eight novel cellular partners of CCM1 containing PTB or PH domains were identified.","method":"Molecular cloning, protein binding assays, structural simulation combined with existing X-ray crystallography and NMR data, RT-qPCR","journal":"Biochimica et biophysica acta. Proteins and proteomics","confidence":"Medium","confidence_rationale":"Tier 3 — binding assays with structural modeling, single lab, limited functional validation","pmids":["28698152"],"is_preprint":false},{"year":2022,"finding":"NGBR (NOGOB receptor) is required for maintaining CCM1/2 expression in endothelial cells via HBO1-mediated histone H4 acetylation; loss of NGBR reduces HBO1 and histone acetylation at CCM1 and CCM2 promoters (H4K5 and H4K12), resulting in CCM1/2 deficiency and cerebrovascular lesions.","method":"Endothelial-specific Ngbr knockout mice, RNA-seq, ChIP-qPCR for HBO1 and acetylated histone H4K5/H4K12 at CCM1/CCM2 promoters","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 — ChIP-qPCR mechanistic evidence for epigenetic regulation, in vivo mouse model, RNA-seq","pmids":["35316220"],"is_preprint":false}],"current_model":"KRIT1 is a multidomain scaffold protein (containing ankyrin repeats, a Nudix domain, three NPXY motifs, and a FERM domain) that functions as a Rap1 GTPase effector at endothelial cell-cell junctions, where it suppresses actin stress fibers, stabilizes junctional integrity via VE-cadherin and β-catenin, antagonizes ICAP-1-mediated β1-integrin inside-out activation by competing with integrin β1 for ICAP-1 binding, restrains canonical Wnt/β-catenin transcription, activates DLL4-Notch signaling to maintain endothelial quiescence, controls ROCK1/ROCK2 balance in the endothelium, dampens mechanosensitive KLF2/KLF4 expression downstream of HEG1, and limits NADPH oxidase/Nox4-driven ROS production; loss-of-function of KRIT1 leads to increased RhoA/ROCK1-dependent contractility, aberrant ECM remodeling, excessive VEGF-A/VEGFR2 and β-catenin signaling, and pathological vascular dilation underlying cerebral cavernous malformations."},"narrative":{"teleology":[{"year":1997,"claim":"The identity of KRIT1 as a Rap1A-interacting protein was unknown; yeast two-hybrid screening revealed that KRIT1 specifically binds Krev-1/Rap1A but not Ras, establishing it as a candidate Rap1 effector with ankyrin repeats and a C-terminal domain.","evidence":"Yeast two-hybrid screen of HeLa cDNA library with domain mapping","pmids":["9285558"],"confidence":"High","gaps":["No cellular function assigned","No endothelial context established","Mechanism of Rap1 effector function unknown"]},{"year":1999,"claim":"The genetic basis of hereditary cerebral cavernous malformations (CCM1) was unresolved; positional cloning identified truncating mutations in KRIT1/CCM1 in affected families, establishing loss-of-function of KRIT1 as the cause of CCM1 disease.","evidence":"Positional cloning and mutation analysis in CCM1 families","pmids":["10508515"],"confidence":"High","gaps":["No mechanism linking KRIT1 loss to vascular phenotype","Downstream signaling pathways unknown"]},{"year":2002,"claim":"How KRIT1 connects to integrin signaling was unknown; identification of the KRIT1–ICAP-1 interaction via an NPXY motif, combined with its microtubule association in endothelial cells, placed KRIT1 at the interface of integrin-cytoskeletal signaling.","evidence":"Yeast two-hybrid, GST pulldown, site-directed mutagenesis (ICAP-1 interaction); immunofluorescence and co-IP in endothelial cells (microtubule association)","pmids":["11854171","12140362"],"confidence":"High","gaps":["Role at cell-cell junctions not yet identified","Functional consequence of ICAP-1 binding on integrin activation unknown"]},{"year":2007,"claim":"Whether KRIT1 functions as a true Rap1 effector at endothelial junctions was untested; KRIT1 was shown to localize to cell-cell junctions via its FERM domain under Rap1 control, and its depletion blocked Rap1-mediated junction stabilization and increased stress fibers, while CCM2 was identified as an additional NPXY-dependent partner.","evidence":"Co-IP, siRNA knockdown, Rap1 activation assays in endothelial cells; yeast two-hybrid and co-IP for CCM2 interaction","pmids":["17954608","17290187"],"confidence":"High","gaps":["Downstream transcriptional consequences of junction destabilization unknown","ROCK isoform specificity not addressed"]},{"year":2009,"claim":"Whether KRIT1 regulates transcriptional signaling beyond junction stability was unknown; KRIT1 depletion was shown to cause β-catenin dissociation from VE-cadherin, nuclear accumulation, and increased β-catenin-dependent transcription, with in vivo validation in ApcMin/+ mice.","evidence":"siRNA knockdown, β-catenin reporter assays, nuclear fractionation, ApcMin/+ mouse cross","pmids":["20007487"],"confidence":"High","gaps":["Specific transcriptional targets of β-catenin in CCM context not fully defined","Connection to VEGF-A upregulation not yet made"]},{"year":2010,"claim":"How KRIT1 controls angiogenic sprouting was unclear; KRIT1 was found to suppress sprouting angiogenesis by inducing DLL4-Notch signaling, with Notch inhibition rescuing the effect, linking KRIT1 to endothelial quiescence control.","evidence":"siRNA knockdown in endothelial cells, SCID mouse xenograft model, Notch pathway inhibition, phosphorylation assays","pmids":["20616044"],"confidence":"High","gaps":["Whether Notch induction is direct or secondary to β-catenin signaling unclear","Interplay with VEGF signaling not resolved"]},{"year":2013,"claim":"The structural basis of KRIT1–ICAP-1 competition with integrin β1 was unknown; co-crystal structures revealed KRIT1 binds ICAP-1 via a bidentate surface that directly competes with the integrin β1 tail, and loss of CCM1 was shown to destabilize ICAP-1, increase β1-integrin activation, RhoA-dependent contractility, and aberrant fibronectin remodeling.","evidence":"X-ray crystallography at 2.54 Å and 3.0 Å resolution, competition binding assays, traction force microscopy, β1-integrin activation assays, CCM mouse models","pmids":["23317506","23918940"],"confidence":"High","gaps":["Structural basis of KRIT1-Rap1 interaction at junctions not resolved","Whether ICAP-1 destabilization is sufficient to drive CCM lesions alone unclear"]},{"year":2014,"claim":"The link between KRIT1 loss, β-catenin transcription, and autocrine VEGF signaling was not established; KRIT1 depletion was shown to upregulate VEGF-A via nuclear β-catenin, activating VEGFR2 and altering cytoskeletal organization and barrier function in vitro and in vivo.","evidence":"siRNA knockdown, western blot, VEGFR2 signaling assays, β-catenin reporter, in vivo permeability in Krit1+/- mice","pmids":["25320085"],"confidence":"High","gaps":["Therapeutic targeting of VEGF pathway in CCM not tested","Contribution of VEGF versus other β-catenin targets to lesion formation unknown"]},{"year":2017,"claim":"The roles of ROS and ROCK isoform balance downstream of KRIT1 loss were uncharacterized; KRIT1 depletion was found to increase Nox4/NADPH oxidase-driven ROS and NF-κB activity (rescued by targeted antioxidants in vivo), and KRIT1 oligomerization via NPXY-FERM interactions was demonstrated, expanding the KRIT1 interactome to 28 PTB/PH-domain proteins.","evidence":"siRNA knockdown, intravital microscopy in Krit1+/- mice with targeted antioxidant rescue, Nox4 expression analysis; molecular cloning and binding assays with structural modeling","pmids":["28811547","28698152"],"confidence":"High","gaps":["Functional significance of KRIT1 oligomerization in vivo untested","Relative contribution of ROS versus contractility to barrier loss not delineated"]},{"year":2018,"claim":"How KRIT1 integrates mechanosensing and ROCK isoform balance was unclear; HEG1 was shown to stabilize Krit1 to dampen flow-induced klf2a expression and regulate cardiac valve formation, while the CCM1-CCM2 complex was found to scaffold ROCK2 at VE-cadherin and restrain ROCK1, with ROCK1 silencing rescuing ccm1 mutant zebrafish.","evidence":"Zebrafish genetic mutants with flow manipulation; isoform-specific siRNA knockdown, traction force microscopy, VE-cadherin co-IP, zebrafish rescue experiments","pmids":["29364115","30030370"],"confidence":"High","gaps":["Direct mechanosensor identity upstream of KRIT1 in mammalian endothelium unresolved","Structural basis of ROCK1 versus ROCK2 selectivity by CCM complex unknown"]},{"year":2021,"claim":"How HEG1 recruits KRIT1 at the structural level was not defined; a crystal structure of a small-molecule inhibitor bound to the KRIT1 FERM domain confirmed the HEG1 cytoplasmic tail binding pocket, and acute pharmacological disruption increased KLF2/KLF4 and Akt signaling.","evidence":"High-throughput screening, crystal structure of inhibitor–KRIT1 FERM complex, endothelial reporter assays, zebrafish klf2a expression analysis","pmids":["33977234"],"confidence":"High","gaps":["In vivo pharmacological modulation in mammalian CCM models not demonstrated","Full structural model of KRIT1 in complex with Rap1 and HEG1 simultaneously lacking"]},{"year":2022,"claim":"How KRIT1 expression itself is epigenetically regulated was unknown; NGBR was shown to maintain CCM1/CCM2 transcription via HBO1-mediated H4K5/H4K12 acetylation at their promoters, with NGBR loss in endothelial cells phenocopying CCM.","evidence":"Endothelial-specific Ngbr knockout mice, RNA-seq, ChIP-qPCR for HBO1 and acetylated histones at CCM1/CCM2 promoters","pmids":["35316220"],"confidence":"High","gaps":["Whether HBO1-mediated regulation is specific to endothelial cells or general is untested","Chromatin accessibility landscape at the KRIT1 locus not mapped"]},{"year":null,"claim":"A complete structural model of the full-length KRIT1 protein in complex with Rap1, HEG1, and CCM2 simultaneously is lacking, and the relative contributions of individual KRIT1-regulated pathways (β-catenin, ROCK1, Nox4/ROS, integrin activation) to CCM lesion initiation versus progression remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No full-length KRIT1 structure available","Pathway hierarchy in CCM pathogenesis not established by epistasis in mammalian models","Whether KRIT1 oligomerization is required for in vivo function untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,4,10,15]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[8,9,11,13]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[4,16]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[3]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[7]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,4,8,9,12]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[4,8,15]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[6,14]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,6,11]}],"complexes":["CCM1-CCM2 complex"],"partners":["RAP1A","ICAP1","CCM2","HEG1","ROCK1","ROCK2","CTNNB1","CDH5"],"other_free_text":[]},"mechanistic_narrative":"KRIT1 is a multidomain scaffold protein that functions as a Rap1 GTPase effector at endothelial cell-cell junctions, where it suppresses stress fiber formation, stabilizes VE-cadherin/β-catenin complexes, restrains canonical Wnt/β-catenin transcription, and limits sprouting angiogenesis through DLL4-Notch signaling [PMID:17954608, PMID:20007487, PMID:20616044]. Structurally, KRIT1 contains ankyrin repeats, a Nudix domain, three NPXY motifs, and a FERM domain; the FERM domain mediates junctional recruitment by HEG1 and Rap1, while the NPXY motifs bind ICAP-1 and CCM2, with crystal structures demonstrating that KRIT1 antagonizes ICAP-1-mediated β1-integrin inside-out activation by competing for the same binding surface [PMID:23317506, PMID:33977234, PMID:11854171]. Loss of KRIT1 deregulates ROCK1-dependent contractility, increases NADPH oxidase/Nox4-driven ROS production and NF-κB activity, elevates VEGF-A/VEGFR2 signaling, and disrupts mechanosensitive KLF2/KLF4 dampening downstream of HEG1, collectively compromising endothelial barrier integrity and vascular morphogenesis [PMID:30030370, PMID:28811547, PMID:25320085, PMID:29364115]. Truncating mutations in KRIT1 (CCM1) cause hereditary cerebral cavernous malformations [PMID:10508515]."},"prefetch_data":{"uniprot":{"accession":"O00522","full_name":"Krev interaction trapped protein 1","aliases":["Cerebral cavernous malformations 1 protein"],"length_aa":736,"mass_kda":84.3,"function":"Component of the CCM signaling pathway which is a crucial regulator of heart and vessel formation and integrity (By similarity). Negative regulator of angiogenesis. Inhibits endothelial proliferation, apoptosis, migration, lumen formation and sprouting angiogenesis in primary endothelial cells. Promotes AKT phosphorylation in a NOTCH-dependent and independent manner, and inhibits ERK1/2 phosphorylation indirectly through activation of the DELTA-NOTCH cascade. Acts in concert with CDH5 to establish and maintain correct endothelial cell polarity and vascular lumen and these effects are mediated by recruitment and activation of the Par polarity complex and RAP1B. Required for the localization of phosphorylated PRKCZ, PARD3, TIAM1 and RAP1B to the cell junction, and cell junction stabilization. Plays a role in integrin signaling via its interaction with ITGB1BP1; this prevents the interaction between ITGB1 and ITGB1BP1. Microtubule-associated protein that binds to phosphatidylinositol 4,5-bisphosphate (PIP2)-containing membranes in a GTP-bound RAP1-dependent manner. Plays an important role in the maintenance of the intracellular reactive oxygen species (ROS) homeostasis to prevent oxidative cellular damage. Regulates the homeostasis of intracellular ROS through an antioxidant pathway involving FOXO1 and SOD2. Facilitates the down-regulation of cyclin-D1 (CCND1) levels required for cell transition from proliferative growth to quiescence by preventing the accumulation of intracellular ROS through the modulation of FOXO1 and SOD2 levels. May play a role in the regulation of macroautophagy through the down-regulation of the mTOR pathway (PubMed:26417067)","subcellular_location":"Cytoplasm, cytoskeleton; Cell membrane; Cell junction","url":"https://www.uniprot.org/uniprotkb/O00522/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KRIT1","classification":"Not Classified","n_dependent_lines":8,"n_total_lines":1208,"dependency_fraction":0.006622516556291391},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ITPR3","stoichiometry":0.2},{"gene":"PTGES3","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/KRIT1","total_profiled":1310},"omim":[{"mim_id":"619538","title":"CEREBRAL CAVERNOUS MALFORMATIONS 4; CCM4","url":"https://www.omim.org/entry/619538"},{"mim_id":"614182","title":"HEART DEVELOPMENT PROTEIN WITH EGF-LIKE DOMAINS 1; HEG1","url":"https://www.omim.org/entry/614182"},{"mim_id":"609118","title":"PROGRAMMED CELL DEATH 10; PDCD10","url":"https://www.omim.org/entry/609118"},{"mim_id":"608354","title":"CAPILLARY MALFORMATION-ARTERIOVENOUS MALFORMATION 1; CMAVM1","url":"https://www.omim.org/entry/608354"},{"mim_id":"607929","title":"CCM2 SCAFFOLD PROTEIN; CCM2","url":"https://www.omim.org/entry/607929"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Vesicles","reliability":"Uncertain"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/KRIT1"},"hgnc":{"alias_symbol":["CAM"],"prev_symbol":["CCM1"]},"alphafold":{"accession":"O00522","domains":[{"cath_id":"3.30.70.2240","chopping":"9-179","consensus_level":"high","plddt":80.3739,"start":9,"end":179},{"cath_id":"1.25.40.20","chopping":"283-416","consensus_level":"high","plddt":94.4461,"start":283,"end":416},{"cath_id":"3.10.20.90","chopping":"422-515","consensus_level":"high","plddt":96.0553,"start":422,"end":515},{"cath_id":"1.20.80.10","chopping":"547-631","consensus_level":"high","plddt":95.0764,"start":547,"end":631},{"cath_id":"2.30.29.30","chopping":"639-730","consensus_level":"high","plddt":90.1114,"start":639,"end":730}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O00522","model_url":"https://alphafold.ebi.ac.uk/files/AF-O00522-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O00522-F1-predicted_aligned_error_v6.png","plddt_mean":82.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KRIT1","jax_strain_url":"https://www.jax.org/strain/search?query=KRIT1"},"sequence":{"accession":"O00522","fasta_url":"https://rest.uniprot.org/uniprotkb/O00522.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O00522/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O00522"}},"corpus_meta":[{"pmid":"9422695","id":"PMC_9422695","title":"Sensitivity of CaM kinase II to the frequency of Ca2+ oscillations.","date":"1998","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/9422695","citation_count":1032,"is_preprint":false},{"pmid":"7530878","id":"PMC_7530878","title":"The CaM kinase II hypothesis for the storage of synaptic memory.","date":"1994","source":"Trends in neurosciences","url":"https://pubmed.ncbi.nlm.nih.gov/7530878","citation_count":421,"is_preprint":false},{"pmid":"11264466","id":"PMC_11264466","title":"Ca(2+)/CaM-dependent kinases: from activation to function.","date":"2001","source":"Annual review of pharmacology and toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/11264466","citation_count":411,"is_preprint":false},{"pmid":"10508515","id":"PMC_10508515","title":"Truncating mutations in CCM1, encoding KRIT1, cause hereditary cavernous angiomas.","date":"1999","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10508515","citation_count":367,"is_preprint":false},{"pmid":"26523774","id":"PMC_26523774","title":"The pineapple genome and the evolution of CAM photosynthesis.","date":"2015","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26523774","citation_count":344,"is_preprint":false},{"pmid":"7541632","id":"PMC_7541632","title":"Axonin-1, Nr-CAM, and Ng-CAM play different roles in the in vivo guidance of chick commissural neurons.","date":"1995","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/7541632","citation_count":290,"is_preprint":false},{"pmid":"31394063","id":"PMC_31394063","title":"CaM Kinase: Still Inspiring at 40.","date":"2019","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/31394063","citation_count":272,"is_preprint":false},{"pmid":"17954608","id":"PMC_17954608","title":"KRIT-1/CCM1 is a Rap1 effector that regulates endothelial cell cell junctions.","date":"2007","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/17954608","citation_count":265,"is_preprint":false},{"pmid":"10451481","id":"PMC_10451481","title":"The role of CD146 (Mel-CAM) in biology and pathology.","date":"1999","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/10451481","citation_count":202,"is_preprint":false},{"pmid":"10398165","id":"PMC_10398165","title":"Expression of Ep-CAM in normal, regenerating, metaplastic, and neoplastic liver.","date":"1999","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/10398165","citation_count":180,"is_preprint":false},{"pmid":"9285558","id":"PMC_9285558","title":"Association of Krev-1/rap1a with Krit1, a novel ankyrin repeat-containing protein encoded by a gene mapping to 7q21-22.","date":"1997","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/9285558","citation_count":178,"is_preprint":false},{"pmid":"15150072","id":"PMC_15150072","title":"Ecophysiology of Crassulacean Acid Metabolism (CAM).","date":"2004","source":"Annals of botany","url":"https://pubmed.ncbi.nlm.nih.gov/15150072","citation_count":173,"is_preprint":false},{"pmid":"20616044","id":"PMC_20616044","title":"Cerebral cavernous malformation protein CCM1 inhibits sprouting angiogenesis by activating DELTA-NOTCH signaling.","date":"2010","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/20616044","citation_count":165,"is_preprint":false},{"pmid":"11854171","id":"PMC_11854171","title":"KRIT1 association with the integrin-binding protein ICAP-1: a new direction in the elucidation of cerebral cavernous malformations (CCM1) pathogenesis.","date":"2002","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/11854171","citation_count":159,"is_preprint":false},{"pmid":"19088124","id":"PMC_19088124","title":"A two-hit mechanism causes cerebral cavernous malformations: complete inactivation of CCM1, CCM2 or CCM3 in affected endothelial cells.","date":"2008","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19088124","citation_count":155,"is_preprint":false},{"pmid":"7646896","id":"PMC_7646896","title":"Postsynaptic injection of CA2+/CaM induces synaptic potentiation requiring CaMKII and PKC activity.","date":"1995","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/7646896","citation_count":155,"is_preprint":false},{"pmid":"7982473","id":"PMC_7982473","title":"N-CAM and N-cadherin expression during in vitro chondrogenesis.","date":"1994","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/7982473","citation_count":151,"is_preprint":false},{"pmid":"10664617","id":"PMC_10664617","title":"The regulation of phosphoenolpyruvate carboxylase in CAM plants.","date":"2000","source":"Trends in plant science","url":"https://pubmed.ncbi.nlm.nih.gov/10664617","citation_count":137,"is_preprint":false},{"pmid":"24642847","id":"PMC_24642847","title":"Facultative crassulacean acid metabolism (CAM) plants: powerful tools for unravelling the functional elements of CAM photosynthesis.","date":"2014","source":"Journal of experimental botany","url":"https://pubmed.ncbi.nlm.nih.gov/24642847","citation_count":136,"is_preprint":false},{"pmid":"15235119","id":"PMC_15235119","title":"Expression profiling-based identification of CO2-responsive genes regulated by CCM1 controlling a carbon-concentrating mechanism in Chlamydomonas reinhardtii.","date":"2004","source":"Plant physiology","url":"https://pubmed.ncbi.nlm.nih.gov/15235119","citation_count":134,"is_preprint":false},{"pmid":"26153373","id":"PMC_26153373","title":"A roadmap for research on crassulacean acid metabolism (CAM) to enhance sustainable food and bioenergy production in a hotter, drier world.","date":"2015","source":"The New phytologist","url":"https://pubmed.ncbi.nlm.nih.gov/26153373","citation_count":134,"is_preprint":false},{"pmid":"15718512","id":"PMC_15718512","title":"Biallelic somatic and germ line CCM1 truncating mutations in a cerebral cavernous malformation lesion.","date":"2005","source":"Stroke","url":"https://pubmed.ncbi.nlm.nih.gov/15718512","citation_count":130,"is_preprint":false},{"pmid":"34088891","id":"PMC_34088891","title":"Cancer-secreted exosomal miR-21-5p induces angiogenesis and vascular permeability by targeting KRIT1.","date":"2021","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/34088891","citation_count":127,"is_preprint":false},{"pmid":"11287669","id":"PMC_11287669","title":"Ccm1, a regulatory gene controlling the induction of a carbon-concentrating mechanism in Chlamydomonas reinhardtii by sensing CO2 availability.","date":"2001","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/11287669","citation_count":118,"is_preprint":false},{"pmid":"3621349","id":"PMC_3621349","title":"Formation of heterotypic adherens-type junctions between L-CAM-containing liver cells and A-CAM-containing lens cells.","date":"1987","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/3621349","citation_count":106,"is_preprint":false},{"pmid":"27869799","id":"PMC_27869799","title":"Transcript, protein and metabolite temporal dynamics in the CAM plant Agave.","date":"2016","source":"Nature plants","url":"https://pubmed.ncbi.nlm.nih.gov/27869799","citation_count":104,"is_preprint":false},{"pmid":"21529938","id":"PMC_21529938","title":"Analysis of CaM-kinase signaling in cells.","date":"2011","source":"Cell calcium","url":"https://pubmed.ncbi.nlm.nih.gov/21529938","citation_count":100,"is_preprint":false},{"pmid":"20007487","id":"PMC_20007487","title":"Rap1 and its effector KRIT1/CCM1 regulate beta-catenin signaling.","date":"2009","source":"Disease models & mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/20007487","citation_count":98,"is_preprint":false},{"pmid":"3891323","id":"PMC_3891323","title":"Specific regulation of N-CAM/D2-CAM cell adhesion molecule during skeletal muscle development.","date":"1985","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/3891323","citation_count":98,"is_preprint":false},{"pmid":"17217938","id":"PMC_17217938","title":"Derepression of pathological cardiac genes by members of the CaM kinase superfamily.","date":"2006","source":"Cardiovascular research","url":"https://pubmed.ncbi.nlm.nih.gov/17217938","citation_count":97,"is_preprint":false},{"pmid":"12140362","id":"PMC_12140362","title":"KRIT1, a gene mutated in cerebral cavernous malformation, encodes a microtubule-associated protein.","date":"2002","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12140362","citation_count":94,"is_preprint":false},{"pmid":"15257325","id":"PMC_15257325","title":"Neurobiology of Acupuncture: Toward CAM.","date":"2004","source":"Evidence-based complementary and alternative medicine : eCAM","url":"https://pubmed.ncbi.nlm.nih.gov/15257325","citation_count":92,"is_preprint":false},{"pmid":"15509522","id":"PMC_15509522","title":"Loss of p53 sensitizes mice with a mutation in Ccm1 (KRIT1) to development of cerebral vascular malformations.","date":"2004","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/15509522","citation_count":92,"is_preprint":false},{"pmid":"30753871","id":"PMC_30753871","title":"The KN-93 Molecule Inhibits Calcium/Calmodulin-Dependent Protein Kinase II (CaMKII) Activity by Binding to Ca2+/CaM.","date":"2019","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/30753871","citation_count":92,"is_preprint":false},{"pmid":"18469344","id":"PMC_18469344","title":"ccm1 cell autonomously regulates endothelial cellular morphogenesis and vascular tubulogenesis in zebrafish.","date":"2008","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/18469344","citation_count":90,"is_preprint":false},{"pmid":"30210932","id":"PMC_30210932","title":"The chick chorioallantoic membrane (CAM) as a versatile patient-derived xenograft (PDX) platform for precision medicine and preclinical research.","date":"2018","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/30210932","citation_count":90,"is_preprint":false},{"pmid":"1324121","id":"PMC_1324121","title":"Decoding calcium signals by multifunctional CaM kinase.","date":"1992","source":"Cell calcium","url":"https://pubmed.ncbi.nlm.nih.gov/1324121","citation_count":88,"is_preprint":false},{"pmid":"14755725","id":"PMC_14755725","title":"Clinical features of cerebral cavernous malformations patients with KRIT1 mutations.","date":"2004","source":"Annals of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/14755725","citation_count":87,"is_preprint":false},{"pmid":"23918940","id":"PMC_23918940","title":"CCM1-ICAP-1 complex controls β1 integrin-dependent endothelial contractility and fibronectin remodeling.","date":"2013","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/23918940","citation_count":86,"is_preprint":false},{"pmid":"18847309","id":"PMC_18847309","title":"L1-CAM in cancerous tissues.","date":"2008","source":"Expert opinion on biological therapy","url":"https://pubmed.ncbi.nlm.nih.gov/18847309","citation_count":85,"is_preprint":false},{"pmid":"30810162","id":"PMC_30810162","title":"Ecophysiology of constitutive and facultative CAM photosynthesis.","date":"2019","source":"Journal of experimental botany","url":"https://pubmed.ncbi.nlm.nih.gov/30810162","citation_count":83,"is_preprint":false},{"pmid":"1849722","id":"PMC_1849722","title":"Regulation of Cl- channels by multifunctional CaM kinase.","date":"1991","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/1849722","citation_count":77,"is_preprint":false},{"pmid":"23317506","id":"PMC_23317506","title":"Mechanism for KRIT1 release of ICAP1-mediated suppression of integrin activation.","date":"2013","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/23317506","citation_count":71,"is_preprint":false},{"pmid":"10807272","id":"PMC_10807272","title":"Mutations in KRIT1 in familial cerebral cavernous malformations.","date":"2000","source":"Neurosurgery","url":"https://pubmed.ncbi.nlm.nih.gov/10807272","citation_count":70,"is_preprint":false},{"pmid":"8750196","id":"PMC_8750196","title":"Refined localization of the cerebral cavernous malformation gene (CCM1) to a 4-cM interval of chromosome 7q contained in a well-defined YAC contig.","date":"1995","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/8750196","citation_count":68,"is_preprint":false},{"pmid":"17290187","id":"PMC_17290187","title":"Interaction between krit1 and malcavernin: implications for the pathogenesis of cerebral cavernous malformations.","date":"2007","source":"Neurosurgery","url":"https://pubmed.ncbi.nlm.nih.gov/17290187","citation_count":66,"is_preprint":false},{"pmid":"24638902","id":"PMC_24638902","title":"Shared origins of a key enzyme during the evolution of C4 and CAM metabolism.","date":"2014","source":"Journal of experimental botany","url":"https://pubmed.ncbi.nlm.nih.gov/24638902","citation_count":65,"is_preprint":false},{"pmid":"22182521","id":"PMC_22182521","title":"Ccm3 functions in a manner distinct from Ccm1 and Ccm2 in a zebrafish model of CCM vascular disease.","date":"2011","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/22182521","citation_count":65,"is_preprint":false},{"pmid":"11914398","id":"PMC_11914398","title":"Cerebral cavernous malformations: mutations in Krit1.","date":"2002","source":"Neurology","url":"https://pubmed.ncbi.nlm.nih.gov/11914398","citation_count":58,"is_preprint":false},{"pmid":"25320085","id":"PMC_25320085","title":"KRIT1 protein depletion modifies endothelial cell behavior via increased vascular endothelial growth factor (VEGF) signaling.","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25320085","citation_count":53,"is_preprint":false},{"pmid":"21029238","id":"PMC_21029238","title":"Mutation analysis of CCM1, CCM2 and CCM3 genes in a cohort of Italian patients with cerebral cavernous malformation.","date":"2010","source":"Brain pathology (Zurich, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/21029238","citation_count":53,"is_preprint":false},{"pmid":"26478212","id":"PMC_26478212","title":"L1-CAM and N-CAM: From Adhesion Proteins to Pharmacological Targets.","date":"2015","source":"Trends in pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/26478212","citation_count":52,"is_preprint":false},{"pmid":"29364115","id":"PMC_29364115","title":"Heg1 and Ccm1/2 proteins control endocardial mechanosensitivity during zebrafish valvulogenesis.","date":"2018","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/29364115","citation_count":50,"is_preprint":false},{"pmid":"28811547","id":"PMC_28811547","title":"Up-regulation of NADPH oxidase-mediated redox signaling contributes to the loss of barrier function in KRIT1 deficient endothelium.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28811547","citation_count":49,"is_preprint":false},{"pmid":"26084473","id":"PMC_26084473","title":"Neurogranin regulates CaM dynamics at dendritic spines.","date":"2015","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/26084473","citation_count":46,"is_preprint":false},{"pmid":"15046662","id":"PMC_15046662","title":"KRIT1/cerebral cavernous malformation 1 protein localizes to vascular endothelium, astrocytes, and pyramidal cells of the adult human cerebral cortex.","date":"2004","source":"Neurosurgery","url":"https://pubmed.ncbi.nlm.nih.gov/15046662","citation_count":45,"is_preprint":false},{"pmid":"11696550","id":"PMC_11696550","title":"Alx4 binding to LEF-1 regulates N-CAM promoter activity.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11696550","citation_count":45,"is_preprint":false},{"pmid":"28670834","id":"PMC_28670834","title":"Temporal and spatial transcriptomic and microRNA dynamics of CAM photosynthesis in pineapple.","date":"2017","source":"The Plant journal : for cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/28670834","citation_count":43,"is_preprint":false},{"pmid":"24567493","id":"PMC_24567493","title":"Synthetic biology as it relates to CAM photosynthesis: challenges and opportunities.","date":"2014","source":"Journal of experimental botany","url":"https://pubmed.ncbi.nlm.nih.gov/24567493","citation_count":42,"is_preprint":false},{"pmid":"16373645","id":"PMC_16373645","title":"CCM2 expression parallels that of CCM1.","date":"2005","source":"Stroke","url":"https://pubmed.ncbi.nlm.nih.gov/16373645","citation_count":41,"is_preprint":false},{"pmid":"30030370","id":"PMC_30030370","title":"The CCM1-CCM2 complex controls complementary functions of ROCK1 and ROCK2 that are required for endothelial integrity.","date":"2018","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/30030370","citation_count":40,"is_preprint":false},{"pmid":"12204286","id":"PMC_12204286","title":"Krit1/cerebral cavernous malformation 1 mRNA is preferentially expressed in neurons and epithelial cells in embryo and adult.","date":"2002","source":"Mechanisms of development","url":"https://pubmed.ncbi.nlm.nih.gov/12204286","citation_count":40,"is_preprint":false},{"pmid":"1955110","id":"PMC_1955110","title":"Expression of polysialylated N-CAM during rat heart development.","date":"1991","source":"Differentiation; research in biological diversity","url":"https://pubmed.ncbi.nlm.nih.gov/1955110","citation_count":40,"is_preprint":false},{"pmid":"9210232","id":"PMC_9210232","title":"Cell signalling and CAM-mediated neurite outgrowth.","date":"1997","source":"Society of General Physiologists series","url":"https://pubmed.ncbi.nlm.nih.gov/9210232","citation_count":39,"is_preprint":false},{"pmid":"10696830","id":"PMC_10696830","title":"Elevated concentration of N-CAM VASE isoforms in schizophrenia.","date":"2000","source":"Journal of psychiatric research","url":"https://pubmed.ncbi.nlm.nih.gov/10696830","citation_count":39,"is_preprint":false},{"pmid":"11310633","id":"PMC_11310633","title":"Germline mutations in the CCM1 gene, encoding Krit1, cause cerebral cavernous malformations.","date":"2001","source":"Annals of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/11310633","citation_count":38,"is_preprint":false},{"pmid":"28246289","id":"PMC_28246289","title":"Hepatic Activation of the FAM3C-HSF1-CaM Pathway Attenuates Hyperglycemia of Obese Diabetic Mice.","date":"2017","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/28246289","citation_count":36,"is_preprint":false},{"pmid":"33425742","id":"PMC_33425742","title":"Cadherins, Selectins, and Integrins in CAM-DR in Leukemia.","date":"2020","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/33425742","citation_count":35,"is_preprint":false},{"pmid":"18812969","id":"PMC_18812969","title":"Krit1 modulates beta 1-integrin-mediated endothelial cell proliferation.","date":"2008","source":"Neurosurgery","url":"https://pubmed.ncbi.nlm.nih.gov/18812969","citation_count":35,"is_preprint":false},{"pmid":"11161791","id":"PMC_11161791","title":"Cloning of the murine Krit1 cDNA reveals novel mammalian 5' coding exons.","date":"2000","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/11161791","citation_count":34,"is_preprint":false},{"pmid":"26674562","id":"PMC_26674562","title":"CaM Kinases: From Memories to Addiction.","date":"2015","source":"Trends in pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/26674562","citation_count":33,"is_preprint":false},{"pmid":"25403688","id":"PMC_25403688","title":"PTEN/PI3K/Akt/VEGF signaling and the cross talk to KRIT1, CCM2, and PDCD10 proteins in cerebral cavernous malformations.","date":"2014","source":"Neurosurgical review","url":"https://pubmed.ncbi.nlm.nih.gov/25403688","citation_count":33,"is_preprint":false},{"pmid":"37698538","id":"PMC_37698538","title":"The CAM lineages of planet Earth.","date":"2023","source":"Annals of botany","url":"https://pubmed.ncbi.nlm.nih.gov/37698538","citation_count":33,"is_preprint":false},{"pmid":"9221966","id":"PMC_9221966","title":"Familial cavernous malformations in a large French kindred: mapping of the gene to the CCM1 locus on chromosome 7q.","date":"1997","source":"Journal of neurology, neurosurgery, and psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/9221966","citation_count":31,"is_preprint":false},{"pmid":"31284077","id":"PMC_31284077","title":"Understanding trait diversity associated with crassulacean acid metabolism (CAM).","date":"2019","source":"Current opinion in plant biology","url":"https://pubmed.ncbi.nlm.nih.gov/31284077","citation_count":30,"is_preprint":false},{"pmid":"17440989","id":"PMC_17440989","title":"Highly variable penetrance in subjects affected with cavernous cerebral angiomas (CCM) carrying novel CCM1 and CCM2 mutations.","date":"2007","source":"American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/17440989","citation_count":30,"is_preprint":false},{"pmid":"11342228","id":"PMC_11342228","title":"Identification of eight novel 5'-exons in cerebral capillary malformation gene-1 (CCM1) encoding KRIT1.","date":"2001","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/11342228","citation_count":29,"is_preprint":false},{"pmid":"30870557","id":"PMC_30870557","title":"Shared expression of crassulacean acid metabolism (CAM) genes pre-dates the origin of CAM in the genus Yucca.","date":"2019","source":"Journal of experimental botany","url":"https://pubmed.ncbi.nlm.nih.gov/30870557","citation_count":27,"is_preprint":false},{"pmid":"9168198","id":"PMC_9168198","title":"Shared cell adhesion molecule (CAM) homology domains point to CAMs signalling via FGF receptors.","date":"1996","source":"Perspectives on developmental neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/9168198","citation_count":27,"is_preprint":false},{"pmid":"33375811","id":"PMC_33375811","title":"Ca2+-CaM Dependent Inactivation of RyR2 Underlies Ca2+ Alternans in Intact Heart.","date":"2020","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/33375811","citation_count":26,"is_preprint":false},{"pmid":"12682320","id":"PMC_12682320","title":"Molecular genetic investigations in the CCM1 gene in sporadic cerebral cavernomas.","date":"2003","source":"Neurology","url":"https://pubmed.ncbi.nlm.nih.gov/12682320","citation_count":26,"is_preprint":false},{"pmid":"26321910","id":"PMC_26321910","title":"Activity dependent CAM cleavage and neurotransmission.","date":"2015","source":"Frontiers in cellular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/26321910","citation_count":25,"is_preprint":false},{"pmid":"20948304","id":"PMC_20948304","title":"Cell adhesion molecules in context: CAM function depends on the neighborhood.","date":"2011","source":"Cell adhesion & migration","url":"https://pubmed.ncbi.nlm.nih.gov/20948304","citation_count":24,"is_preprint":false},{"pmid":"29483251","id":"PMC_29483251","title":"Grip and slip of L1-CAM on adhesive substrates direct growth cone haptotaxis.","date":"2018","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/29483251","citation_count":24,"is_preprint":false},{"pmid":"30487773","id":"PMC_30487773","title":"Two Novel KRIT1 and CCM2 Mutations in Patients Affected by Cerebral Cavernous Malformations: New Information on CCM2 Penetrance.","date":"2018","source":"Frontiers in neurology","url":"https://pubmed.ncbi.nlm.nih.gov/30487773","citation_count":24,"is_preprint":false},{"pmid":"34725799","id":"PMC_34725799","title":"Establishment, characterization, and transfection potential of a new continuous fish cell line (CAM) derived from the muscle tissue of grass goldfish (Carassius auratus).","date":"2021","source":"In vitro cellular & developmental biology. Animal","url":"https://pubmed.ncbi.nlm.nih.gov/34725799","citation_count":23,"is_preprint":false},{"pmid":"23872064","id":"PMC_23872064","title":"miR-21 coordinates tumor growth and modulates KRIT1 levels.","date":"2013","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/23872064","citation_count":21,"is_preprint":false},{"pmid":"35316220","id":"PMC_35316220","title":"NOGOB receptor deficiency increases cerebrovascular permeability and hemorrhage via impairing histone acetylation-mediated CCM1/2 expression.","date":"2022","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/35316220","citation_count":21,"is_preprint":false},{"pmid":"22514323","id":"PMC_22514323","title":"Regulation of neuronal mRNA translation by CaM-kinase I phosphorylation of eIF4GII.","date":"2012","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/22514323","citation_count":20,"is_preprint":false},{"pmid":"24692645","id":"PMC_24692645","title":"Genomic analyses of the CAM plant pineapple.","date":"2014","source":"Journal of experimental botany","url":"https://pubmed.ncbi.nlm.nih.gov/24692645","citation_count":19,"is_preprint":false},{"pmid":"34008329","id":"PMC_34008329","title":"Electrical therapies act on the Ca2+ /CaM signaling pathway to enhance bone regeneration with bioactive glass [S53P4] and allogeneic grafts.","date":"2021","source":"Journal of biomedical materials research. Part B, Applied biomaterials","url":"https://pubmed.ncbi.nlm.nih.gov/34008329","citation_count":18,"is_preprint":false},{"pmid":"34448569","id":"PMC_34448569","title":"Tetrahydropalmatine Regulates BDNF through TrkB/CAM Interaction to Alleviate the Neurotoxicity Induced by Methamphetamine.","date":"2021","source":"ACS chemical neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/34448569","citation_count":18,"is_preprint":false},{"pmid":"37849902","id":"PMC_37849902","title":"Biosystems Design to Accelerate C3-to-CAM Progression.","date":"2020","source":"Biodesign research","url":"https://pubmed.ncbi.nlm.nih.gov/37849902","citation_count":17,"is_preprint":false},{"pmid":"27088716","id":"PMC_27088716","title":"Australia lacks stem succulents but is it depauperate in plants with crassulacean acid metabolism (CAM)?","date":"2016","source":"Current opinion in plant biology","url":"https://pubmed.ncbi.nlm.nih.gov/27088716","citation_count":17,"is_preprint":false},{"pmid":"12810002","id":"PMC_12810002","title":"Identification of a novel KRIT1 mutation in an Italian family with cerebral cavernous malformation by the protein truncation test.","date":"2003","source":"Journal of the neurological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/12810002","citation_count":17,"is_preprint":false},{"pmid":"18202004","id":"PMC_18202004","title":"Significance of zinc in a regulatory protein, CCM1, which regulates the carbon-concentrating mechanism in Chlamydomonas reinhardtii.","date":"2008","source":"Plant & cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/18202004","citation_count":17,"is_preprint":false},{"pmid":"33977234","id":"PMC_33977234","title":"Inhibition of the HEG1-KRIT1 interaction increases KLF4 and KLF2 expression in endothelial cells.","date":"2021","source":"FASEB bioAdvances","url":"https://pubmed.ncbi.nlm.nih.gov/33977234","citation_count":16,"is_preprint":false},{"pmid":"28441650","id":"PMC_28441650","title":"MicroRNA-1185 Induces Endothelial Cell Apoptosis by Targeting UVRAG and KRIT1.","date":"2017","source":"Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/28441650","citation_count":16,"is_preprint":false},{"pmid":"28698152","id":"PMC_28698152","title":"Novel functions of CCM1 delimit the relationship of PTB/PH domains.","date":"2017","source":"Biochimica et biophysica acta. Proteins and proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/28698152","citation_count":16,"is_preprint":false},{"pmid":"26991244","id":"PMC_26991244","title":"CRISPR-Cas-Assisted Multiplexing (CAM): Simple Same-Day Multi-Locus Engineering in Yeast.","date":"2016","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/26991244","citation_count":16,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":44702,"output_tokens":4805,"usd":0.103091},"stage2":{"model":"claude-opus-4-6","input_tokens":8360,"output_tokens":3611,"usd":0.198112},"total_usd":0.301203,"stage1_batch_id":"msgbatch_01Mgbec4vM6c9vXht7JVJzss","stage2_batch_id":"msgbatch_01JkuuH5RB2BdJNsgnhjbC6s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"KRIT1 (Krev Interaction Trapped 1) was identified as a binding partner of Krev-1/Rap1A GTPase via yeast two-hybrid screening of a HeLa cell cDNA library. The protein contains an N-terminal ankyrin repeat domain and a C-terminal domain; it interacts strongly with Krev-1/Rap1A but only weakly with Ras, suggesting specificity for Rap1A signaling.\",\n      \"method\": \"Yeast two-hybrid screen, domain mapping\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — original discovery by two-hybrid with domain mapping, foundational paper replicated by subsequent studies\",\n      \"pmids\": [\"9285558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Truncating mutations in CCM1, which encodes KRIT1, cause hereditary cerebral cavernous angiomas (CCM1 families), establishing loss-of-function of KRIT1 as the molecular basis of CCM1 disease and implicating the RAP1A signal transduction pathway in vasculogenesis or angiogenesis.\",\n      \"method\": \"Positional cloning, mutation analysis in CCM1 families\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mutation identification in human families, independently replicated\",\n      \"pmids\": [\"10508515\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"KRIT1 associates with integrin cytoplasmic domain-associated protein-1 (ICAP-1) via an NPXY motif at the N-terminus of KRIT1; mutagenesis of this NPXY sequence completely abrogates the KRIT1/ICAP-1 interaction, suggesting KRIT1 is involved in integrin-cytoskeleton signaling.\",\n      \"method\": \"Yeast two-hybrid screening, GST pulldown of endogenous ICAP-1 from 293T cells, site-directed mutagenesis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — multiple orthogonal methods including in vitro pulldown and mutagenesis confirming interaction site\",\n      \"pmids\": [\"11854171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"KRIT1 colocalizes with microtubules in endothelial cells during interphase and localizes to spindle pole bodies, mitotic spindle, and microtubule plus ends during mitosis, establishing KRIT1 as a microtubule-associated protein potentially involved in microtubule targeting and endothelial cell shape.\",\n      \"method\": \"Immunofluorescence microscopy, coimmunoprecipitation with anti-KRIT1 antibodies in endothelial cells\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP and direct imaging, single lab, but orthogonal methods used\",\n      \"pmids\": [\"12140362\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"KRIT1 is a Rap1 effector in endothelial cells: KRIT1 is present at cell-cell junctions via its FERM domain, colocalizes and physically associates with junctional proteins, and Rap1 activity regulates junctional localization of KRIT1. KRIT1 depletion by siRNA blocks Rap1-mediated stabilization of endothelial junctions and leads to increased actin stress fibers.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, immunofluorescence, Rap1 activation assays in endothelial cells\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, domain mapping, clean KD with defined cellular phenotype, Rap1 manipulation\",\n      \"pmids\": [\"17954608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"KRIT1 interacts with CCM2 (malcavernin) through its NPXY motifs; malcavernin independently binds to two of the three NPXY motifs in KRIT1, and at steady state malcavernin shuttles between nucleus and cytoplasm, with KRIT1 potentially regulating its nuclear localization.\",\n      \"method\": \"Yeast two-hybrid, in vivo coimmunoprecipitation, epitope mapping, immunocytochemistry\",\n      \"journal\": \"Neurosurgery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP with epitope mapping, single lab\",\n      \"pmids\": [\"17290187\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Loss of ccm1 in zebrafish embryos leads to severe progressive dilation of major vessels with endothelial cell spreading and thinning of vessel walls despite normal cell-cell contacts; ccm1 function is cell-autonomous in endothelial cells, establishing that CCM1 regulates endothelial cellular morphogenesis.\",\n      \"method\": \"Zebrafish genetic mutant analysis, mosaic rescue experiments, electron microscopy, cell transplantation\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic loss-of-function in vertebrate model with cell-autonomous rescue, orthogonal morphological analyses\",\n      \"pmids\": [\"18469344\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"KRIT1 depletion reduces endothelial cell proliferation and decreases phosphorylation along the β1-integrin/FAK/ERK/MAPK pathway; KRIT1 colocalizes with ICAP-1α in nucleus and cytoplasm and stabilizes/shuttles ICAP-1α, modulating β1-integrin-mediated signal transduction.\",\n      \"method\": \"siRNA knockdown in HeLa, HUVEC, and microvascular endothelial cells; western blot for pathway phosphorylation; immunocytochemistry\",\n      \"journal\": \"Neurosurgery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with defined signaling phenotype, colocalization, single lab\",\n      \"pmids\": [\"18812969\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"KRIT1 and Rap1 are negative regulators of canonical β-catenin signaling; depletion of endothelial KRIT1 causes β-catenin to dissociate from VE-cadherin and accumulate in the nucleus with increased β-catenin-dependent transcription. This effect requires intact cell-cell junctions and KRIT1. Hemizygous Krit1 deficiency in vivo increases intestinal polyps in ApcMin/+ mice.\",\n      \"method\": \"siRNA knockdown, Rap1 activation, β-catenin reporter assays, ApcMin/+ mouse cross, nuclear fractionation\",\n      \"journal\": \"Disease models & mechanisms\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods in vitro and in vivo, pathway placement via epistasis and reporter assay\",\n      \"pmids\": [\"20007487\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CCM1/KRIT1 inhibits sprouting angiogenesis by strongly inducing DLL4-NOTCH signaling in endothelial cells, promoting AKT phosphorylation while reducing ERK phosphorylation; blocking NOTCH activity alleviates CCM1 effects. Loss of CCM1 leads to excessive capillary sprouting.\",\n      \"method\": \"siRNA knockdown in primary human endothelial cells, SCID mouse xenograft model, NOTCH pathway inhibition, phosphorylation assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — pathway rescue by NOTCH inhibition, in vitro and in vivo, multiple orthogonal methods\",\n      \"pmids\": [\"20616044\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Crystal structures of KRIT1 bound to ICAP1 and ICAP1 bound to integrin β1 cytoplasmic tail were solved to 2.54 Å and 3.0 Å resolution. KRIT1 binds ICAP1 via a bidentate surface that directly competes with integrin β1, antagonizing ICAP1-mediated suppression of integrin inside-out activation. KRIT1 also contains an N-terminal Nudix domain previously considered unstructured.\",\n      \"method\": \"X-ray crystallography (co-crystal structures), competition binding assays, integrin activation functional assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structures with functional validation and competition assay, single rigorous study with multiple orthogonal methods\",\n      \"pmids\": [\"23317506\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The CCM1-ICAP-1 complex controls β1 integrin-dependent endothelial contractility and ECM remodeling; loss of CCM1/2 destabilizes ICAP-1, increases β1 integrin activation, and leads to increased RhoA-dependent contractility and aberrant fibronectin remodeling, destabilizing endothelial barrier function via a positive feedback loop between aberrant ECM and cellular tension.\",\n      \"method\": \"siRNA knockdown, traction force microscopy, β1 integrin activation assays, CCM1/2 mouse models, RhoA activity assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods in vitro and in vivo mouse models, pathway dissection with mechanistic follow-up\",\n      \"pmids\": [\"23918940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Loss of KRIT1 (but not CCM2) increases nuclear β-catenin signaling and up-regulates VEGF-A protein expression in endothelial cells; increased VEGF-A leads to VEGFR2 activation with consequent altered cytoskeletal organization, migration, barrier function, and in vivo endothelial permeability in KRIT1-deficient animals.\",\n      \"method\": \"siRNA knockdown, western blot, VEGFR2 signaling assays, β-catenin reporter, in vivo permeability measurements in Krit1+/- mice\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vitro and in vivo experiments, pathway dissection, multiple orthogonal methods\",\n      \"pmids\": [\"25320085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KRIT1 depletion increases endothelial ROS production via NADPH oxidase/Nox4 signaling and NF-κB-dependent promoter activity, directly contributing to loss of barrier function; targeted antioxidant delivery reversed permeability increases in KRIT1 heterozygous mice in vivo.\",\n      \"method\": \"siRNA knockdown, intravital microscopy in Krit1+/- mice with targeted antioxidant enzymes, Nox4 expression analysis, NF-κB reporter assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vitro and in vivo rescue experiments, mechanistic pathway identification, multiple methods\",\n      \"pmids\": [\"28811547\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Zebrafish Krit1 regulates cardiac valve formation; HEG1 expression is induced by blood flow, Heg1 stabilizes Krit1 protein levels, and Heg1/Krit1 dampen mechanosensitive klf2a expression. Loss of Krit1 increases klf2a and notch1b throughout the endocardium and prevents valve leaflet formation.\",\n      \"method\": \"Zebrafish genetic mutants, morpholino knockdown, blood flow manipulation, in situ hybridization, protein level analysis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis in zebrafish, mechanosensitive pathway placement, multiple orthogonal methods\",\n      \"pmids\": [\"29364115\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The CCM1-CCM2 complex controls complementary functions of ROCK1 and ROCK2: CCM proteins act as a scaffold promoting ROCK2 interactions with VE-cadherin and limiting ROCK1 kinase activity. Loss of CCM1 produces excessive ROCK1-dependent actin stress fibers; silencing ROCK1 (but not ROCK2) restores endothelial homeostasis and rescues ccm1 mutant zebrafish cardiovascular defects.\",\n      \"method\": \"siRNA knockdown of CCM1/CCM2 and ROCK isoforms, traction force microscopy, VE-cadherin co-IP, zebrafish ccm1 mutant rescue experiments\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — isoform-specific genetic epistasis in vitro and in zebrafish, Co-IP, mechanistic pathway placement\",\n      \"pmids\": [\"30030370\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"HEG1 directly binds to and recruits KRIT1 to endothelial junctions via the KRIT1 FERM domain; a crystal structure of a small-molecule HEG1-KRIT1 inhibitor (HKi2) bound to the KRIT1 FERM domain revealed it occupies the same binding pocket as the HEG1 cytoplasmic tail. Acute inhibition of HEG1-KRIT1 interaction increases KLF4 and KLF2 expression and activates Akt signaling in endothelial cells.\",\n      \"method\": \"High-throughput screening, crystal structure of inhibitor-KRIT1 FERM complex, in vitro colocalization assay, endothelial cell reporter assays, zebrafish klf2a expression analysis\",\n      \"journal\": \"FASEB bioAdvances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with functional validation in vitro and in vivo, multiple orthogonal methods\",\n      \"pmids\": [\"33977234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CCM1/KRIT1 contains three NPXY motifs that interact with a spectrum of PTB and PH domain-containing proteins; the KRIT1 F3 lobe of the FERM domain acts as a functional PH domain to interact with NPXY motifs, and KRIT1 can form oligomers through intermolecular interaction between its F3 FERM lobe and an NPXY motif. Twenty-eight novel cellular partners of CCM1 containing PTB or PH domains were identified.\",\n      \"method\": \"Molecular cloning, protein binding assays, structural simulation combined with existing X-ray crystallography and NMR data, RT-qPCR\",\n      \"journal\": \"Biochimica et biophysica acta. Proteins and proteomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — binding assays with structural modeling, single lab, limited functional validation\",\n      \"pmids\": [\"28698152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NGBR (NOGOB receptor) is required for maintaining CCM1/2 expression in endothelial cells via HBO1-mediated histone H4 acetylation; loss of NGBR reduces HBO1 and histone acetylation at CCM1 and CCM2 promoters (H4K5 and H4K12), resulting in CCM1/2 deficiency and cerebrovascular lesions.\",\n      \"method\": \"Endothelial-specific Ngbr knockout mice, RNA-seq, ChIP-qPCR for HBO1 and acetylated histone H4K5/H4K12 at CCM1/CCM2 promoters\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP-qPCR mechanistic evidence for epigenetic regulation, in vivo mouse model, RNA-seq\",\n      \"pmids\": [\"35316220\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KRIT1 is a multidomain scaffold protein (containing ankyrin repeats, a Nudix domain, three NPXY motifs, and a FERM domain) that functions as a Rap1 GTPase effector at endothelial cell-cell junctions, where it suppresses actin stress fibers, stabilizes junctional integrity via VE-cadherin and β-catenin, antagonizes ICAP-1-mediated β1-integrin inside-out activation by competing with integrin β1 for ICAP-1 binding, restrains canonical Wnt/β-catenin transcription, activates DLL4-Notch signaling to maintain endothelial quiescence, controls ROCK1/ROCK2 balance in the endothelium, dampens mechanosensitive KLF2/KLF4 expression downstream of HEG1, and limits NADPH oxidase/Nox4-driven ROS production; loss-of-function of KRIT1 leads to increased RhoA/ROCK1-dependent contractility, aberrant ECM remodeling, excessive VEGF-A/VEGFR2 and β-catenin signaling, and pathological vascular dilation underlying cerebral cavernous malformations.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"KRIT1 is a multidomain scaffold protein that functions as a Rap1 GTPase effector at endothelial cell-cell junctions, where it suppresses stress fiber formation, stabilizes VE-cadherin/β-catenin complexes, restrains canonical Wnt/β-catenin transcription, and limits sprouting angiogenesis through DLL4-Notch signaling [PMID:17954608, PMID:20007487, PMID:20616044]. Structurally, KRIT1 contains ankyrin repeats, a Nudix domain, three NPXY motifs, and a FERM domain; the FERM domain mediates junctional recruitment by HEG1 and Rap1, while the NPXY motifs bind ICAP-1 and CCM2, with crystal structures demonstrating that KRIT1 antagonizes ICAP-1-mediated β1-integrin inside-out activation by competing for the same binding surface [PMID:23317506, PMID:33977234, PMID:11854171]. Loss of KRIT1 deregulates ROCK1-dependent contractility, increases NADPH oxidase/Nox4-driven ROS production and NF-κB activity, elevates VEGF-A/VEGFR2 signaling, and disrupts mechanosensitive KLF2/KLF4 dampening downstream of HEG1, collectively compromising endothelial barrier integrity and vascular morphogenesis [PMID:30030370, PMID:28811547, PMID:25320085, PMID:29364115]. Truncating mutations in KRIT1 (CCM1) cause hereditary cerebral cavernous malformations [PMID:10508515].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"The identity of KRIT1 as a Rap1A-interacting protein was unknown; yeast two-hybrid screening revealed that KRIT1 specifically binds Krev-1/Rap1A but not Ras, establishing it as a candidate Rap1 effector with ankyrin repeats and a C-terminal domain.\",\n      \"evidence\": \"Yeast two-hybrid screen of HeLa cDNA library with domain mapping\",\n      \"pmids\": [\"9285558\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No cellular function assigned\", \"No endothelial context established\", \"Mechanism of Rap1 effector function unknown\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"The genetic basis of hereditary cerebral cavernous malformations (CCM1) was unresolved; positional cloning identified truncating mutations in KRIT1/CCM1 in affected families, establishing loss-of-function of KRIT1 as the cause of CCM1 disease.\",\n      \"evidence\": \"Positional cloning and mutation analysis in CCM1 families\",\n      \"pmids\": [\"10508515\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No mechanism linking KRIT1 loss to vascular phenotype\", \"Downstream signaling pathways unknown\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"How KRIT1 connects to integrin signaling was unknown; identification of the KRIT1–ICAP-1 interaction via an NPXY motif, combined with its microtubule association in endothelial cells, placed KRIT1 at the interface of integrin-cytoskeletal signaling.\",\n      \"evidence\": \"Yeast two-hybrid, GST pulldown, site-directed mutagenesis (ICAP-1 interaction); immunofluorescence and co-IP in endothelial cells (microtubule association)\",\n      \"pmids\": [\"11854171\", \"12140362\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Role at cell-cell junctions not yet identified\", \"Functional consequence of ICAP-1 binding on integrin activation unknown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Whether KRIT1 functions as a true Rap1 effector at endothelial junctions was untested; KRIT1 was shown to localize to cell-cell junctions via its FERM domain under Rap1 control, and its depletion blocked Rap1-mediated junction stabilization and increased stress fibers, while CCM2 was identified as an additional NPXY-dependent partner.\",\n      \"evidence\": \"Co-IP, siRNA knockdown, Rap1 activation assays in endothelial cells; yeast two-hybrid and co-IP for CCM2 interaction\",\n      \"pmids\": [\"17954608\", \"17290187\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream transcriptional consequences of junction destabilization unknown\", \"ROCK isoform specificity not addressed\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Whether KRIT1 regulates transcriptional signaling beyond junction stability was unknown; KRIT1 depletion was shown to cause β-catenin dissociation from VE-cadherin, nuclear accumulation, and increased β-catenin-dependent transcription, with in vivo validation in ApcMin/+ mice.\",\n      \"evidence\": \"siRNA knockdown, β-catenin reporter assays, nuclear fractionation, ApcMin/+ mouse cross\",\n      \"pmids\": [\"20007487\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific transcriptional targets of β-catenin in CCM context not fully defined\", \"Connection to VEGF-A upregulation not yet made\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"How KRIT1 controls angiogenic sprouting was unclear; KRIT1 was found to suppress sprouting angiogenesis by inducing DLL4-Notch signaling, with Notch inhibition rescuing the effect, linking KRIT1 to endothelial quiescence control.\",\n      \"evidence\": \"siRNA knockdown in endothelial cells, SCID mouse xenograft model, Notch pathway inhibition, phosphorylation assays\",\n      \"pmids\": [\"20616044\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Notch induction is direct or secondary to β-catenin signaling unclear\", \"Interplay with VEGF signaling not resolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"The structural basis of KRIT1–ICAP-1 competition with integrin β1 was unknown; co-crystal structures revealed KRIT1 binds ICAP-1 via a bidentate surface that directly competes with the integrin β1 tail, and loss of CCM1 was shown to destabilize ICAP-1, increase β1-integrin activation, RhoA-dependent contractility, and aberrant fibronectin remodeling.\",\n      \"evidence\": \"X-ray crystallography at 2.54 Å and 3.0 Å resolution, competition binding assays, traction force microscopy, β1-integrin activation assays, CCM mouse models\",\n      \"pmids\": [\"23317506\", \"23918940\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of KRIT1-Rap1 interaction at junctions not resolved\", \"Whether ICAP-1 destabilization is sufficient to drive CCM lesions alone unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"The link between KRIT1 loss, β-catenin transcription, and autocrine VEGF signaling was not established; KRIT1 depletion was shown to upregulate VEGF-A via nuclear β-catenin, activating VEGFR2 and altering cytoskeletal organization and barrier function in vitro and in vivo.\",\n      \"evidence\": \"siRNA knockdown, western blot, VEGFR2 signaling assays, β-catenin reporter, in vivo permeability in Krit1+/- mice\",\n      \"pmids\": [\"25320085\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Therapeutic targeting of VEGF pathway in CCM not tested\", \"Contribution of VEGF versus other β-catenin targets to lesion formation unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"The roles of ROS and ROCK isoform balance downstream of KRIT1 loss were uncharacterized; KRIT1 depletion was found to increase Nox4/NADPH oxidase-driven ROS and NF-κB activity (rescued by targeted antioxidants in vivo), and KRIT1 oligomerization via NPXY-FERM interactions was demonstrated, expanding the KRIT1 interactome to 28 PTB/PH-domain proteins.\",\n      \"evidence\": \"siRNA knockdown, intravital microscopy in Krit1+/- mice with targeted antioxidant rescue, Nox4 expression analysis; molecular cloning and binding assays with structural modeling\",\n      \"pmids\": [\"28811547\", \"28698152\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional significance of KRIT1 oligomerization in vivo untested\", \"Relative contribution of ROS versus contractility to barrier loss not delineated\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"How KRIT1 integrates mechanosensing and ROCK isoform balance was unclear; HEG1 was shown to stabilize Krit1 to dampen flow-induced klf2a expression and regulate cardiac valve formation, while the CCM1-CCM2 complex was found to scaffold ROCK2 at VE-cadherin and restrain ROCK1, with ROCK1 silencing rescuing ccm1 mutant zebrafish.\",\n      \"evidence\": \"Zebrafish genetic mutants with flow manipulation; isoform-specific siRNA knockdown, traction force microscopy, VE-cadherin co-IP, zebrafish rescue experiments\",\n      \"pmids\": [\"29364115\", \"30030370\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct mechanosensor identity upstream of KRIT1 in mammalian endothelium unresolved\", \"Structural basis of ROCK1 versus ROCK2 selectivity by CCM complex unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"How HEG1 recruits KRIT1 at the structural level was not defined; a crystal structure of a small-molecule inhibitor bound to the KRIT1 FERM domain confirmed the HEG1 cytoplasmic tail binding pocket, and acute pharmacological disruption increased KLF2/KLF4 and Akt signaling.\",\n      \"evidence\": \"High-throughput screening, crystal structure of inhibitor–KRIT1 FERM complex, endothelial reporter assays, zebrafish klf2a expression analysis\",\n      \"pmids\": [\"33977234\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo pharmacological modulation in mammalian CCM models not demonstrated\", \"Full structural model of KRIT1 in complex with Rap1 and HEG1 simultaneously lacking\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"How KRIT1 expression itself is epigenetically regulated was unknown; NGBR was shown to maintain CCM1/CCM2 transcription via HBO1-mediated H4K5/H4K12 acetylation at their promoters, with NGBR loss in endothelial cells phenocopying CCM.\",\n      \"evidence\": \"Endothelial-specific Ngbr knockout mice, RNA-seq, ChIP-qPCR for HBO1 and acetylated histones at CCM1/CCM2 promoters\",\n      \"pmids\": [\"35316220\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether HBO1-mediated regulation is specific to endothelial cells or general is untested\", \"Chromatin accessibility landscape at the KRIT1 locus not mapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A complete structural model of the full-length KRIT1 protein in complex with Rap1, HEG1, and CCM2 simultaneously is lacking, and the relative contributions of individual KRIT1-regulated pathways (β-catenin, ROCK1, Nox4/ROS, integrin activation) to CCM lesion initiation versus progression remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No full-length KRIT1 structure available\", \"Pathway hierarchy in CCM pathogenesis not established by epistasis in mammalian models\", \"Whether KRIT1 oligomerization is required for in vivo function untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 4, 10, 15]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [8, 9, 11, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [4, 16]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 4, 8, 9, 12]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [4, 8, 15]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [6, 14]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 6, 11]}\n    ],\n    \"complexes\": [\n      \"CCM1-CCM2 complex\"\n    ],\n    \"partners\": [\n      \"RAP1A\",\n      \"ICAP1\",\n      \"CCM2\",\n      \"HEG1\",\n      \"ROCK1\",\n      \"ROCK2\",\n      \"CTNNB1\",\n      \"CDH5\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}