Affinage

CCM2

Cerebral cavernous malformations 2 protein · UniProt Q9BSQ5

Length
444 aa
Mass
48.8 kDa
Annotated
2026-06-09
59 papers in source corpus 21 papers cited in narrative 21 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CCM2 (malcavernin/OSM) is a scaffold/adaptor protein that organizes a core ternary complex with CCM1 (KRIT1) and CCM3 (PDCD10) to maintain endothelial vascular integrity (PMID:16037064, PMID:18300272). CCM2 binds KRIT1 through its phosphotyrosine-binding (PTB) domain, which adopts a Dab-like fold and preferentially engages the third NPX(Y/F) motif of KRIT1; disease-associated CCM2 missense mutations destabilize this domain and disrupt the interaction (PMID:16037064, PMID:25525273). Its N-terminal region is required for CCM1 binding and ternary-complex assembly, while its C-terminal harmonin-homology domain provides structural integrity (PMID:18300272, PMID:23266514); long isoforms additionally carry an atypical PTB domain that CCM1 and CCM3 bind competitively (PMID:31676827). CCM2 is required in endothelial cells for proper angiogenesis and vascular development, and endothelial loss produces CCM-like venous lesions, with the endothelial cell established as the cell of disease origin (PMID:19259391, PMID:21859843, PMID:19088124). Mechanistically, the CCM1-CCM2 complex restrains MEKK3 kinase activity, thereby suppressing MEK5/ERK5 signaling and KLF4 transcription—the latter requiring two CCM2 PTB domains to cluster on a single KRIT1 scaffold (PMID:26540726, PMID:27513872, PMID:41688454)—and acts as a scaffold favoring ROCK2 association with VE-cadherin while limiting ROCK1 activity to preserve cell-cell junctions and prevent actin stress fibers, fibronectin matrix defects, and ROCK-dependent senescence-associated secretory phenotype (PMID:30030370, PMID:34342749, PMID:32515053). Independent of its vascular role, CCM2 mediates TrkA receptor-induced apoptosis through its PTB and Karet domains in partnership with the GCKIII kinase STK25, which phosphorylates CCM2 to drive death signaling (PMID:19755102, PMID:22782892).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 2005 High

    Established the physical basis of the CCM complex by showing CCM2 binds CCM1 through its PTB domain and seeds a ternary complex, explaining how distinct CCM gene products converge on one pathway.

    Evidence Co-IP, FRET, and localization assays with a familial missense mutant in cells

    PMID:16037064

    Open questions at the time
    • Did not define the KRIT1 motif bound
    • MEKK3 role within the complex not functionally tested
  2. 2007 Medium

    Extended the complex to include CCM3 and linked CCM2 to GCKIII signaling by identifying STK25 as a binding partner.

    Evidence Co-IP, immunofluorescence colocalization, and yeast two-hybrid

    PMID:17657516

    Open questions at the time
    • No functional consequence of CCM2-STK25 binding tested
    • Stoichiometry of CCM2/CCM3 interaction undefined
  3. 2008 Medium

    Mapped domain requirements for complex assembly, showing the N-terminal region is needed for CCM1 binding while CCM3 binding is retained, and that full-length CCM2 is the essential core of the ternary complex.

    Evidence Exon-2 deletion mutant expression with Co-IP for two partners

    PMID:18300272

    Open questions at the time
    • Single lab
    • Structural impact of deletion not resolved
  4. 2008 Medium

    Identified the endothelial cell as the cell of disease origin by demonstrating endothelial-specific second-hit loss of CCM2 protein in human cavernous lesions.

    Evidence IHC of CCM tissue from germline mutation carriers

    PMID:19088124

    Open questions at the time
    • IHC is a lower-tier method
    • Does not establish downstream mechanism of lesion formation
  5. 2009 High

    Defined the in vivo requirement for CCM2 in endothelial vascular morphogenesis and showed cell-type specificity by contrasting endothelial versus neuroglial deletion.

    Evidence Tissue-specific conditional KO mice with embryonic phenotyping

    PMID:19259391

    Open questions at the time
    • Molecular effector of the angiogenic defect not identified in this study
    • Embryonic lethality limits adult lesion analysis
  6. 2009 High

    Revealed a vascular-independent function: CCM2 transmits TrkA receptor-induced apoptosis via its PTB and Karet domains, expanding its role beyond endothelial scaffolding.

    Evidence Co-IP, domain mutation mapping, siRNA, and cell death assays in tumor cells

    PMID:19755102

    Open questions at the time
    • Kinase coupling death signal not yet identified at this stage
    • Relevance to endothelial complex unclear
  7. 2011 High

    Showed that timing of CCM2 loss determines outcome, with postnatal endothelial deletion producing venous CCM-like lesions, modeling the human disease.

    Evidence Inducible postnatal endothelial-specific KO mice with histology and MRI

    PMID:21859843

    Open questions at the time
    • Why lesions are restricted to the venous bed not explained
    • Downstream signaling not addressed here
  8. 2011 High

    Genetically distinguished CCM2 from the CCM3/STK25 pathway, showing ccm2 defects are not rescued by stk25b and synergize with ccm3 loss.

    Evidence Zebrafish mutants, morpholino knockdown, epistasis, and overexpression rescue

    PMID:22182521

    Open questions at the time
    • Molecular basis of CCM2/CCM3 divergence undefined
    • Does not reconcile with shared ternary complex
  9. 2012 High

    Solidified the CCM2-STK25 axis in apoptosis by showing STK25 (not STK24) phosphorylates CCM2 and its kinase activity is required for TrkA/CCM2 death signaling.

    Evidence Affinity proteomics, Co-IP, kinase assay with catalytic mutant, siRNA, cell death assays

    PMID:22782892

    Open questions at the time
    • CCM2 phosphosites not mapped
    • Connection to endothelial CCM function unresolved
  10. 2012 High

    Provided atomic-level architecture of the C-terminus, identifying a monomeric harmonin-homology domain that contributes structural integrity to CCM2.

    Evidence X-ray crystallography at 1.9 Å and analytical ultracentrifugation

    PMID:23266514

    Open questions at the time
    • No binding partner assigned to the HHD
    • Functional role of the domain in vivo untested
  11. 2013 Medium

    Placed CCM2 within the Heg-CCM cardiovascular pathway and mapped the CCM1 regions binding CCM2 and the paralog CCM2L.

    Evidence Zebrafish morpholino, mRNA rescue, Co-IP, and deletion mapping

    PMID:23328253

    Open questions at the time
    • Functional redundancy between CCM2 and CCM2L not fully resolved
    • Single lab
  12. 2014 High

    Defined the molecular recognition code, showing the Dab-like CCM2 PTB domain preferentially binds the third KRIT1 NPX(Y/F) motif and that disease mutants destabilize this interface.

    Evidence Co-crystal structure at 2.75 Å, binding preference mapping, missense mutant analysis

    PMID:25525273

    Open questions at the time
    • Stoichiometry of PTB engagement not resolved at this stage
    • Downstream effect of binding loss not measured here
  13. 2015 High

    Established the effector mechanism of the vascular complex: CCM2 (and CCM2L) bind MEKK3 to suppress its kinase activity and the ERK5 transcriptional program, with mekk3 silencing rescuing ccm2 phenotypes.

    Evidence In vitro Co-IP, MEKK3-MEK5 kinase assay, endothelial siRNA, and zebrafish epistasis

    PMID:26540726

    Open questions at the time
    • Did not define the transcription factors downstream of ERK5
    • Mechanism of MEKK3 inhibition structurally undefined
  14. 2016 Medium

    Confirmed MEKK3 as the genetically epistatic effector in vivo, with Mekk3 heterozygosity preventing CCM lesions in Ccm2-deficient endothelium.

    Evidence Micro-CT of mouse brains combining endothelial Ccm2 deletion with Mekk3 heterozygosity

    PMID:27513872

    Open questions at the time
    • Single rescue method
    • Does not address the cytoskeletal arm of CCM2 function
  15. 2016 High

    Defined a parallel cytoskeletal mechanism: the CCM1-CCM2 scaffold promotes ROCK2-VE-cadherin association and limits ROCK1, with ROCK1 silencing restoring junction stability and rescuing zebrafish defects.

    Evidence siRNA, Co-IP, traction force microscopy, isoform-specific knockdown, zebrafish rescue

    PMID:30030370

    Open questions at the time
    • How CCM2 differentially partitions ROCK1 vs ROCK2 structurally unknown
    • Integration with the MEKK3 arm not resolved
  16. 2017 Medium

    Connected CCM2 to ANP/GC-A signaling, showing it is required downstream for PAK4-dependent MLC phosphorylation and endothelial cell spreading.

    Evidence siRNA, MLC phosphorylation Western blot, and cell spreading assay

    PMID:28432261

    Open questions at the time
    • Direct CCM2-PAK4 interaction not established
    • Single lab
  17. 2019 Medium

    Revealed isoform diversity by identifying an atypical PTB domain in long CCM2 isoforms that binds CCM1 and CCM3 competitively, making CCM2 a dual-PTB protein with distinct subcellular distributions.

    Evidence Cloning, subcellular localization, and competitive-binding Co-IP of splice variants

    PMID:31676827

    Open questions at the time
    • Functional consequence of competitive CCM1/CCM3 binding untested
    • Tissue specificity of isoform roles unknown
  18. 2020 Medium

    Identified a shared downstream output, showing CCM2 loss (like CCM1/CCM3) impairs fibronectin matrix production and that fibronectin supplementation rescues morphology and suppresses stress fibers.

    Evidence CRISPR/Cas9 KO in human endothelial cells, fibronectin rescue, spheroid and actin imaging

    PMID:32515053

    Open questions at the time
    • Mechanism linking CCM2 loss to reduced fibronectin not defined
    • Single lab
  19. 2021 Medium

    Extended the cytoskeletal phenotype to cell-state reprogramming, showing CCM2 silencing drives a ROCK-dependent senescence-associated secretory phenotype that recruits neighboring cells.

    Evidence siRNA, SA-β-gal senescence assays, traction force microscopy, transcriptomics, ECM invasion

    PMID:34342749

    Open questions at the time
    • Causal transcriptional drivers of SASP not pinpointed
    • Single lab
  20. 2023 Medium

    Broadened the developmental role beyond endothelium, showing epicardial CCM2 maintains cytoskeletal/matrix protein production needed for cardiac development and post-infarction regeneration.

    Evidence Epicardial-specific conditional KO mice, ex vivo cell assays, proteomics, MI model

    PMID:38510716

    Open questions at the time
    • Molecular pathway in epicardium not linked to MEKK3 or ROCK arms
    • Single lab
  21. 2026 High

    Resolved the stoichiometry of transcriptional control, showing two CCM2 PTB domains must cluster on a single KRIT1 (binding the second and third NPxF motifs) to restrain KLF4 expression, a novel dual-PTB recruitment mechanism.

    Evidence Endothelial knockdown/reconstitution, Co-IP, biophysics of purified proteins, co-crystallography

    PMID:41688454

    Open questions at the time
    • How KLF4 restraint integrates with MEKK3/ERK5 signaling not fully mapped
    • Relevance of dual-PTB clustering to ROCK arm untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CCM2's distinct functional arms—MEKK3/KLF4 transcriptional restraint, ROCK1/ROCK2 cytoskeletal control, fibronectin matrix production, and TrkA/STK25 apoptosis—are coordinated within or partitioned across its domains and isoforms remains unresolved.
  • No unified structural model integrating MEKK3 and ROCK functions
  • Functional division of labor among CCM2 isoforms undefined
  • Mechanistic link between scaffold loss and reduced fibronectin not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 5 GO:0098772 molecular function regulator activity 3 GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0005829 cytosol 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 3 R-HSA-1474244 Extracellular matrix organization 2 R-HSA-5357801 Programmed Cell Death 2
Partners
KLF4KRIT1MAP3K3NTRK1PDCD10ROCK1ROCK2STK25
Complex memberships
CCM complex (CCM1-CCM2-CCM3)

Evidence

Reading pass · 21 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 CCM2 (malcavernin/OSM) directly interacts with CCM1 (KRIT1) via the phosphotyrosine binding (PTB) domain of CCM2, and this interaction is dependent on the PTB domain. A familial CCM2 missense mutation abrogates the CCM1/CCM2 interaction. CCM2 also forms a ternary complex with CCM1 and MEKK3. CCM2 and ICAP1 bound to CCM1 via their respective PTB domains differentially influence the subcellular localization of CCM1. Co-immunoprecipitation, fluorescence resonance energy transfer (FRET), subcellular localization assays, missense mutant analysis Human molecular genetics High 16037064
2007 CCM3 (PDCD10) coprecipitates and colocalizes with CCM2, indicating a physical interaction. STK25 also forms a protein complex with CCM2, linking CCM2 to GCKIII kinase signaling. Co-immunoprecipitation, colocalization by immunofluorescence, Yeast two-hybrid Neurogenetics Medium 17657516
2008 An in-frame deletion of CCM2 exon 2 (p.P11_K68del) results in a protein that can bind CCM3 but loses the ability to interact with CCM1 and to form a CCM1/CCM2/CCM3 ternary complex, demonstrating that the N-terminal region of CCM2 is required for CCM1 binding and that full-length CCM2 is the essential core of the CCM1/CCM2/CCM3 complex. Cell culture expression of deletion mutant, co-immunoprecipitation Human mutation Medium 18300272
2009 CCM2 is required in endothelial cells for proper vascular development; endothelial-specific deletion of CCM2 severely impairs angiogenesis, causing morphogenic defects in major arterial/venous blood vessels and heart, leading to embryonic lethality at mid-gestation. Deletion from neuroglial precursor cells does not produce cerebrovascular defects. Tissue-specific conditional knockout mice (Cre-lox), embryonic phenotype analysis Disease models & mechanisms High 19259391
2009 CCM2 interacts with the juxtamembrane region of TrkA receptor tyrosine kinase via its PTB domain and mediates TrkA-induced cell death. Both the PTB domain (for interaction specificity) and the Karet domain (for linking to death pathways) of CCM2 are required for TrkA-dependent cell death. Downregulation of CCM2 attenuates TrkA-dependent death in medulloblastoma and neuroblastoma cells. Co-immunoprecipitation, domain deletion/mutation analysis, siRNA knockdown, cell death assays Neuron High 19755102
2011 Endothelial-specific Ccm2 deletion at postnatal day 1 in mice results in vascular lesions mimicking human CCM, restricted to the venous bed in cerebellum and retina. The consequences of Ccm2 loss depend on the developmental timing of ablation. Inducible endothelial-specific conditional knockout mice (postnatal Cre-lox), histology, MRI The Journal of experimental medicine High 21859843
2011 In zebrafish, ccm2 (valentine) mutants display heart and circulation defects distinct from ccm3 mutants. ccm2 defects cannot be rescued by overexpression of stk25b (unlike ccm3), and additional loss of ccm3 in ccm2 mutants produces synergistic cranial vessel dilation, supporting CCM2 and CCM3 acting via distinct pathways. Zebrafish genetic mutants, morpholino knockdown, epistasis/genetic interaction analysis, overexpression rescue Developmental biology High 22182521
2012 STK25 (GCKIII kinase) interacts with CCM2 and is identified as a novel CCM2 interactor by affinity proteomics. STK25, but not STK24, mediates TrkA/CCM2-dependent cell death in medulloblastoma cells; CCM2 can be phosphorylated by STK25, and STK25 kinase activity is required for death signaling downstream of TrkA/CCM2. Affinity proteomics (BioID/AP-MS), co-immunoprecipitation, siRNA knockdown, kinase assay, cell death assay The Journal of biological chemistry High 22782892
2012 The C-terminal domain of CCM2 adopts a folded helical structure homologous to the N-terminal domain of harmonin, named the CCM2 harmonin-homology domain (HHD). The crystal structure was determined at 1.9 Å resolution; analytical ultracentrifugation showed this domain is monomeric. X-ray crystallography (1.9 Å), analytical ultracentrifugation FEBS letters High 23266514
2013 ccm2-like (ccm2l) binds CCM1 (Ccm1) and acts as a component of the Heg-CCM pathway in zebrafish cardiovascular development. ccm2 overexpression can partially rescue ccm2l morphant defects. Deletion and mutational analyses defined the regions of CCM1 that mediate binding to CCM2l and CCM2. Morpholino knockdown in zebrafish, mRNA overexpression rescue, co-immunoprecipitation, deletion/mutational analysis Developmental biology Medium 23328253
2014 The CCM2 PTB domain displays preferential binding to the third NPX(Y/F) motif of KRIT1. The 2.75 Å co-crystal structure of the CCM2 PTB domain with a KRIT1 NPX(Y/F)3 peptide reveals a Dab-like PTB fold for CCM2. Disease-associated CCM2 missense mutations can destabilize the CCM2 PTB domain and disrupt the KRIT1-CCM2 interaction. X-ray crystallography (co-crystal at 2.75 Å), binding preference mapping, missense mutant functional analysis The Journal of biological chemistry High 25525273
2015 Both CCM2 and CCM2L bind MEKK3 in a complex with CCM1 and interfere with MEKK3 activation and its ability to phosphorylate MEK5 (downstream target). In endothelial cells, CCM2 deletion leads to activation of ERK5 and a MEKK3-dependent transcriptional program. In zebrafish, silencing of mekk3 rescues the big heart and body axis phenotype caused by ccm2l/ccm2 knockdown. Co-immunoprecipitation (in vitro), MEKK3 kinase assay (MEK5 phosphorylation), siRNA knockdown in endothelial cells, zebrafish morpholino knockdown and genetic rescue Proceedings of the National Academy of Sciences of the United States of America High 26540726
2016 The CCM1-CCM2 complex acts as a scaffold to promote ROCK2 interactions with VE-cadherin and to limit ROCK1 kinase activity. Loss of CCM2 leads to excessive ROCK1-dependent actin stress fibers and destabilized intercellular junctions. Silencing of ROCK1 (but not ROCK2) restores adhesive and mechanical homeostasis of CCM1/CCM2-depleted endothelial monolayers and rescues cardiovascular defects in ccm1 mutant zebrafish. siRNA knockdown, Co-IP, traction force microscopy, zebrafish genetic rescue, ROCK1/ROCK2 isoform-specific knockdown Journal of cell science High 30030370
2016 Micro-CT imaging in mice showed that Mekk3 heterozygosity prevents CCM lesion formation in Ccm2-deficient neonatal endothelium, placing MEKK3 downstream of CCM2 in a genetic epistasis relationship in vivo. Micro-CT imaging of mouse brains, Ccm2 endothelial-specific deletion combined with Mekk3 heterozygous KO PloS one Medium 27513872
2017 CCM2 and PAK4 are required downstream of ANP/GC-A signaling for phosphorylation of myosin light chain (MLC) and promotion of endothelial cell spreading. siRNA knockdown of CCM2 abolishes ANP-induced MLC phosphorylation and cell spreading in GC-A-expressing mouse endothelial cells. siRNA knockdown, MLC phosphorylation assay (Western blot), cell spreading assay The Biochemical journal Medium 28432261
2019 CCM2 has an atypical PTB (aPTB) domain identified from alternatively spliced isoforms. Both CCM1 and CCM3 can bind competitively to this aPTB domain. Some long CCM2 isoforms contain both a typical PTB and the aPTB domain, making CCM2 a dual PTB domain-containing protein. CCM2 isoforms show distinct subcellular compartmentalization and cell/tissue-specific expression patterns. Molecular cloning, subcellular localization assays, co-immunoprecipitation (competitive binding), splice variant characterization Scientific reports Medium 31676827
2021 CCM2-silenced endothelial cells undergo a ROCK-dependent reprogramming into senescence-associated secretory phenotype (SASP), driving extracellular matrix invasion and chemoattraction of surrounding wild-type endothelial and immune cells. This SASP is driven by cytoskeletal, molecular, and transcriptomic disorders provoked by ROCK dysfunction. siRNA knockdown of CCM2, senescence assays (SA-β-gal), traction force microscopy, transcriptomic analysis, ECM invasion assay Angiogenesis Medium 34342749
2023 CCM2 in epicardial cells is required for cardiac development and regeneration. Loss of epicardial Ccm2 delays cardiac function recovery and aggravates cardiac fibrosis after myocardial infarction. Mechanistically, CCM2 targets production of cytoskeletal and matrix proteins to maintain epicardial cell adhesion, polarity, spreading, and migration. Epicardial-specific Ccm2 conditional knockout mice, ex vivo epicardial cell assays (adhesion, polarity, spreading, migration), proteomics/Western blot for cytoskeletal proteins, myocardial infarction model JACC. Basic to translational science Medium 38510716
2020 CRISPR/Cas9-mediated knockout of CCM1 or CCM2 (as well as CCM3) in human endothelial cells impairs fibronectin expression and reduces fibronectin fiber formation in the extracellular matrix, demonstrating that impaired production of a functional fibronectin matrix is a common feature of CCM1-, CCM2-, and CCM3-deficient endothelial cells. Fibronectin supplementation rescued aberrant spheroid formation and altered EC morphology, and suppressed actin stress fiber formation. CRISPR/Cas9 KO in human endothelial cells, fibronectin rescue experiments, spheroid assay, actin imaging FASEB journal Medium 32515053
2026 To restrain KLF4 expression in endothelial cells, two CCM2 molecules must cluster on a single KRIT1, with the PTB domain of each CCM2 binding either the second or third NPxF motif within KRIT1. This dual PTB-domain recruitment to a single peptide scaffold is a previously unobserved mechanism. Loss of either KRIT1 or CCM2 causes over-expression of KLF4. Knockdown and reconstitution in endothelial cell lines, co-immunoprecipitation, biophysical analysis of purified proteins, co-crystallography Nature communications High 41688454
2008 Complete localized loss of CCM2 protein expression (but not CCM1 or CCM3) is observed specifically in cavernous endothelial cells of CCM2 germline mutation carriers, establishing endothelial cell-specific somatic second-hit loss of function and identifying the endothelial cell as the cell of disease origin. Immunohistochemistry of human CCM tissue from germline mutation carriers, protein expression analysis Human molecular genetics Medium 19088124

Source papers

Stage 0 corpus · 59 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 CCM1 and CCM2 protein interactions in cell signaling: implications for cerebral cavernous malformations pathogenesis. Human molecular genetics 200 16037064
2004 Mutations within the MGC4607 gene cause cerebral cavernous malformations. American journal of human genetics 180 14740320
2008 A two-hit mechanism causes cerebral cavernous malformations: complete inactivation of CCM1, CCM2 or CCM3 in affected endothelial cells. Human molecular genetics 157 19088124
2007 CCM3 interacts with CCM2 indicating common pathogenesis for cerebral cavernous malformations. Neurogenetics 139 17657516
2011 Developmental timing of CCM2 loss influences cerebral cavernous malformations in mice. The Journal of experimental medicine 124 21859843
2009 Tissue-specific conditional CCM2 knockout mice establish the essential role of endothelial CCM2 in angiogenesis: implications for human cerebral cavernous malformations. Disease models & mechanisms 92 19259391
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
2006 Deletions in CCM2 are a common cause of cerebral cavernous malformations. American journal of human genetics 67 17160895
2011 Ccm3 functions in a manner distinct from Ccm1 and Ccm2 in a zebrafish model of CCM vascular disease. Developmental biology 65 22182521
2015 The cerebral cavernous malformation proteins CCM2L and CCM2 prevent the activation of the MAP kinase MEKK3. Proceedings of the National Academy of Sciences of the United States of America 62 26540726
2010 Differential angiogenesis function of CCM2 and CCM3 in cerebral cavernous malformations. Neurosurgical focus 58 20809750
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
2006 Neuronal expression of the Ccm2 gene in a new mouse model of cerebral cavernous malformations. Mammalian genome : official journal of the International Mammalian Genome Society 48 16465592
2009 CCM2 mediates death signaling by the TrkA receptor tyrosine kinase. Neuron 47 19755102
2007 Mouse preimplantation embryo responses to culture medium osmolarity include increased expression of CCM2 and p38 MAPK activation. BMC developmental biology 43 17214902
2018 The CCM1-CCM2 complex controls complementary functions of ROCK1 and ROCK2 that are required for endothelial integrity. Journal of cell science 42 30030370
2005 CCM2 expression parallels that of CCM1. Stroke 41 16373645
2014 Structural basis for the disruption of the cerebral cavernous malformations 2 (CCM2) interaction with Krev interaction trapped 1 (KRIT1) by disease-associated mutations. The Journal of biological chemistry 35 25525273
2014 PTEN/PI3K/Akt/VEGF signaling and the cross talk to KRIT1, CCM2, and PDCD10 proteins in cerebral cavernous malformations. Neurosurgical review 34 25403688
2012 Structural studies of cerebral cavernous malformations 2 (CCM2) reveal a folded helical domain at its C-terminus. FEBS letters 33 23266514
2007 Highly variable penetrance in subjects affected with cavernous cerebral angiomas (CCM) carrying novel CCM1 and CCM2 mutations. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 30 17440989
2013 ccm2-like is required for cardiovascular development as a novel component of the Heg-CCM pathway. Developmental biology 29 23328253
2003 Linkage to the CCM2 locus and genetic heterogeneity in familial cerebral cavernous malformation. The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques 25 12774951
2018 Two Novel KRIT1 and CCM2 Mutations in Patients Affected by Cerebral Cavernous Malformations: New Information on CCM2 Penetrance. Frontiers in neurology 24 30487773
2021 CCM2-deficient endothelial cells undergo a ROCK-dependent reprogramming into senescence-associated secretory phenotype. Angiogenesis 20 34342749
2019 Alternatively spliced isoforms reveal a novel type of PTB domain in CCM2 protein. Scientific reports 20 31676827
2012 STK25 protein mediates TrkA and CCM2 protein-dependent death in pediatric tumor cells of neural origin. The Journal of biological chemistry 20 22782892
2007 Study of cerebral cavernous malformation in Spain and Portugal: high prevalence of a 14 bp deletion in exon 5 of MGC4607 (CCM2 gene). Journal of neurology 15 17345049
2016 Micro-CT Imaging Reveals Mekk3 Heterozygosity Prevents Cerebral Cavernous Malformations in Ccm2-Deficient Mice. PloS one 14 27513872
2011 A founder mutation in the Ashkenazi Jewish population affecting messenger RNA splicing of the CCM2 gene causes cerebral cavernous malformations. Genetics in medicine : official journal of the American College of Medical Genetics 14 21543988
2010 Genetic variations within KRIT1/CCM1, MGC4607/CCM2 and PDCD10/CCM3 in a large Italian family harbouring a Krit1/CCM1 mutation. Journal of molecular neuroscience : MN 14 20419355
2012 CCM2 gene polymorphisms in Italian sporadic patients with cerebral cavernous malformation: a case-control study. International journal of molecular medicine 12 22378217
2020 Fibronectin rescues aberrant phenotype of endothelial cells lacking either CCM1, CCM2 or CCM3. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 11 32515053
2017 High-throughput sequencing of the entire genomic regions of CCM1/KRIT1, CCM2 and CCM3/PDCD10 to search for pathogenic deep-intronic splice mutations in cerebral cavernous malformations. European journal of medical genetics 10 28645800
2016 A Novel CCM2 Gene Mutation Associated with Familial Cerebral Cavernous Malformation. Frontiers in aging neuroscience 9 27708576
2015 Expression of CCM2 and CCM3 during mouse gonadogenesis. Journal of assisted reproduction and genetics 9 26386873
2012 Identification of a novel CCM2 gene mutation in an Italian family with multiple cerebral cavernous malformations and epilepsy: a causative mutation? Gene 9 23000020
2023 Epicardial CCM2 Promotes Cardiac Development and Repair Via its Regulation on Cytoskeletal Reorganization. JACC. Basic to translational science 8 38510716
2020 A Novel CCM2 Gene Mutation Associated With Cerebral Cavernous Malformation. Frontiers in neurology 8 32117029
2019 CCM1 and CCM2 variants in patients with cerebral cavernous malformation in an ethnically Chinese population in Taiwan. Scientific reports 8 31455779
2019 Novel Pathogenic Variants in a Cassette Exon of CCM2 in Patients With Cerebral Cavernous Malformations. Frontiers in neurology 7 31824402
2015 A Novel MGC4607/CCM2 Gene Mutation Associated with Cerebral Spinal and Cutaneous Cavernous Angiomas. Journal of molecular neuroscience : MN 6 25869611
2012 De novo MGC4607 gene heterozygous missense variants in a child with multiple cerebral cavernous malformations. Journal of molecular neuroscience : MN 6 22415356
2024 Loss of heterozygosity in CCM2 cDNA revealing a structural variant causing multiple cerebral cavernous malformations. European journal of human genetics : EJHG 5 38755314
2018 Novel KRIT1/CCM1 and MGC4607/CCM2 Gene Variants in Chinese Families With Cerebral Cavernous Malformations. Frontiers in neurology 5 30622508
2016 A novel CCM2 variant in a family with non-progressive cognitive complaints and cerebral microbleeds. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 5 27277535
2009 CCM2 and CCM3 proteins contribute to vasculogenesis and angiogenesis in human placenta. Histology and histopathology 5 19688696
2019 Two Novel CCM2 Heterozygous Mutations Associated with Cerebral Cavernous Malformation in a Chinese Family. Journal of molecular neuroscience : MN 4 30701383
2017 CCM2 and PAK4 act downstream of atrial natriuretic peptide signaling to promote cell spreading. The Biochemical journal 4 28432261
2024 Cerebral cavernous malformation proteins, CCM1, CCM2 and CCM3, are decreased in metastatic lesions in a murine breast carcinoma model. Biotechnic & histochemistry : official publication of the Biological Stain Commission 3 38293758
2021 A Novel CCM2 Missense Variant Caused Cerebral Cavernous Malformations in a Chinese Family. Frontiers in neuroscience 3 33469417
2012 Crystallization and preliminary X-ray analysis of the C-terminal domain of CCM2, part of a novel adaptor protein involved in cerebral cavernous malformations. Acta crystallographica. Section F, Structural biology and crystallization communications 3 22684070
2024 Comprehensive analysis of Novel mutations in CCM1/KRIT1 and CCM2/MGC4607 and their clinical implications in Cerebral Cavernous malformations. Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association 2 39181174
2020 First Report of Concomitant Pathogenic Mutations Within MGC4607/CCM2 and KRIT1/CCM1 in a Familial Cerebral Cavernous Malformation Patient. World neurosurgery 2 32615293
2011 CCM2 expression during prenatal development and adult human neocortex. International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience 2 21569831
2009 Live or let die: CCM2 provides the link. Neuron 2 19755097
2022 In-silico analysis of nonsynonymous genomic variants within CCM2 gene reaffirm the existence of dual cores within typical PTB domain. Biochemistry and biophysics reports 1 35128084
2020 Familial cerebral cavernous malformation presenting with epilepsy caused by mutation in the CCM2 gene: A case report. Medicine 1 32702807
2026 Dual recruitment of two CCM2 molecules to KRIT1 suppresses KLF4 expression. Nature communications 0 41688454

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