Affinage

CCM2

Cerebral cavernous malformations 2 protein · UniProt Q9BSQ5

Round 2 corrected
Length
444 aa
Mass
48.8 kDa
Annotated
2026-04-28
130 papers in source corpus 27 papers cited in narrative 26 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CCM2 (malcavernin) is an endothelial scaffold protein whose loss-of-function mutations cause cerebral cavernous malformations through a two-hit mechanism (PMID:14624391, PMID:19088123). Its Dab-like PTB domain binds the third NPXY motif of KRIT1 (CCM1) and recruits the E3 ubiquitin ligase Smurf1 to promote RhoA degradation, while its C-terminal harmonin-homology domain and association with CCM3/GCKIII kinases organize a ternary CCM complex that suppresses MEKK3 kinase activity and downstream KLF2/KLF4 transcriptional signaling (PMID:25525273, PMID:19318350, PMID:27027284). Loss of CCM2 in endothelial cells causes RHOA/ROCK1 hyperactivation, cytoskeletal disorganization, junction destabilization, and MEKK3-driven transcriptional reprogramming that collectively produce the dilated, hemorrhagic vascular lesions of CCM disease (PMID:19151728, PMID:20308363, PMID:30030370). Endothelial-specific deletion in neonatal mice recapitulates human CCM lesions, and these are rescued by genetic reduction of Mekk3 or pharmacological ROCK inhibition (PMID:21859843, PMID:27513872).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2003 High

    Identification of CCM2 as the causative gene for type 2 cerebral cavernous malformations resolved the molecular basis of the second CCM locus and revealed that the encoded protein harbors a PTB domain suggestive of integrin-associated signaling.

    Evidence Positional cloning and mutation analysis in nine CCM2 families

    PMID:14624391 PMID:14740320

    Open questions at the time
    • Binding partners and signaling pathway unknown
    • Mechanism connecting CCM2 loss to vascular lesion formation uncharacterized
  2. 2005 High

    Demonstrating that CCM2 directly binds KRIT1 (CCM1) via its PTB domain and that both co-assemble with MEKK3 into a ternary complex established the biochemical core of the CCM signaling pathway and explained why mutations in different CCM genes produce the same disease.

    Evidence Co-immunoprecipitation, FRET, subcellular localization, and disease-mutation functional analysis in cell culture

    PMID:16037064

    Open questions at the time
    • Structural basis of CCM2–KRIT1 interaction unresolved
    • Downstream signaling consequences of the CCM2–MEKK3 interaction unknown
  3. 2007 High

    Discovery that CCM3 and GCKIII kinases (STK25) co-precipitate with CCM2 extended the CCM complex to include all three disease gene products and linked them to a common kinase signaling axis.

    Evidence Co-immunoprecipitation, yeast two-hybrid, co-localization, kinase assays

    PMID:17290187 PMID:17657516

    Open questions at the time
    • Functional consequence of STK25-mediated phosphorylation on CCM2 unknown
    • Whether CCM3 acts solely through CCM2 or has independent functions unclear
  4. 2008 High

    Identification of biallelic (germline + somatic) CCM2 mutations restricted to endothelial cells within lesions established a two-hit tumor-suppressor mechanism for CCM pathogenesis, explaining lesion focality.

    Evidence Subcloning/sequencing of CCM lesion tissue with immunohistochemistry for CCM protein loss

    PMID:19088123 PMID:19088124

    Open questions at the time
    • Clonal origin of lesion endothelial cells not fully established
    • Whether complete CCM2 loss is sufficient or requires additional stochastic events unclear
  5. 2009 High

    Endothelial-specific Ccm2 knockout mice revealed that CCM2 loss activates RhoA, disrupts vascular lumen formation, and causes embryonic lethality—phenotypes rescued by statin treatment—while the parallel discovery that CCM2 recruits Smurf1 for ubiquitin-dependent RhoA degradation provided the molecular mechanism underlying RhoA hyperactivation.

    Evidence Endothelial-specific conditional knockout mice, Rho activity assays, simvastatin rescue, Smurf1 co-IP, ubiquitination assays, cell migration assays

    PMID:19151727 PMID:19151728 PMID:19259391 PMID:19318350

    Open questions at the time
    • Whether Smurf1-mediated RhoA degradation is the sole mechanism of RhoA regulation by CCM2
    • Relative contribution of lumen defects versus junction defects to lesion formation unresolved
  6. 2009 High

    The finding that the CCM1–CCM2 complex localizes to cell–cell junctions and that haploinsufficient mice exhibit ROCK-dependent vascular leak reversible by fasudil established ROCK as a therapeutic target and connected CCM2 to endothelial barrier maintenance.

    Evidence Mouse haploinsufficiency models, permeability assays, ROCK inhibitor treatment, human CCM tissue immunohistochemistry

    PMID:20308363

    Open questions at the time
    • ROCK1 versus ROCK2 isoform specificity not yet distinguished
    • Long-term efficacy and safety of ROCK inhibition in CCM not tested
  7. 2009 High

    CCM2 was shown to bind the TrkA receptor via its PTB domain and mediate neurotrophin-induced cell death in neural tumor cells, broadening CCM2 function beyond vascular biology.

    Evidence Co-immunoprecipitation, domain mutagenesis, siRNA knockdown, cell death assays in medulloblastoma/neuroblastoma lines

    PMID:19755102

    Open questions at the time
    • Relevance of TrkA–CCM2 interaction to CCM vascular disease unclear
    • Downstream death signaling cascade from CCM2/TrkA incompletely mapped
  8. 2012 High

    High-resolution crystal structures of the CCM2 harmonin-homology domain and, subsequently, the CCM2 PTB–KRIT1 NPX(Y/F)3 co-crystal provided the atomic framework for understanding how disease mutations disrupt complex assembly.

    Evidence X-ray crystallography (1.9 Å HHD; 2.75 Å PTB-peptide complex), analytical ultracentrifugation, peptide binding and mutant analysis

    PMID:23266514 PMID:25525273

    Open questions at the time
    • No full-length CCM2 structure available
    • Structural basis of MEKK3 binding to CCM2 unresolved
  9. 2015 High

    Demonstrating that CCM2 (and CCM2L) directly inhibit MEKK3 kinase activity toward MEK5, and that mekk3 silencing rescues ccm2 zebrafish defects, placed MEKK3 suppression as a central output of the CCM complex.

    Evidence In vitro kinase assay (MEKK3→MEK5), co-immunoprecipitation, zebrafish morpholino epistasis, endothelial CCM2 deletion transcriptomics

    PMID:26540726

    Open questions at the time
    • Mechanism by which CCM2 inhibits MEKK3 kinase activity not structurally resolved
    • Relative contribution of ERK5 versus p38 arms downstream of MEKK3 in lesion formation unclear
  10. 2016 High

    Landmark genetic epistasis in neonatal mice showed that CCM2 loss drives lesion formation through gain-of-function MEKK3–KLF2/KLF4 transcriptional signaling, and that a disease-causing CCM2 mutation selectively disrupts MEKK3 interaction while preserving the CCM1–CCM2–CCM3 complex, separating MEKK3 suppression from complex assembly as distinct CCM2 functions.

    Evidence Neonatal endothelial-specific Ccm2/Mekk3/Klf2/Klf4 knockout mice, lesion endothelial cell transcriptomics, micro-CT quantification, human CCM tissue analysis, CCM2 mutant biochemistry

    PMID:27027284 PMID:27513872

    Open questions at the time
    • Molecular basis of how CCM2 suppresses MEKK3 without disrupting complex formation unresolved
    • Whether KLF2/KLF4 are redundant or each drive distinct pathological features not fully dissected
  11. 2018 High

    Resolution of ROCK isoform specificity showed that the CCM1–CCM2 complex limits ROCK1 activity while promoting ROCK2–VE-cadherin interactions, establishing that selective ROCK1 hyperactivation drives the cytoskeletal and junctional defects in CCM.

    Evidence ROCK1/ROCK2-selective siRNA, co-immunoprecipitation, traction force microscopy, zebrafish rescue

    PMID:30030370

    Open questions at the time
    • How CCM2 discriminates between ROCK1 and ROCK2 at the molecular level unknown
    • Whether ROCK1-selective inhibitors have therapeutic advantage over pan-ROCK inhibitors untested in CCM models

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include the structural mechanism by which CCM2 inhibits MEKK3, whether CCM2 isoform diversity contributes to tissue-specific disease manifestations, and whether the senescence-associated secretory phenotype induced by CCM2 loss represents a therapeutically targetable step in lesion progression.
  • No full-length CCM2 structure or CCM2–MEKK3 co-structure exists
  • Functional significance of >20 predicted CCM2 protein isoforms largely untested
  • SASP contribution to CCM lesion progression observed only in vitro

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 6 GO:0098772 molecular function regulator activity 4
Localization
GO:0005886 plasma membrane 3 GO:0005634 nucleus 1 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 7 R-HSA-1643685 Disease 6 R-HSA-1500931 Cell-Cell communication 3 R-HSA-5357801 Programmed Cell Death 2
Partners
HEG1KRIT1MAP3K3NTRK1PDCD10SMURF1STK24STK25
Complex memberships
CCM1-CCM2-CCM3 complexCCM2-MEKK3 complex

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 CCM2 (MGC4607/malcavernin) was identified as the causative gene for type 2 cerebral cavernous malformations; it encodes a novel protein containing a phosphotyrosine-binding (PTB) domain, similar to the KRIT1 binding partner ICAP1α, suggesting involvement in integrin signaling pathways. Positional cloning, mutation analysis in CCM2 families, domain analysis American journal of human genetics High 14624391
2004 CCM2 gene (MGC4607) was confirmed as the CCM2 locus gene by identification of large genomic deletions and point mutations (loss-of-function) in familial CCM patients; the gene is of unknown function but its inactivation causes cerebral cavernous malformations. High-density microsatellite genotyping, direct sequencing, deletion mapping American journal of human genetics High 14740320
2005 CCM2 (malcavernin/OSM) directly interacts with CCM1 (KRIT1) via its PTB domain; this interaction is required for proper subcellular localization of CCM1; a familial CCM2 missense mutation abrogates the CCM1/CCM2 interaction; CCM1, CCM2, and MEKK3 form a ternary complex; CCM2 is also involved in p38 MAPK signaling. Co-immunoprecipitation, fluorescence resonance energy transfer (FRET), subcellular localization studies, missense mutation functional analysis Human molecular genetics High 16037064
2007 CCM3 (PDCD10) co-precipitates and co-localizes with CCM2; CCM2 forms a protein complex with STK25 (SOK1/YSK1); CCM3 is phosphorylated by STK25 and dephosphorylated by FAP-1 phosphatase, linking all three CCM proteins in a common signaling pathway. Co-immunoprecipitation, co-localization, yeast two-hybrid, kinase/phosphatase assays Neurogenetics High 17657516
2007 Malcavernin (CCM2) binds two of the three NPXY motifs of KRIT1 via its PTB domain; malcavernin protein is cytoplasmic at steady state but can shuttle between nucleus and cytoplasm despite lacking classical nuclear localization or export signals. Yeast two-hybrid, co-immunoprecipitation, epitope mapping, immunocytochemistry Neurosurgery High 17290187
2007 Mouse preimplantation embryos express CCM2 (the mammalian ortholog of OSM, the osmosensing scaffold for MEKK3) throughout development; CCM2 protein levels increase in response to hyperosmotic media in conjunction with elevated p38 MAPK activation, identifying CCM2 as part of the MEKK3–p38 MAPK osmosensing pathway. RT-PCR, Western blot, immunofluorescence, hyperosmotic stress assay in embryos BMC developmental biology Medium 17214902
2008 An in-frame deletion of CCM2 exon 2 (p.P11_K68del) produces a protein that can interact with CCM3 but loses the ability to interact with CCM1 or to form the 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 core of the CCM complex. Cell culture expression, co-immunoprecipitation, functional mutation analysis Human mutation High 18300272
2009 CCM2 loss in mice results in failed vascular lumen formation and early embryonic death via an endothelial cell-autonomous mechanism; loss of CCM2 activates RHOA GTPase, causing cytoskeletal and cell-junction defects; these phenotypes are rescued by simvastatin (a Rho GTPase inhibitor), establishing CCM2 as a regulator of endothelial cytoskeletal architecture through RHOA. Endothelial-specific Ccm2 knockout mice, in vitro lumen formation assays, Rho activity assays, pharmacological rescue with simvastatin Nature medicine High 19151728
2009 The physical interaction between KRIT1 (CCM1) and CCM2 is required for localization of both proteins to endothelial cell-cell junctions; loss of either protein sustains RHOA and Rho kinase (ROCK) activity, destabilizing barrier function; Krit1+/− and Ccm2+/− mice exhibit increased vascular leak reversible by the ROCK inhibitor fasudil; human CCM endothelium shows increased myosin light chain phosphorylation consistent with ROCK hyperactivity. Protein interaction studies, mouse haploinsufficiency models, in vitro permeability assays, ROCK inhibitor treatment, human CCM tissue analysis The Journal of experimental medicine High 20308363
2009 CCM2 interacts with the E3 ubiquitin ligase Smurf1 via its PTB domain; this interaction promotes Smurf1-mediated ubiquitin-dependent degradation of RhoA; CCM2 does not alter Smurf1 catalytic activity but localizes Smurf1 for RhoA degradation; CCM2 knockdown in brain endothelial cells increases RhoA protein and impairs directed cell migration. Co-immunoprecipitation, siRNA knockdown, RhoA degradation assay, cell migration assay The Journal of biological chemistry High 19318350
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 and Karet domains of CCM2 are required for TrkA-dependent death signaling; downregulation of CCM2 in medulloblastoma or neuroblastoma cells attenuates TrkA-dependent death. Co-immunoprecipitation, domain mutagenesis, siRNA knockdown, cell death assays in tumor cell lines Neuron High 19755102
2009 HEG1 receptor is selectively expressed in endothelial cells and couples to KRIT1 at cell junctions; Heg1−/−; Ccm2lacZ/+ mice and Ccm2lacZ/lacZ mice have severe cardiovascular defects, establishing the HEG1-CCM signaling pathway as a crucial regulator of heart and vessel integrity; CCM2 loss in endothelial cells reproduces these junction defects in vitro. Mouse genetics (knockout, hypomorphic alleles), zebrafish morpholino knockdown, biochemical/imaging analysis of junctions, cell culture Nature medicine High 19151727
2009 Endothelial-specific CCM2 deletion causes embryonic lethality with severe angiogenesis defects in major vessels and heart, while neuroglial-specific deletion causes no cerebrovascular defects, establishing that CCM2 is required cell-autonomously in endothelial cells for proper vascular development. Tissue-specific conditional Ccm2 knockout mice (Cre-lox), embryonic phenotyping Disease models & mechanisms High 19259391
2011 Postnatal endothelial-specific Ccm2 deletion (day P1) in mice produces vascular lesions that mimic human CCM, predominantly in the venous bed of cerebellum and retina; CCM lesion formation depends on the developmental timing of Ccm2 ablation, demonstrating that the postnatal angiogenic window is critical for CCM lesion development. Inducible endothelial-specific Ccm2 conditional knockout mice, histopathology, comparison with Ccm1/Ccm3 deletions The Journal of experimental medicine High 21859843
2011 In zebrafish, ccm3 but not ccm2 defects can be rescued by overexpression of stk25b (GCKIII kinase); additional loss of ccm3 in ccm2 mutants synergistically increases cranial vessel dilation, supporting a model where CCM3 acts via GCKIII activity in a pathway distinct from CCM1/CCM2. Zebrafish genetic epistasis, morpholino knockdown, overexpression rescue experiments Developmental biology High 22182521
2012 STK25 and STK24 (GCKIII kinases) are novel CCM2 interactors; STK25 (but not STK24) is part of the TrkA/CCM2 death-signaling pathway, can phosphorylate CCM2, and its kinase activity is required for NGF/TrkA-induced death in medulloblastoma cells. Affinity proteomics (AP-MS), siRNA knockdown, in vitro kinase assay, cell death assay The Journal of biological chemistry High 22782892
2012 The C-terminus of CCM2 contains a previously uncharacterized folded helical domain structurally homologous to the N-terminal domain of harmonin, named the CCM2 harmonin-homology domain (HHD); the 1.9 Å crystal structure reveals two conformations and an unusually long 13-residue 3(10) helix; analytical ultracentrifugation characterizes its oligomerization state. X-ray crystallography (1.9 Å resolution), analytical ultracentrifugation FEBS letters High 23266514
2013 CCM2-like (ccm2l) binds CCM1 (Ccm1) and functions as part of the Heg-CCM pathway in zebrafish cardiovascular development; ccm2 overexpression partially rescues ccm2l morphant defects; deletion and mutational analyses define regions of CCM1 required for binding CCM2, CCM2L, and HEG. Zebrafish morpholino knockdown, co-injection epistasis, protein binding assays, deletion/mutational mapping Developmental biology High 23328253
2014 The CCM2 PTB domain displays preferential binding to the third of three KRIT1 NPX(Y/F) motifs; the 2.75 Å co-crystal structure of the CCM2 PTB domain with KRIT1 NPX(Y/F)3 peptide reveals a Dab-like PTB fold; several disease-associated CCM2 missense mutations destabilize the PTB domain and disrupt KRIT1 binding. X-ray co-crystallography (2.75 Å), peptide binding assays, missense mutation functional analysis The Journal of biological chemistry High 25525273
2015 Both CCM2 and CCM2L bind MEKK3 in complex with CCM1 and inhibit MEKK3 activation and its phosphorylation of MEK5; knockdown of ccm2l and ccm2 together in zebrafish causes more severe cardiac and body axis defects than ccm2 alone; silencing of mekk3 rescues these defects; CCM2 deletion in endothelial cells activates ERK5 and a transcriptional program downstream of MEKK3. Co-immunoprecipitation, in vitro kinase assay (MEKK3→MEK5), zebrafish morpholino epistasis, endothelial cell CCM2 deletion Proceedings of the National Academy of Sciences of the United States of America High 26540726
2016 CCM disease arises from endothelial gain-of-function of MEKK3-KLF2/4 signaling: loss of CCM2 (or CCM1/CCM3) in neonatal mouse endothelium upregulates MEKK3 target genes Klf2 and Klf4, and increases Rho activity; endothelial-specific loss of Mekk3, Klf2, or Klf4 markedly prevents CCM lesion formation; a disease-causing CCM2 mutation abrogates MEKK3 interaction without disrupting CCM complex formation. Neonatal endothelial-specific knockout mice, transcriptomics of CCM lesion endothelial cells, genetic epistasis, human familial/sporadic CCM tissue analysis, mutant CCM2 biochemistry Nature High 27027284
2016 Mekk3 heterozygosity prevents CCM lesion formation in Ccm2-deficient neonatal mice, demonstrated by quantitative micro-CT imaging, confirming that MEKK3 is a downstream effector of CCM2 in vivo. Micro-CT imaging of mouse brains, genetic epistasis (Ccm2 deletion + Mekk3 heterozygosity) PloS one High 27513872
2018 The CCM1-CCM2 complex directly orchestrates complementary roles of ROCK1 and ROCK2: CCM proteins act as a scaffold promoting ROCK2 interactions with VE-cadherin and limiting ROCK1 kinase activity; loss of CCM1 or CCM2 leads to excessive ROCK1-dependent actin stress fibers and destabilized junctions; silencing ROCK1 (not ROCK2) restores adhesive/mechanical homeostasis and rescues cardiovascular defects in ccm1 zebrafish. Co-immunoprecipitation, siRNA knockdown of ROCK isoforms, traction force microscopy, zebrafish rescue experiments Journal of cell science High 30030370
2019 CCM2 gene has 29 novel exons and 4 novel promoters, generating 50 novel alternatively spliced isoforms and 22 novel protein isoforms with distinct subcellular localization and tissue expression patterns; a novel 'atypical PTB (aPTB) domain' distinct from the canonical PTB domain was discovered; both CCM1 and CCM3 competitively bind this aPTB domain, identifying CCM2 as a dual PTB-domain protein and the cornerstone of the CCM signaling complex. Genomic/transcriptomic analysis, subcellular fractionation, Co-immunoprecipitation, tissue-specific expression profiling Scientific reports Medium 31676827
2021 CCM1- and CCM2-silenced endothelial cells enter a senescence-associated secretory phenotype (SASP) driven by ROCK dysfunction; SASP enables CCM2-deficient cells to invade extracellular matrix and attract surrounding wild-type endothelial and immune cells; ROCK inhibition abrogates this SASP program. siRNA knockdown, senescence markers (SA-β-gal, p21), transcriptomics, traction force microscopy, ROCK inhibitor treatment, invasion assay Angiogenesis Medium 34342749
2008 A two-hit mechanism underlies CCM pathogenesis: biallelic (germline + somatic) mutations in CCM1, CCM2, or CCM3 were identified in affected endothelial cells from CCM lesions; somatic mutations are found only in a subset of lesion endothelial cells, not in interstitial cells, confirming that complete loss of function of a CCM gene in endothelial cells drives lesion formation. Subcloning and sequencing of bulk amplicons from CCM lesion tissue, immunohistochemistry for CCM protein loss Human molecular genetics High 19088123 19088124

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
1994 Association and activation of Jak-Tyk kinases by CNTF-LIF-OSM-IL-6 beta receptor components. Science (New York, N.Y.) 929 8272873
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
1997 OSM-9, a novel protein with structural similarity to channels, is required for olfaction, mechanosensation, and olfactory adaptation in Caenorhabditis elegans. The Journal of neuroscience : the official journal of the Society for Neuroscience 468 9334401
2015 Widespread macromolecular interaction perturbations in human genetic disorders. Cell 454 25910212
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
1996 Dual oncostatin M (OSM) receptors. Cloning and characterization of an alternative signaling subunit conferring OSM-specific receptor activation. The Journal of biological chemistry 344 8999038
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2009 The cerebral cavernous malformation signaling pathway promotes vascular integrity via Rho GTPases. Nature medicine 304 19151728
2010 Cerebral cavernous malformations proteins inhibit Rho kinase to stabilize vascular integrity. The Journal of experimental medicine 277 20308363
2003 Mutations in a gene encoding a novel protein containing a phosphotyrosine-binding domain cause type 2 cerebral cavernous malformations. American journal of human genetics 266 14624391
1998 Multilocus linkage identifies two new loci for a mendelian form of stroke, cerebral cavernous malformation, at 7p15-13 and 3q25.2-27. Human molecular genetics 256 9811928
2016 Cerebral cavernous malformations arise from endothelial gain of MEKK3-KLF2/4 signalling. Nature 255 27027284
2008 Biallelic somatic and germline mutations in cerebral cavernous malformations (CCMs): evidence for a two-hit mechanism of CCM pathogenesis. Human molecular genetics 225 19088123
1998 Analysis of osm-6, a gene that affects sensory cilium structure and sensory neuron function in Caenorhabditis elegans. Genetics 203 9475731
2005 CCM1 and CCM2 protein interactions in cell signaling: implications for cerebral cavernous malformations pathogenesis. Human molecular genetics 199 16037064
2001 The C. elegans homolog of the murine cystic kidney disease gene Tg737 functions in a ciliogenic pathway and is disrupted in osm-5 mutant worms. Development (Cambridge, England) 196 11290289
2009 Regulation of cardiovascular development and integrity by the heart of glass-cerebral cavernous malformation protein pathway. Nature medicine 194 19151727
2004 Mutations within the MGC4607 gene cause cerebral cavernous malformations. American journal of human genetics 179 14740320
2013 The protein interaction landscape of the human CMGC kinase group. Cell reports 174 23602568
2009 Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip. American journal of human genetics 164 19913121
2006 Mechanism of transport of IFT particles in C. elegans cilia by the concerted action of kinesin-II and OSM-3 motors. The Journal of cell biology 158 17000880
2008 A two-hit mechanism causes cerebral cavernous malformations: complete inactivation of CCM1, CCM2 or CCM3 in affected endothelial cells. Human molecular genetics 155 19088124
2003 Human chromosome 7: DNA sequence and biology. Science (New York, N.Y.) 154 12690205
2007 CCM3 interacts with CCM2 indicating common pathogenesis for cerebral cavernous malformations. Neurogenetics 139 17657516
2019 Mapping the proximity interaction network of the Rho-family GTPases reveals signalling pathways and regulatory mechanisms. Nature cell biology 137 31871319
2017 RNA-binding activity of TRIM25 is mediated by its PRY/SPRY domain and is required for ubiquitination. BMC biology 135 29117863
2011 Developmental timing of CCM2 loss influences cerebral cavernous malformations in mice. The Journal of experimental medicine 122 21859843
2010 Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score. Molecular medicine (Cambridge, Mass.) 108 20379614
1995 Exclusive expression of C. elegans osm-3 kinesin gene in chemosensory neurons open to the external environment. Journal of molecular biology 103 7714894
2001 The bld1 mutation identifies the Chlamydomonas osm-6 homolog as a gene required for flagellar assembly. Current biology : CB 102 11676919
1993 C. elegans osm-3 gene mediating osmotic avoidance behaviour encodes a kinesin-like protein. Neuroreport 102 7690265
2017 Overexpression of OSM and IL-6 impacts the polarization of pro-fibrotic macrophages and the development of bleomycin-induced lung fibrosis. Scientific reports 94 29038604
2010 Genome-wide YFP fluorescence complementation screen identifies new regulators for telomere signaling in human cells. Molecular & cellular proteomics : MCP 93 21044950
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 OSM-11 facilitates LIN-12 Notch signaling during Caenorhabditis elegans vulval development. PLoS biology 92 18700817
2006 Autoinhibition regulates the motility of the C. elegans intraflagellar transport motor OSM-3. The Journal of cell biology 91 17000874
2008 ccm1 cell autonomously regulates endothelial cellular morphogenesis and vascular tubulogenesis in zebrafish. Human molecular genetics 90 18469344
2021 Heterocellular OSM-OSMR signalling reprograms fibroblasts to promote pancreatic cancer growth and metastasis. Nature communications 89 34921158
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
1999 Reconstitution of the functional mouse oncostatin M (OSM) receptor: molecular cloning of the mouse OSM receptor beta subunit. Blood 83 9920829
2004 Large-scale cDNA transfection screening for genes related to cancer development and progression. Proceedings of the National Academy of Sciences of the United States of America 82 15498874
2009 Cerebral cavernous malformation 2 protein promotes smad ubiquitin regulatory factor 1-mediated RhoA degradation in endothelial cells. The Journal of biological chemistry 73 19318350
2010 Crystal structure of CCM3, a cerebral cavernous malformation protein critical for vascular integrity. The Journal of biological chemistry 72 20489202
1994 Oncostatin M (OSM) inhibits the differentiation of pluripotent embryonic stem cells in vitro. Cytokine 72 8003633
2007 Interaction between krit1 and malcavernin: implications for the pathogenesis of cerebral cavernous malformations. Neurosurgery 66 17290187
2006 Deletions in CCM2 are a common cause of cerebral cavernous malformations. American journal of human genetics 66 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 Phospho-tyrosine dependent protein-protein interaction network. Molecular systems biology 61 25814554
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 61 26540726
2009 Oncostatin M (OSM) is increased in asthma with incompletely reversible airflow obstruction. Experimental lung research 61 19916861
2023 The clinical relevance of OSM in inflammatory diseases: a comprehensive review. Frontiers in immunology 59 37841259
2010 Differential angiogenesis function of CCM2 and CCM3 in cerebral cavernous malformations. Neurosurgical focus 58 20809750
2015 Oncostatin M (OSM) protects against cardiac ischaemia/reperfusion injury in diabetic mice by regulating apoptosis, mitochondrial biogenesis and insulin sensitivity. Journal of cellular and molecular medicine 57 25752217
1996 Characteristic localization of gp130 (the signal-transducing receptor component used in common for IL-6/IL-11/CNTF/LIF/OSM) in the rat brain. The European journal of neuroscience 56 8921254
2006 The molecular identities of the Caenorhabditis elegans intraflagellar transport genes dyf-6, daf-10 and osm-1. Genetics 54 16648645
2010 Mutation analysis of CCM1, CCM2 and CCM3 genes in a cohort of Italian patients with cerebral cavernous malformation. Brain pathology (Zurich, Switzerland) 53 21029238
2019 Diabetes-Associated Myelopoiesis Drives Stem Cell Mobilopathy Through an OSM-p66Shc Signaling Pathway. Diabetes 51 30936144
2019 HIGH expression of OSM and IL-6 are associated with decreased breast cancer survival: synergistic induction of IL-6 secretion by OSM and IL-1β. Oncotarget 50 31007849
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
1993 The genes for oncostatin M (OSM) and leukemia inhibitory factor (LIF) are tightly linked on human chromosome 22. Genomics 47 8406444
2018 OSM potentiates preintravasation events, increases CTC counts, and promotes breast cancer metastasis to the lung. Breast cancer research : BCR 45 29898744
2011 The Caenorhabditis elegans mucin-like protein OSM-8 negatively regulates osmosensitive physiology via the transmembrane protein PTR-23. PLoS genetics 45 21253570
2008 OSM, LIF, its receptors, and its relationship with the malignance in human breast carcinoma (in situ and in infiltrative). Cancer investigation 44 18317962
2007 Mouse preimplantation embryo responses to culture medium osmolarity include increased expression of CCM2 and p38 MAPK activation. BMC developmental biology 43 17214902
2006 Oncostatin M (OSM) cytostasis of breast tumor cells: characterization of an OSM receptor beta-specific kernel. Cancer research 43 17108126
2021 Novel mechanism for OSM-promoted extracellular matrix remodeling in breast cancer: LOXL2 upregulation and subsequent ECM alignment. Breast cancer research : BCR 42 34011405
1995 The gp 130 family cytokines IL-6, LIF and OSM but not IL-11 can reverse the anti-proliferative effect of dexamethasone on human myeloma cells. British journal of haematology 42 7647014
2013 Pulmonary expression of oncostatin M (OSM) promotes inducible BALT formation independently of IL-6, despite a role for IL-6 in OSM-driven pulmonary inflammation. Journal of immunology (Baltimore, Md. : 1950) 41 23797667
2005 CCM2 expression parallels that of CCM1. Stroke 41 16373645
2018 The CCM1-CCM2 complex controls complementary functions of ROCK1 and ROCK2 that are required for endothelial integrity. Journal of cell science 40 30030370
1998 Inhibition of growth and induction of differentiation of glioma cell lines by oncostatin M (OSM). Growth factors (Chur, Switzerland) 40 9505169
1996 Oncostatin M (OSM) stimulates resorption and inhibits synthesis of proteoglycan in porcine articular cartilage explants. Cytokine 40 8818547
2017 MicroRNA-20a-5p suppresses IL-17 production by targeting OSM and CCL1 in patients with Vogt-Koyanagi-Harada disease. The British journal of ophthalmology 37 28972028
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
2000 Relationship between circulating interleukin-10 (IL-10) with interleukin-6 (IL-6) type cytokines (IL-6, interleukin-11 (IL-11), oncostatin M (OSM)) and soluble interleukin-6 (IL-6) receptor (sIL-6R) in patients with multiple myeloma. European cytokine network 35 11022130
2021 Exploring the oncostatin M (OSM) feed-forward signaling of glioblastoma via STAT3 in pan-cancer analysis. Cancer cell international 34 34702277
2014 PTEN/PI3K/Akt/VEGF signaling and the cross talk to KRIT1, CCM2, and PDCD10 proteins in cerebral cavernous malformations. Neurosurgical review 33 25403688
2012 The Janus face of OSM-mediated cardiomyocyte dedifferentiation during cardiac repair and disease. Cell cycle (Georgetown, Tex.) 33 22262173
2012 Structural studies of cerebral cavernous malformations 2 (CCM2) reveal a folded helical domain at its C-terminus. FEBS letters 33 23266514
2020 OSM-9 and OCR-2 TRPV channels are accessorial warm receptors in Caenorhabditis elegans temperature acclimatisation. Scientific reports 31 33122746
2020 The role of the oncostatin M/OSM receptor β axis in activating dermal microvascular endothelial cells in systemic sclerosis. Arthritis research & therapy 30 32736577
2016 Nicotinamide is an endogenous agonist for a C. elegans TRPV OSM-9 and OCR-4 channel. Nature communications 30 27731314
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
2005 Oncostatin M-induced activation of stress-activated MAP kinases depends on tyrosine 861 in the OSM receptor and requires Jak1 but not Src kinases. Cellular signalling 30 15935618
2003 Molecular cloning and characterisation of a carp (Cyprinus carpio) cytokine-like cDNA that shares sequence similarity with IL-6 subfamily cytokines CNTF, OSM and LIF. Developmental and comparative immunology 30 12543126
2013 ccm2-like is required for cardiovascular development as a novel component of the Heg-CCM pathway. Developmental biology 29 23328253
2015 Notch3/Akt signaling contributes to OSM-induced protection against cardiac ischemia/reperfusion injury. Apoptosis : an international journal on programmed cell death 28 26093524
2011 Involvement of ADAMTS5 and hyaluronidase in aggrecan degradation and release from OSM-stimulated cartilage. European cells & materials 28 21225593
2020 Molecular Simulation of Oncostatin M and Receptor (OSM-OSMR) Interaction as a Potential Therapeutic Target for Inflammatory Bowel Disease. Frontiers in molecular biosciences 27 32195265
2016 OSM mitigates post-infarction cardiac remodeling and dysfunction by up-regulating autophagy through Mst1 suppression. Biochimica et biophysica acta. Molecular basis of disease 27 27825852
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
2020 Osteal Tissue Macrophages Are Involved in Endplate Osteosclerosis through the OSM-STAT3/YAP1 Signaling Axis in Modic Changes. Journal of immunology (Baltimore, Md. : 1950) 24 32690652
2018 The AB loop of oncostatin M (OSM) determines species-specific signaling in humans and mice. The Journal of biological chemistry 24 30373773
2018 Two Novel KRIT1 and CCM2 Mutations in Patients Affected by Cerebral Cavernous Malformations: New Information on CCM2 Penetrance. Frontiers in neurology 24 30487773
1993 Tandem linkage of genes coding for leukemia inhibitory factor (LIF) and oncostatin M (OSM) on human chromosome 22. Cytogenetics and cell genetics 23 8404048
2018 The AB loop and D-helix in binding site III of human Oncostatin M (OSM) are required for OSM receptor activation. The Journal of biological chemistry 22 29511087
2017 Anti-OSM Antibody Inhibits Tubulointerstitial Lesion in a Murine Model of Lupus Nephritis. Mediators of inflammation 21 28626343
2015 Stimulation of the JAK/STAT pathway by LIF and OSM in the human granulosa cell line COV434. Journal of reproductive immunology 21 25817464
2023 CD34+ cell-derived fibroblast-macrophage cross-talk drives limb ischemia recovery through the OSM-ANGPTL signaling axis. Science advances 20 37043578
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
2021 Cross-reactivity of two human IL-6 family cytokines OSM and LIF explored by protein-protein docking and molecular dynamics simulation. Biochimica et biophysica acta. General subjects 19 33845142
2017 Cos2/Kif7 and Osm-3/Kif17 regulate onset of outer segment development in zebrafish photoreceptors through distinct mechanisms. Developmental biology 19 28341548
2022 OSM/OSMR and Interleukin 6 Family Cytokines in Physiological and Pathological Condition. International journal of molecular sciences 18 36232392
2015 Caenorhabditis elegans OSM-11 signaling regulates SKN-1/Nrf during embryonic development and adult longevity and stress response. Developmental biology 18 25637691
2015 The Effect of OSM on MC3T3-E1 Osteoblastic Cells in Simulated Microgravity with Radiation. PloS one 17 26030441
2009 Oncostatin M (OSM) primes IL-13- and IL-4-induced eotaxin responses in fibroblasts: regulation of the type-II IL-4 receptor chains IL-4Ralpha and IL-13Ralpha1. Experimental cell research 17 19799897
2016 A Screen for Modifiers of Cilia Phenotypes Reveals Novel MKS Alleles and Uncovers a Specific Genetic Interaction between osm-3 and nphp-4. PLoS genetics 16 26863025
2009 Role of a LIF antagonist in LIF and OSM induced MMP-1, MMP-3, and TIMP-1 expression by primary articular chondrocytes. Cytokine 16 19342253
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
1996 Leukemia inhibitory factor (LIF) and oncastsin M (OSM) high affinity binding require additional receptor subunits besides GP130 and GP190. Cytokine 15 8833034
2016 Micro-CT Imaging Reveals Mekk3 Heterozygosity Prevents Cerebral Cavernous Malformations in Ccm2-Deficient Mice. PloS one 14 27513872
2015 OSM is overexpressed in knee osteoarthritis and Notch signaling is involved in the effects of OSM on MC3T3-E1 cell proliferation and differentiation. International journal of molecular medicine 14 25845347
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
2009 Mice overexpressing murine oncostatin M (OSM) exhibit changes in hematopoietic and other organs that are distinct from those of mice overexpressing human OSM or bovine OSM. Veterinary pathology 14 19112126
2005 Organization of phenylalanine ammonia lyase (PAL), acidic PR-5 and osmotin-like (OSM) defence-response gene families in the potato genome. Molecular genetics and genomics : MGG 14 16133161
2000 Temporal expression of mRNAs for neuropoietic cytokines, interleukin-11 (IL-11), oncostatin M (OSM), cardiotrophin-1 (CT-1) and their receptors (IL-11Ralpha and OSMRbeta) in peripheral nerve injury. Neurochemical research 14 11055749
2020 Feiyangchangweiyan capsule protects against ulcerative colitis in mice by modulating the OSM/OSMR pathway and improving gut microbiota. Phytomedicine : international journal of phytotherapy and phytopharmacology 13 33113505
2023 OSMR deficiency aggravates pressure overload-induced cardiac hypertrophy by modulating macrophages and OSM/LIFR/STAT3 signalling. Journal of translational medicine 12 37120549
2012 CCM2 gene polymorphisms in Italian sporadic patients with cerebral cavernous malformation: a case-control study. International journal of molecular medicine 12 22378217
1993 Localization of the human oncostatin M gene (OSM) to chromosome 22q12, distal to the Ewing's sarcoma breakpoint. Cytogenetics and cell genetics 12 8422753