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Showing PDCD10 — CCM3 is a alias.

PDCD10

Programmed cell death protein 10 · UniProt Q9BUL8

Length
212 aa
Mass
24.7 kDa
Annotated
2026-06-10
100 papers in source corpus 34 papers cited in narrative 34 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PDCD10/CCM3 is an all-alpha-helical scaffold/adaptor protein that organizes germinal center kinase III (GCKIII) signaling to control endothelial and epithelial barrier integrity, cytoskeletal organization, and membrane trafficking (PMID:18782753, PMID:20489202, PMID:21561863). It resides within the STRIPAK phosphatase-kinase complex and binds the GCKIII kinases MST4, STK24, and STK25 through its N-terminal dimerization domain, which heterodimerizes with the kinase C-terminal tail using the same surface that mediates CCM3 homodimerization (PMID:18782753, PMID:21561863, PMID:23541896); through these interactions CCM3 stabilizes GCKIII protein levels and potentiates their kinase activity toward substrates including the ERM proteins ezrin/radixin/moesin (PMID:17360971, PMID:20332113, PMID:22291017, PMID:22652780). CCM3 additionally assembles with CCM1/CCM2 (scaffolded by full-length CCM2) and, via the conserved HP1 pocket of its C-terminal FAT-homology domain, binds paxillin LD motifs at focal adhesions, where it competes with focal adhesion kinase to tune FAK/Src/paxillin mechanotransduction and YAP/TAZ activation (PMID:17657516, PMID:18300272, PMID:20489202, PMID:21632544, PMID:34226698). In endothelium, loss of CCM3 disrupts barrier function through multiple convergent routes: tonic ERK1/2 activation that destabilizes cortactin and tight junctions, RhoA/ROCK-driven stress fiber formation, increased UNC13B/VAMP3-dependent angiopoietin-2 exocytosis, caveolae-Tie2 signaling, suppression of DLL4-Notch with downstream EphB4/VEGF activation, and Wnt-independent beta-catenin activation driving endothelial-to-mesenchymal transition (PMID:25122144, PMID:27548575, PMID:26109568, PMID:26385474, PMID:33495460, PMID:28371279). PDCD10 also regulates vesicle trafficking and organelle organization, controlling AQP2 membrane targeting in kidney tubules and endomembrane/Golgi integrity in epithelia (PMID:20332113, PMID:34156031, PMID:38037455), and contributes to apoptotic control downstream of gamma-protocadherins (PMID:21041308). CCM3 protein abundance is itself controlled by ubiquitin-dependent turnover, with TRIM59 antagonizing RNFT1-mediated K63 polyubiquitination and p62-selective autophagic degradation (PMID:30408026). Loss-of-function disrupts these protein interactions and signaling outputs, producing cerebral cavernous malformations, a disease in which Pdcd10 acts both in brain endothelium and, through a gut-brain axis, in gut epithelial barrier maintenance (PMID:20332113, PMID:20592472, PMID:25122144, PMID:31776290).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2007 High

    Establishing CCM3 as a direct binding partner and substrate of GCKIII kinases defined it as a kinase-associated adaptor rather than a standalone effector, and linked it physically to the other CCM proteins.

    Evidence Yeast two-hybrid, co-IP, in vitro kinase/phosphatase assays and functional knockdown/overexpression with ERK readout for STK25 and MST4

    PMID:17360971 PMID:17657516

    Open questions at the time
    • Did not resolve which GCKIII activities are physiologically dominant in vivo
    • Phosphorylation site function on CCM3 not defined
  2. 2008 High

    Placing a large fraction of CCM3 within the STRIPAK complex established its biochemical context as a hub coupling PP2A phosphatase activity to GCKIII kinases, and a mutant CCM2 experiment defined CCM2 as the core scaffold of the CCM1/CCM2/CCM3 trimer.

    Evidence Iterative AP-MS for STRIPAK membership; co-IP of CCM2 deletion mutant for trimer architecture

    PMID:18300272 PMID:18782753

    Open questions at the time
    • Stoichiometry and dynamics of CCM3 within STRIPAK not defined
    • How CCM3 partitions between STRIPAK and the CCM1/2/3 complex unresolved
  3. 2010 High

    The crystal structure of CCM3 partitioned its functions into an N-terminal dimerization domain and a C-terminal FAT-homology domain whose HP1 pocket mediates CCM2 binding and focal-adhesion/paxillin colocalization, providing a structural basis for distinct interaction modes.

    Evidence X-ray crystallography at 2.5 A with HP1-mutant co-IP and colocalization

    PMID:20489202

    Open questions at the time
    • Did not determine GCKIII binding surface (resolved later)
    • Functional consequence of homo- vs heterodimer switching unaddressed
  4. 2010 High

    Loss-of-function and rescue experiments demonstrated that CCM3 stabilizes GCKIII kinases and maintains Golgi integrity, cell migration, and endothelial barrier function, with disease mutants failing to bind GCKIII kinases and failing to rescue.

    Evidence siRNA knockdown, co-IP, wound-healing assays in cells, and zebrafish morpholino epistasis with Rho/moesin and barrier assays; disease-mutant rescue tests

    PMID:20332113 PMID:20592472

    Open questions at the time
    • Mechanism coupling GCKIII stabilization to Golgi and barrier phenotypes incompletely defined
    • Cell type specificity of these effects not resolved
  5. 2011 High

    Mapping the GCKIII-binding surface to the N-terminal dimerization domain showed CCM3 preferentially heterodimerizes with GCKIII kinases over homodimerizing, defining the molecular logic of the CCM3-kinase module.

    Evidence Domain-truncation binding assays and sequence analysis

    PMID:21561863

    Open questions at the time
    • Did not quantify homo/hetero equilibrium in cells
    • Regulation of the switch not addressed (resolved structurally in 2013)
  6. 2011 High

    Structural definition of CCM3-paxillin LD-motif binding via the HP1 FAT surface, with micromolar affinity and pericyte colocalization, established a direct CCM3 link to focal adhesion biology.

    Evidence Multiple crystal structures, SPR affinity measurement, and immunofluorescence colocalization in cerebral pericytes

    PMID:21632544

    Open questions at the time
    • Functional consequence of paxillin binding not yet established (addressed in 2021)
    • Competition with other LD-motif partners not tested here
  7. 2011 High

    Conditional in vivo deletion separated cell-autonomous (Akt activation, proliferation/survival) from non-cell-autonomous vascular consequences, framing CCM3 loss as engaging multiple signaling axes including PKA and Rho-GTPase.

    Evidence Neural-cell-specific conditional KO mice with IHC, RNA-seq, and Western blot

    PMID:21321212

    Open questions at the time
    • Causal chain from Akt to vascular lesions not dissected
    • Direct CCM3 effector for Akt activation unknown
  8. 2013 High

    The CCM3-MST4 complex crystal structure revealed a flexible-linker-driven conformational rotation enabling homodimer disassembly and heterodimer formation, tying the structural switch to kinase-activity-dependent proliferation and migration.

    Evidence X-ray crystallography with in vivo co-IP and kinase-inhibitor-dependent functional assays

    PMID:23541896

    Open questions at the time
    • Trigger controlling the conformational switch in cells unknown
    • Whether STRIPAK regulates this transition unaddressed
  9. 2012 Medium

    Demonstrating CCM3-dependent, MST4-driven ERM phosphorylation under oxidative stress and STK25 protein stabilization connected the CCM3-GCKIII module to stress responses and cell survival.

    Evidence siRNA knockdown, phospho-ERM Western blot, proteasome inhibition, and viability/apoptosis assays under H2O2

    PMID:22291017 PMID:22652780

    Open questions at the time
    • Single-lab apoptosis findings with limited mechanistic depth (idx 11)
    • Direction of CCM3 effect on cell death context-dependent and unresolved
  10. 2014 High

    Conditional KO in radial glia and neurons showed CCM3 controls RhoA activity and cytoskeletal organization required for neuronal migration and cortical lamination, generalizing its cytoskeletal regulatory role beyond endothelium.

    Evidence Cell-type-specific conditional KO mice, RhoA activity assays, cytoskeletal staining, lamination analysis

    PMID:24595293

    Open questions at the time
    • Direct link to Cdk5/RhoA not biochemically established
    • GCKIII dependence of the neuronal phenotype untested here
  11. 2015 High

    Endothelial-specific studies defined two distinct barrier-disrupting mechanisms downstream of CCM3 loss: ERK1/2-driven cortactin destabilization of tight junctions, and Wnt-independent beta-catenin activation driving endothelial-to-mesenchymal transition, both pharmacologically rescuable.

    Evidence siRNA and conditional KO mice, barrier permeability assays, luciferase reporters, ERK inhibitor and sulindac rescue

    PMID:26109568 PMID:26385474

    Open questions at the time
    • How CCM3 loss elevates tonic ERK1/2 not fully defined
    • Relationship between the cortactin and beta-catenin arms unresolved
  12. 2016 High

    Linking CCM3 loss to RhoA/ROCK-driven permeability and to UNC13B/VAMP3-dependent angiopoietin-2 exocytosis, with in vivo genetic and antibody rescue, established trafficking-level control of endothelial junction stability.

    Evidence siRNA, ROCK and permeability assays, mouse genetics, exocytosis assays, UNC13B KO and ANGPT2-neutralizing antibody rescue

    PMID:25122144 PMID:27548575

    Open questions at the time
    • Mechanism connecting CCM3 to the exocytic machinery not defined at molecular level
    • Relative contribution of ROCK vs ANGPT2 arms in vivo unresolved
  13. 2018 High

    Defining a TRIM59/RNFT1 ubiquitin and p62-autophagy axis that sets PDCD10 abundance, and showing PDCD10 suppresses RhoA-ROCK1 to control cancer cell invasion mode, established post-translational control of CCM3 levels and a role in tumor cell biology.

    Evidence Co-IP, ubiquitination and autophagy-flux assays, knockdown, invasion assays with ROCK inhibitor rescue in breast cancer cells

    PMID:30408026

    Open questions at the time
    • Physiological contexts where this turnover operates not mapped
    • Whether endothelial CCM3 levels are similarly regulated untested
  14. 2017 Medium

    Invertebrate genetics extended the CCM3-GCKIII partnership to intercellular bridge stability and RAB-11-mediated endocytic recycling, establishing conserved roles in cytokinesis, lumen formation, and membrane trafficking with STRIPAK-dependent localization control.

    Evidence C. elegans knockdown/knockout, live imaging, recycling assays, biochemical STRIPAK characterization

    PMID:28285996 PMID:28285997

    Open questions at the time
    • Conservation of the recycling role in mammalian endothelium not directly shown
    • Single-organism findings (idx 22, 23)
  15. 2019 High

    Tissue-specific KO revealed that Pdcd10, unlike Krit1, is required for the colonic mucosal barrier, defining a gut-brain disease axis in which gut epithelial integrity modulates brain cavernous malformation burden.

    Evidence Tissue-specific conditional KO mice, gut permeability assays, Mucin-2 manipulation, dexamethasone rescue

    PMID:31776290

    Open questions at the time
    • Molecular basis of CCM3 function in gut epithelium not defined
    • How gut signals reach brain endothelium unresolved
  16. 2021 High

    A series of conditional KO and interaction studies broadened CCM3 to lymphatic, renal, mechanosensing, and caveolar contexts—binding KPNA2 to restrain NF-kB/VEGFR3, controlling AQP2 trafficking via STK24/25-ERM, competing with FAK for paxillin to tune YAP/TAZ, and restraining caveolae-Tie2 signaling.

    Evidence Conditional KO mice in lymphatic/kidney/brain endothelium and cancer-associated fibroblasts, co-IP (KPNA2, FAK/paxillin), two-photon imaging, caveolin-1 KO epistasis, and pharmacological rescues

    PMID:33495460 PMID:34156031 PMID:34226698 PMID:34670407

    Open questions at the time
    • Whether these tissue-specific mechanisms share a unifying biochemical step is unclear
    • Direct structural basis of FAK competition not solved
  17. 2024 Medium

    Additional tumor and angiogenesis studies positioned PDCD10 as a regulator of MST4-mediated RB/ERK phosphorylation in pancreatic cancer and of Hippo/YAP-TAZ in endothelium, reinforcing its adaptor role across proliferative and angiogenic programs.

    Evidence Proximity ligation assay, CRISPR KO, organoid models, and siRNA with verteporfin rescue

    PMID:38320423 PMID:39212293

    Open questions at the time
    • Single-lab signaling readouts (idx 29, 31)
    • Direct vs indirect control of YAP/TAZ in endothelium not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CCM3 dynamically partitions between STRIPAK, the CCM1/2/3 complex, GCKIII heterodimers, and focal-adhesion paxillin to select among its many downstream pathways in a given cell type remains unresolved.
  • No unifying model linking complex membership to pathway choice
  • Spatiotemporal regulation of the homo/heterodimer switch in vivo unknown
  • Quantitative flux between STRIPAK-bound and free CCM3 pools undetermined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4 GO:0098772 molecular function regulator activity 4 GO:0008092 cytoskeletal protein binding 3
Localization
GO:0005856 cytoskeleton 3 GO:0005886 plasma membrane 3 GO:0005794 Golgi apparatus 2 GO:0005815 microtubule organizing center 2
Partners
CCM2FAKKPNA2MST4PTPN13PXNSTK24STK25
Complex memberships
CCM1/CCM2/CCM3 complexCCM3-GCKIII (MST4/STK24/STK25) heterodimerSTRIPAK

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 CCM3/PDCD10 is a component of the large STRIPAK (striatin-interacting phosphatase and kinase) complex, which contains PP2A catalytic and scaffolding subunits, striatins, Mob3, STRIP1/2, and germinal center kinase III family members; affinity purification/mass spectrometry showed that a large portion of CCM3 resides within this complex. Iterative affinity purification/mass spectrometry (AP-MS) Molecular & cellular proteomics : MCP High 18782753
2007 CCM3/PDCD10 directly binds STK25 (SOK1/YSK1), is phosphorylated by STK25, and is dephosphorylated by the phosphatase domain of FAP-1 (PTPN13); CCM3 also co-precipitates and co-localizes with CCM2, and STK25 forms a complex with CCM2, linking all three CCM proteins. Co-immunoprecipitation, yeast two-hybrid, direct binding assays, in vitro kinase/phosphatase assays Neurogenetics High 17657516
2007 PDCD10 interacts with the Ste20-related kinase MST4 (confirmed by co-IP and co-localization), and PDCD10 increases MST4 kinase activity in vitro; co-overexpression promotes cell proliferation and transformation via ERK pathway activation, while siRNA knockdown of either protein reduces ERK activity and cell growth. Yeast two-hybrid, co-immunoprecipitation, co-localization, in vitro kinase assay, siRNA knockdown, anchorage-independent growth assay Molecular biology of the cell High 17360971
2008 A CCM2 in-frame deletion (p.P11_K68del) abolishes CCM2's ability to interact with CCM1 and to form a CCM1/CCM2/CCM3 trimeric complex, while still binding CCM3 alone, establishing that full-length CCM2 with its N-terminal domain is required as the core scaffold of the CCM1/CCM2/CCM3 complex. Co-immunoprecipitation of expressed mutant and wild-type proteins in cell culture Human mutation Medium 18300272
2010 Crystal structure of CCM3 at 2.5 Å revealed an all-alpha-helical protein with two domains: an N-terminal dimerization domain with a novel fold, and a C-terminal FAT-homology domain; CCM3 binds CCM2 via the FAT-homology domain using a conserved hydrophobic pocket (HP1), and mutation of HP1 abrogates CCM3-CCM2 interaction and disrupts CCM3 co-localization with paxillin at focal adhesions. X-ray crystallography (2.5 Å), co-immunoprecipitation with HP1 mutant, fluorescence co-localization The Journal of biological chemistry High 20489202
2010 CCM3 localizes to the Golgi apparatus and forms a complex with GCKIII family kinases and the Golgi-resident protein GM130; CCM3 depletion causes Golgi disassembly, impairs cell reorientation and migration in wound-healing assays, and leads to destabilization of GCKIII proteins and dephosphorylation of their substrate 14-3-3ζ; this phenotype is reversed by wild-type but not disease-associated mutant CCM3. siRNA knockdown, co-immunoprecipitation, immunofluorescence/colocalization, wound-healing assay, Western blot Journal of cell science High 20332113
2010 In zebrafish, CCM3 disease-causing mutant proteins (CCM3Δ) interact with CCM1 and CCM2 but fail to bind MST4, STK24, and STK25; loss of stk genes in zebrafish recapitulates CCM cardiovascular phenotypes, and CCM3/STK25 regulate endothelial barrier function; STKs negatively regulate Rho by directly activating moesin. Co-immunoprecipitation, zebrafish morpholino knockdown (genetic epistasis), endothelial barrier function assays, Rho activity assays The Journal of clinical investigation High 20592472
2011 The N-terminal dimerization domain of CCM3 is necessary and sufficient to bind directly to the C-terminal tail of GCKIII proteins (MST4, STK24, STK25), using the same surface as CCM3 homodimerization; sequence conservation and binding studies indicate preferential CCM3-GCKIII heterodimerization over homodimerization. Biochemical binding assays, domain mapping, sequence analysis The Journal of biological chemistry High 21561863
2011 Crystal structures of CCM3 in complex with paxillin LD1, LD2, and LD4 motifs (at 2.8, 2.7, and 2.5 Å) show that CCM3 binds LD motifs via the conserved HP1 surface of the FAT-homology domain; surface plasmon resonance confirmed micromolar affinity; endogenous CCM3 and paxillin co-localize in mouse cerebral pericytes. X-ray crystallography (multiple structures), surface plasmon resonance, co-localization by immunofluorescence The Journal of biological chemistry High 21632544
2013 Crystal structure of the CCM3-GCKIII (MST4 C-terminal domain) complex demonstrated that CCM3 heterodimerizes with GCKIII kinases structurally analogous to CCM3 homodimerization; a flexible linker mediates large-scale conformational rotation of the FAT domain that permits disassembly of the CCM3 homodimer and subsequent heterodimerization; CCM3 forms a stable complex with MST4 in vivo to promote cell proliferation and migration dependent on MST4 kinase activity. X-ray crystallography, co-immunoprecipitation, cell proliferation and migration assays, kinase inhibitor treatment Structure (London, England : 1993) High 23541896
2012 CCM3 mediates oxidative-stress-induced phosphorylation and activation of ERM (ezrin/radixin/moesin) proteins by the GCKIII kinase MST4; after oxidative stress, MST4 is activated and relocates to the cell periphery in a CCM3-dependent manner; loss of CCM3 impairs ERM phosphorylation and increases cell death upon reactive oxygen species exposure. siRNA knockdown, Western blot for phospho-ERM, cell viability assays, immunofluorescence The Journal of biological chemistry High 22291017
2012 PDCD10 interacts with STK25, stabilizes STK25 protein through a proteasome-dependent pathway, and co-expression of PDCD10 and STK25 accelerates cell apoptosis under H2O2-induced oxidative stress; PDCD10/STK25 interaction modulates ERK activity under oxidative stress. Co-immunoprecipitation, siRNA knockdown, proteasome inhibitor treatment, cell apoptosis assays, ERK activity measurement Frontiers in bioscience (Landmark edition) Medium 22652780
2011 Neural cell-specific (astrocyte/neuron) deletion of Ccm3 in mice causes cell-autonomous activation of Akt signaling, increased astrocyte proliferation and survival, and non-cell-autonomous vascular phenotypes (dilated vasculature, cavernoma-like lesions) involving cytoskeletal remodeling pathways including protein kinase A and Rho-GTPase signaling. Conditional knockout mice (Gfap-Cre, Emx1-Cre), immunohistochemistry, RNA sequencing, Western blot Proceedings of the National Academy of Sciences of the United States of America High 21321212
2010 PDCD10/CCM3 overexpression induces apoptosis (measured by TUNEL, caspase-3 activation, MTT) in endothelial cells, while disease-linked mutant forms do not; serum starvation-induced apoptosis increases CCM3 expression and activates p38; siRNA-mediated CCM3 knockdown reduces p38 activation and decreases cell death. TUNEL assay, MTT assay, caspase-3 activation assay, siRNA knockdown, Western blot Stroke Medium 19246713
2010 PDCD10/CCM3 acts downstream of γ-protocadherins (PCDH-γ) to regulate neuronal survival; PCDH-γ isoforms interact with PDCD10 via their common cytoplasmic domain; RNAi knockdown of PDCD10 prevents apoptosis upon PCDH-γ depletion in chicken spinal neurons; overexpression of PDCD10 alone is sufficient to induce neuronal apoptosis. Co-immunoprecipitation, RNAi knockdown (epistasis), overexpression, apoptosis assay in developing chicken spinal neurons The Journal of biological chemistry Medium 21041308
2013 CCM3 silencing in endothelial cells downregulates core Notch signaling components (DLL4, Notch4, HEY2, HES1) and activates VEGF and ERK pathways, causing hyper-angiogenesis; restoration of DLL4-Notch signaling fully rescued the hyper-angiogenic phenotype, defining DLL4 as a key downstream target of CCM3. siRNA knockdown, recombinant DLL4 rescue, proliferation/migration/sprouting assays, RT-PCR, Western blot Journal of cellular and molecular medicine Medium 23388056
2016 CCM3 suppresses endothelial stress fibers, Rho kinase (ROCK) activity, and vascular permeability; PDCD10 siRNA knockdown in endothelial cells increases stress fibers, ROCK activity, and permeability in vitro, and Pdcd10 heterozygous mice show greater CCM lesion burden than other Ccm genotypes. siRNA knockdown, stress fiber staining, ROCK activity assay, permeability assay, mouse models Genetics in medicine : official journal of the American College of Medical Genetics High 25122144
2016 CCM3 suppresses UNC13B- and VAMP3-dependent exocytosis of angiopoietin-2 (ANGPT2) in brain endothelial cells; CCM3 deficiency augments ANGPT2 secretion, causing destabilized endothelial junctions, enlarged lumens, and pericyte dissociation; UNC13B deficiency or ANGPT2-neutralizing antibody normalizes these defects in endothelial CCM3-deficient mice. Genetic KO mouse model, antibody neutralization, exocytosis assays, vessel imaging, co-IP Nature medicine High 27548575
2015 CCM3 deficiency in endothelial cells causes cell-autonomous, Wnt-receptor-independent stimulation of β-catenin transcriptional activity and endothelial-to-mesenchymal transition; TGF-β/BMP signaling is required for disease progression; sulindac sulfide and sulfone attenuate β-catenin activity and reduce vascular malformations in CCM3-deficient mice. Endothelial-cell-selective CCM3 knockout mice, luciferase reporter assays, pharmacological treatment, histology Proceedings of the National Academy of Sciences of the United States of America High 26109568
2015 CCM3 depletion in brain endothelial cells causes cortactin Ser-phosphorylation via tonic ERK1/2 activation, leading to cortactin dissociation from ZO-1 and actin, redistribution to cytosol, and degradation; this disrupts cortical actin ring organization, tight junction complex stability, and causes constant barrier hyperpermeability; ERK1/2 inhibition restores cortactin and barrier function. siRNA knockdown, immunofluorescence, Western blot, barrier permeability assay (inulin), ERK inhibitor treatment Acta neuropathologica High 26385474
2018 TRIM59 stabilizes PDCD10 by suppressing RNFT1-induced K63 polyubiquitination and subsequent p62/SQSTM1-selective autophagic degradation; PDCD10 mediates suppression of RhoA-ROCK1 signaling, controlling the transition between amoeboid and mesenchymal invasiveness in breast cancer cells. Co-immunoprecipitation, ubiquitination assays, autophagy flux experiments, siRNA/shRNA knockdown, cell migration/invasion assays, ROCK inhibitor rescue PLoS biology High 30408026
2021 CCM3 localizes to focal adhesion sites in cancer-associated fibroblasts and mutually competes with focal adhesion kinase (FAK) for binding to paxillin, fine-tuning FAK/Src/paxillin-driven mechanotransduction and YAP/TAZ activation; specific loss of CCM3 in cancer-associated fibroblasts increases tissue remodeling and exacerbates YAP/TAZ activation in neighboring tumor cells. Immunofluorescence/focal adhesion localization, co-immunoprecipitation (CCM3/FAK/paxillin competition), mouse breast cancer models, YAP/TAZ reporter assays Nature cell biology High 34226698
2017 In C. elegans, CCM-3 and GCK-1 (GCKIII family kinase) work together to promote intercellular bridge stability and limit localization of anillin and non-muscle myosin II (NMM-II) to intercellular bridges; STRIPAK complex components striatin/CASH-1 and GCK-1 differentially control CCM-3 localization and function. C. elegans genetic knockdown/knockout, live imaging, biochemical analysis (STRIPAK complex) Current biology : CB Medium 28285996
2017 In C. elegans, CCM-3 is enriched at the luminal membrane and at contractile rings; loss of ccm-3 causes defective RAB-11-mediated endocytic recycling, disrupting gonadal lumen formation, cytokinesis completion, and cell-surface receptor localization; MO25 ortholog mop-25.2 is required for CCM-3 apical membrane localization. C. elegans genetic knockdown/knockout, fluorescence imaging, endocytic recycling assays Current biology : CB Medium 28285997
2019 Loss of Pdcd10 (but not Krit1) in gut epithelial cells disrupts the colonic mucosal barrier, and chemical disruption of the gut barrier or loss of Mucin-2 augments CCM formation in mouse models, establishing a gut-brain disease axis in which PDCD10 is required for both brain endothelial signaling and gut epithelial barrier function; dexamethasone inhibits CCM formation by acting at both cell types. Tissue-specific conditional KO mice, gut permeability assays, pharmacological treatment, CCM lesion burden quantification Science translational medicine High 31776290
2021 Pdcd10 knockout in kidney tubules causes polyuria; total and phosphorylated AQP2 protein levels at the apical membrane are decreased despite normal Aqp2 mRNA, associated with increased ERM protein expression and impaired intracellular vesicle trafficking; erlotinib (promoting exocytosis/inhibiting endocytosis) partially rescues water reabsorption defects, identifying a PDCD10-STK24/25-ERM signaling pathway regulating vesicle trafficking and AQP2 membrane targeting. Kidney-specific conditional KO mice, immunofluorescence/fractionation for AQP2 localization, pharmacological rescue (erlotinib), Western blot JCI insight High 34156031
2021 CCM3 deletion in lymphatic endothelial cells augments VEGFR3-ERK1/2 signaling driving lymphatic hyperplasia; mechanistically, CCM3 binds importin alpha 2/KPNA2, and CCM3 deletion releases KPNA2 to activate NF-κB p65 nuclear translocation and p65-dependent VEGFR3 transcription; inhibition of VEGFR3 or ERK1/2 rescues lymphatic defects. Lymphatic-specific conditional KO mice, co-immunoprecipitation (CCM3-KPNA2), NF-κB nuclear translocation assay, VEGFR3/ERK1/2 inhibitor rescue, lymphatic function assays Arteriosclerosis, thrombosis, and vascular biology High 34670407
2021 In a brain endothelial-specific Pdcd10-knockout (Pdcd10BECKO) mouse model, CCM lesions initiate from capillary/post-capillary venule protrusions with pericyte dissociation; caveolae are drastically increased in Pdcd10BECKO endothelium, enhancing Tie2 signaling; genetic deletion of caveolin-1 or pharmacological Tie2 blockade normalizes microvascular structure and reduces CCM lesion formation. Brain EC-specific conditional KO mice, two-photon microscopy, caveolin-1 KO epistasis, Tie2 inhibitor treatment Nature communications High 33495460
2014 CCM3 loss leads to RhoA activation, alterations in actin and microtubule cytoskeleton affecting neuronal morphology, and abnormalities in laminar positioning of late-born neurons in the neocortex; CCM3 is specifically required in radial glia and newly born pyramidal neurons for radial glia-dependent locomotion, with possible interaction with the Cdk5/RhoA pathway. Cell-type-specific conditional KO mice (radial glia/neuron-specific), RhoA activity assay, cytoskeletal immunostaining, cortical lamination analysis Development (Cambridge, England) High 24595293
2024 PDCD10 associates with MST4 kinase (demonstrated by proximity ligation assay), translocates it intracellularly, and thereby facilitates phosphorylation of RB and ERK1/2; in pancreatic cancer cells, PDCD10 promotes TGF-β-driven proliferation by inactivating RB via a SMAD4-dependent pathway and promotes EMT by increasing ERK1/2 activation via a non-SMAD4 pathway. Proximity ligation assay, PDCD10 knockout cell lines (CRISPR), Western blot, viability and migration assays, organoid models Clinical science (London, England : 1979) Medium 39212293
2017 CCM3 silencing in endothelial cells upregulates EphB4 mRNA, protein, and kinase activity and activates ERK1/2; EphB4 kinase inhibitor (NVP-BHG712) reverses the hyper-angiogenic phenotype, placing EphB4 downstream of CCM3/DLL4-Notch signaling in the pathway: CCM3→DLL4/Notch→EphB4→ERK1/2. siRNA knockdown, EphB4 kinase inhibitor treatment, in vitro and in vivo angiogenesis assays, RT-PCR, Western blot Journal of cellular and molecular medicine Medium 28371279
2024 CCM3 knockdown in endothelial cells induces activation and nuclear translocation of YAP/TAZ; YAP/TAZ inhibitor verteporfin reverses the pro-angiogenic effects of CCM3 silencing (proliferation, migration, tube formation, VEGF/VEGFR2 upregulation), establishing CCM3 as a regulator of the Hippo/YAP-TAZ pathway in angiogenesis. siRNA knockdown, YAP/TAZ nuclear translocation assay, verteporfin pharmacological rescue, HUVEC functional assays Biochemical and biophysical research communications Medium 38320423
2011 In zebrafish, ccm3 deficiency causes cardiovascular phenotypes distinct from ccm1/ccm2 loss; ccm3 (but not ccm2) defects can be rescued by overexpression of stk25b (GCKIII kinase); morpholino knockdown of stk25b phenocopies ccm3 morphants; double knockdown of ccm3 and ccm2 shows synergistic vessel dilation, supporting a model where CCM3 acts via GCKIII activity in a pathway distinct from CCM1/CCM2. Zebrafish morpholino knockdown, genetic rescue (stk25b overexpression), phenotypic analysis Developmental biology High 22182521
2023 Loss of Pdcd10 in ureter urothelium causes hypertrophy, increased expression of uroplakins and keratins, modification of intracellular membrane systems (vesicle trafficking defects), swelling of Golgi compartments, disruption of mitochondrial cristae, increased lysosomal fusion, decreased fusiform vesicle formation, and increased exosome secretion, indicating PDCD10 regulates endomembrane trafficking and organelle biogenesis in epithelial cells. Conditional KO mice (Cdh16-Cre), immunocytochemistry, confocal and electron microscopy, mRNA expression analysis The FEBS journal Medium 38037455

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 A PP2A phosphatase high density interaction network identifies a novel striatin-interacting phosphatase and kinase complex linked to the cerebral cavernous malformation 3 (CCM3) protein. Molecular & cellular proteomics : MCP 303 18782753
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
2007 PDCD10 interacts with Ste20-related kinase MST4 to promote cell growth and transformation via modulation of the ERK pathway. Molecular biology of the cell 134 17360971
2010 CCM3 signaling through sterile 20-like kinases plays an essential role during zebrafish cardiovascular development and cerebral cavernous malformations. The Journal of clinical investigation 133 20592472
2014 Exceptional aggressiveness of cerebral cavernous malformation disease associated with PDCD10 mutations. Genetics in medicine : official journal of the American College of Medical Genetics 131 25122144
2016 Endothelial exocytosis of angiopoietin-2 resulting from CCM3 deficiency contributes to cerebral cavernous malformation. Nature medicine 104 27548575
2010 CCM3/PDCD10 stabilizes GCKIII proteins to promote Golgi assembly and cell orientation. Journal of cell science 104 20332113
2015 Sulindac metabolites decrease cerebrovascular malformations in CCM3-knockout mice. Proceedings of the National Academy of Sciences of the United States of America 92 26109568
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
2011 Loss of cerebral cavernous malformation 3 (Ccm3) in neuroglia leads to CCM and vascular pathology. Proceedings of the National Academy of Sciences of the United States of America 87 21321212
2013 Loss of CCM3 impairs DLL4-Notch signalling: implication in endothelial angiogenesis and in inherited cerebral cavernous malformations. Journal of cellular and molecular medicine 79 23388056
2018 TRIM59 promotes breast cancer motility by suppressing p62-selective autophagic degradation of PDCD10. PLoS biology 77 30408026
2010 Crystal structure of CCM3, a cerebral cavernous malformation protein critical for vascular integrity. The Journal of biological chemistry 72 20489202
2005 Mutations in apoptosis-related gene, PDCD10, cause cerebral cavernous malformation 3. Neurosurgery 72 16284570
2013 CCM3 Mutations Are Associated with Early-Onset Cerebral Hemorrhage and Multiple Meningiomas. Molecular syndromology 71 23801932
2006 Low frequency of PDCD10 mutations in a panel of CCM3 probands: potential for a fourth CCM locus. Human mutation 70 16329096
2011 CCM3/PDCD10 heterodimerizes with germinal center kinase III (GCKIII) proteins using a mechanism analogous to CCM3 homodimerization. The Journal of biological chemistry 66 21561863
2011 Ccm3 functions in a manner distinct from Ccm1 and Ccm2 in a zebrafish model of CCM vascular disease. Developmental biology 65 22182521
2012 Adaptor protein cerebral cavernous malformation 3 (CCM3) mediates phosphorylation of the cytoskeletal proteins ezrin/radixin/moesin by mammalian Ste20-4 to protect cells from oxidative stress. The Journal of biological chemistry 63 22291017
2009 Apoptotic functions of PDCD10/CCM3, the gene mutated in cerebral cavernous malformation 3. Stroke 63 19246713
2020 Non-canonical signaling pathway of SNAI2 induces EMT in ovarian cancer cells by suppressing miR-222-3p transcription and upregulating PDCD10. Theranostics 60 32483426
2019 Distinct cellular roles for PDCD10 define a gut-brain axis in cerebral cavernous malformation. Science translational medicine 59 31776290
2010 Differential angiogenesis function of CCM2 and CCM3 in cerebral cavernous malformations. Neurosurgical focus 58 20809750
2021 CCM3 is a gatekeeper in focal adhesions regulating mechanotransduction and YAP/TAZ signalling. Nature cell biology 55 34226698
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
2019 Rho Kinase Inhibition Blunts Lesion Development and Hemorrhage in Murine Models of Aggressive Pdcd10/Ccm3 Disease. Stroke 48 30744543
2015 PDCD10 (CCM3) regulates brain endothelial barrier integrity in cerebral cavernous malformation type 3: role of CCM3-ERK1/2-cortactin cross-talk. Acta neuropathologica 46 26385474
2021 Caveolae-mediated Tie2 signaling contributes to CCM pathogenesis in a brain endothelial cell-specific Pdcd10-deficient mouse model. Nature communications 41 33495460
2014 PDCD10 gene mutations in multiple cerebral cavernous malformations. PloS one 41 25354366
2016 MicroRNA-103 suppresses tumor cell proliferation by targeting PDCD10 in prostate cancer. The Prostate 39 26771762
2017 A Sterile 20 Family Kinase and Its Co-factor CCM-3 Regulate Contractile Ring Proteins on Germline Intercellular Bridges. Current biology : CB 38 28285996
2015 Hypoxia-induced miR-181b enhances angiogenesis of retinoblastoma cells by targeting PDCD10 and GATA6. Oncology reports 38 25872572
2007 Two non-homologous brain diseases-related genes, SERPINI1 and PDCD10, are tightly linked by an asymmetric bidirectional promoter in an evolutionarily conserved manner. BMC molecular biology 38 17212813
2018 miRNA‑26a‑5p and miR‑26b‑5p inhibit the proliferation of bladder cancer cells by regulating PDCD10. Oncology reports 36 30272373
2013 Structural mechanism of CCM3 heterodimerization with GCKIII kinases. Structure (London, England : 1993) 36 23541896
2017 EphB4 forward signalling mediates angiogenesis caused by CCM3/PDCD10-ablation. Journal of cellular and molecular medicine 35 28371279
2019 Transcriptome clarifies mechanisms of lesion genesis versus progression in models of Ccm3 cerebral cavernous malformations. Acta neuropathologica communications 34 31426861
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 Concomitant activation of miR-107/PDCD10 and hypoxamir-210/Casp8ap2 and their role in cytoprotection during ischemic preconditioning of stem cells. Antioxidants & redox signaling 33 22482882
2011 Molecular recognition of leucine-aspartate repeat (LD) motifs by the focal adhesion targeting homology domain of cerebral cavernous malformation 3 (CCM3). The Journal of biological chemistry 33 21632544
2017 CCM-3 Promotes C. elegans Germline Development by Regulating Vesicle Trafficking Cytokinesis and Polarity. Current biology : CB 32 28285997
2005 CCM3 mutations are uncommon in cerebral cavernous malformations. Neurology 32 16380626
2020 CircSMARCA5 Facilitates the Progression of Prostate Cancer Through miR-432/PDCD10 Axis. Cancer biotherapy & radiopharmaceuticals 31 32407167
2016 CCM3/SERPINI1 bidirectional promoter variants in patients with cerebral cavernous malformations: a molecular and functional study. BMC medical genetics 31 27737651
2008 PDCD10, the gene mutated in cerebral cavernous malformation 3, is expressed in the neurovascular unit. Neurosurgery 31 18496199
2020 The multifaceted PDCD10/CCM3 gene. Genes & diseases 30 34522709
2012 PDCD10 interacts with STK25 to accelerate cell apoptosis under oxidative stress. Frontiers in bioscience (Landmark edition) 30 22652780
2010 PDCD10/CCM3 acts downstream of {gamma}-protocadherins to regulate neuronal survival. The Journal of biological chemistry 29 21041308
2019 TRIM59 deficiency curtails breast cancer metastasis through SQSTM1-selective autophagic degradation of PDCD10. Autophagy 28 30653426
2015 Detection of Novel Mutation in Ccm3 Causes Familial Cerebral Cavernous Malformations. Journal of molecular neuroscience : MN 25 26115622
2014 Ccm3, a gene associated with cerebral cavernous malformations, is required for neuronal migration. Development (Cambridge, England) 25 24595293
2014 Differential expression of MST4, STK25 and PDCD10 between benign prostatic hyperplasia and prostate cancer. International journal of clinical and experimental pathology 24 25550858
2021 Genome-wide analysis of copy number alterations led to the characterisation of PDCD10 as oncogene in ovarian cancer. Translational oncology 21 33516089
2009 c-Myc regulates the coordinated transcription of brain disease-related PDCD10-SERPINI1 bidirectional gene pair. Molecular and cellular neurosciences 21 19442737
2018 Dual function of programmed cell death 10 (PDCD10) in drug resistance. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 20 29482058
2023 Exosomal miR-30a-5p promoted intrahepatic cholangiocarcinoma progression by increasing angiogenesis and vascular permeability in PDCD10 dependent manner. International journal of biological sciences 18 37781039
2016 Arsenic-induced anti-angiogenesis via miR-425-5p-regulated CCM3. Toxicology letters 18 27132035
2007 Identification of an Arg35X mutation in the PDCD10 gene in a patient with cerebral and multiple spinal cavernous malformations. Journal of the neurological sciences 18 18035376
2021 Pdcd10-Stk24/25 complex controls kidney water reabsorption by regulating Aqp2 membrane targeting. JCI insight 17 34156031
2018 Biallelic CCM3 mutations cause a clonogenic survival advantage and endothelial cell stiffening. Journal of cellular and molecular medicine 17 30549232
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
2020 PDCD10-Deficiency Promotes Malignant Behaviors and Tumor Growth via Triggering EphB4 Kinase Activity in Glioblastoma. Frontiers in oncology 13 32850441
2018 Interrogating the ccm-3 Gene Network. Cell reports 13 30208312
2022 PDCD10 promotes proliferation, migration, and invasion of osteosarcoma by inhibiting apoptosis and activating EMT pathway. Cancer medicine 12 35848121
2021 ATPIF1 maintains normal mitochondrial structure which is impaired by CCM3 deficiency in endothelial cells. Cell & bioscience 12 33422124
2021 CCM3 Loss-Induced Lymphatic Defect Is Mediated by the Augmented VEGFR3-ERK1/2 Signaling. Arteriosclerosis, thrombosis, and vascular biology 12 34670407
2019 CCM3 and cerebral cavernous malformation disease. Stroke and vascular neurology 12 31338212
2017 Lead promotes abnormal angiogenesis induced by CCM3 gene defects via mitochondrial pathway. Journal of developmental origins of health and disease 12 29110746
2017 Arsenic exposure assists ccm3 genetic polymorphism in elevating blood pressure. Oncotarget 12 29435151
2022 Contact-dependent signaling triggers tumor-like proliferation of CCM3 knockout endothelial cells in co-culture with wild-type cells. Cellular and molecular life sciences : CMLS 11 35661927
2022 The Dual Role of PDCD10 in Cancers: A Promising Therapeutic Target. Cancers 11 36497468
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
2022 PDCD10 promotes the aggressive behaviors of pituitary adenomas by up-regulating CXCR2 and activating downstream AKT/ERK signaling. Aging 10 35963638
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
2015 Cerebral cavernous malformations associated to meningioma: High penetrance in a novel family mutated in the PDCD10 gene. The neuroradiology journal 10 26246098
2015 Expression of CCM2 and CCM3 during mouse gonadogenesis. Journal of assisted reproduction and genetics 9 26386873
2022 Transcriptome Analysis Reveals Altered Expression of Genes Involved in Hypoxia, Inflammation and Immune Regulation in Pdcd10-Depleted Mouse Endothelial Cells. Genes 8 35741725
2014 Surveying genetic variants and molecular phylogeny of cerebral cavernous malformation gene, CCM3/PDCD10. Biochemical and biophysical research communications 8 25451273
2013 The CCM3-GCKIII partnership. Histology and histopathology 8 23744102
2020 The interaction of lead exposure and CCM3 defect plays an important role in regulating angiogenesis through eNOS/NO pathway. Environmental toxicology and pharmacology 7 32512318
2024 PDCD10 promotes the tumor-supporting functions of TGF-β in pancreatic cancer. Clinical science (London, England : 1979) 6 39212293
2015 First description of programmed cell death10 (PDCD10) in rock bream (Oplegnathus fasciatus): Potential relations to the regulation of apoptosis by several pathogens. Developmental and comparative immunology 6 26472617
2023 Comprehensive CCM3 Mutational Analysis in Two Patients with Syndromic Cerebral Cavernous Malformation. Translational stroke research 5 36723700
2019 A novel PDCD10 gene mutation in cerebral cavernous malformations: a case report and review of the literature. Journal of pain research 5 31114296
2009 CCM2 and CCM3 proteins contribute to vasculogenesis and angiogenesis in human placenta. Histology and histopathology 5 19688696
2024 Knockdown of CCM3 promotes angiogenesis through activation and nuclear translocation of YAP/TAZ. Biochemical and biophysical research communications 4 38320423
2023 Protumorigenic role of the atypical cadherin FAT1 by the suppression of PDCD10 via RelA/miR221-3p/222-3p axis in glioblastoma. Molecular carcinogenesis 4 37606187
2023 Deficiency of Pdcd10 causes urothelium hypertrophy and vesicle trafficking defects in ureter. The FEBS journal 4 38037455
2012 Crystallization and preliminary crystallographic studies of CCM3 in complex with the C-terminal domain of MST4. Acta crystallographica. Section F, Structural biology and crystallization communications 4 22750858
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
2024 Study on the role of CCM3 gene and lead exposure induced neurotoxicity through neurovascular units. Ecotoxicology and environmental safety 3 38657460
2020 High Levels of Receptor Tyrosine Kinases in CCM3-Deficient Cells Increase Their Susceptibility to Tyrosine Kinase Inhibition. Biomedicines 3 33348877
2025 PDCD10/CCM3, a potential target for pancreatic ductal adenocarcinoma? Clinical science (London, England : 1979) 2 39927779
2024 PDCD10 Is a Key Player in TMZ-Resistance and Tumor Cell Regrowth: Insights into Its Underlying Mechanism in Glioblastoma Cells. Cells 2 39273014
2023 NDR kinase tricornered genetically interacts with Ccm3 and metabolic enzymes in Drosophila melanogaster tracheal development. G3 (Bethesda, Md.) 2 36653023
2020 A novel CCM3 mutation associated with cerebral cavernous malformation in a Chinese family. Therapeutic advances in neurological disorders 2 32071616
2025 Programmed Cell Death Protein 10 (PDCD10) Regulates Vesicle Trafficking and Contributes to the Progression of Clear Cell Renal Cell Carcinoma. Journal of extracellular vesicles 1 40560794
2024 CircFNDC3B inhibits vascular smooth muscle cells proliferation in abdominal aortic aneurysms by targeting the miR-1270/PDCD10 axis. Scandinavian cardiovascular journal : SCJ 1 39658211
2021 Improving clinical interpretation of five KRIT1 and PDCD10 intronic variants. Clinical genetics 1 33604894

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