Affinage

NF2

Merlin · UniProt P35240

Length
595 aa
Mass
69.7 kDa
Annotated
2026-06-10
100 papers in source corpus 39 papers cited in narrative 40 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

Merlin (NF2) is a FERM-domain tumor suppressor that couples cell-cell contact and cortical cytoskeletal organization to the restraint of mitogenic signaling and proliferation (PMID:12695331, PMID:26483553). At the cortex, merlin associates with adherens-junction components and is required for contact-dependent growth arrest and stable junction assembly (PMID:12695331), and it transduces junctional mechanical force through cortical actomyosin to restrict the lateral mobility and internalization of EGFR (PMID:26483553); it likewise accelerates PDGFR internalization and degradation while dampening MAPK and PI3K output (PMID:14612918), and inhibits PI3K via PIKE-L (PMID:15598747) and integrin-driven mTORC1 signaling (PMID:19451229). Merlin activity is governed by a conformational switch and a dense phosphorylation/ubiquitination code: PAK, downstream of Rac/Cdc42, directly phosphorylates merlin at S518 to inactivate it (PMID:11719502, PMID:11782491), and the S518-phosphomimetic form fails to suppress growth and motility (PMID:14724586), whereas dephosphorylation and NEDD4L-mediated ubiquitination at K396 — scaffolded by AMOTL1 — activate merlin for Lats1 binding and anti-mitogenic function (PMID:33058421). Structurally, an auto-inhibitory tail occludes the Lats1/2-binding surface of the FERM domain, and angiomotin binding relieves this auto-inhibition to drive Hippo pathway activation, an event blocked by S518 phosphorylation (PMID:26045165). Merlin acts upstream of Lats1/2-dependent YAP phosphorylation to control cell fate and morphogenesis in vivo (PMID:23791728, PMID:27480037), requires lipid (PI(4,5)P2/PI4P) binding for membrane recruitment and Hippo activation (PMID:32115406), and forms PI4P-dependent solid-like condensates at the medial apical cortex essential for Hippo signaling (PMID:39116228). Through this Hippo/YAP axis merlin also controls contact-dependent ferroptosis, with NF2 loss sensitizing cancer cells to ferroptosis (PMID:31341276). Beyond canonical Hippo signaling, merlin restricts cortical Ezrin to ensure correct centrosome positioning and spindle orientation (PMID:23249734) and inhibits Wnt/β-catenin signaling by binding LRP6 and blocking its phosphorylation (PMID:27285107).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2001 High

    Established that merlin sits in a Rac-PAK signaling axis and that its activity is controlled by phosphorylation, defining the upstream regulation of the tumor suppressor.

    Evidence Nf2-/- mouse cells, activated Rac expression and phosphorylation assays, plus in vitro/in vivo PAK kinase assays identifying S518

    PMID:11703924 PMID:11719502 PMID:11782491

    Open questions at the time
    • Did not establish how S518 phosphorylation alters merlin's downstream effectors at the molecular level
    • Phosphatase(s) reactivating merlin not identified
  2. 2003 High

    Linked merlin to contact-dependent growth arrest by showing it is required for adherens-junction assembly, connecting the molecule to a defined cellular phenotype.

    Evidence Nf2-/- primary cells with colocalization and co-IP against AJ components

    PMID:12695331

    Open questions at the time
    • Direct molecular partner within the junction not pinned down
    • Mechanism connecting AJ assembly to growth arrest left open
  3. 2004 High

    Connected merlin to growth-factor receptor signaling by showing it inhibits PI3K through PIKE-L and that S518 phosphorylation abrogates growth/motility suppression.

    Evidence PI3K activity assays, PIKE-L mutant and RNAi, plus inducible phosphomimetic S518D/S518A merlin in schwannoma cells

    PMID:14724586 PMID:15598747

    Open questions at the time
    • Relative contribution of PIKE-L vs other effectors to tumor suppression unresolved
  4. 2006 High

    Showed merlin restrains FAK/Src/PI3K signaling and receptor trafficking, broadening its role to multiple oncogenic cascades and receptor clearance.

    Evidence Merlin re-expression in mesothelioma cells with FAK/Src/p85 co-IP; Drosophila Mer;ex double-mutant pulse-chase receptor trafficking

    PMID:16581517 PMID:16652148

    Open questions at the time
    • Whether receptor clearance is the primary tumor-suppressive output not established
    • Direct vs indirect effect on FAK phosphorylation unclear
  5. 2007 High

    Defined merlin's interaction with the microtubule cytoskeleton, extending its cortical role to tubulin polymerization regulated by conformation and S518.

    Evidence In vitro tubulin-binding/polymerization assays, domain and phospho-mutants, merlin-deficient Schwann cells

    PMID:17566081

    Open questions at the time
    • Functional consequence of merlin-microtubule binding for tumor suppression not defined
  6. 2009 High

    Connected merlin loss to integrin-driven mTORC1 activation and rapamycin sensitivity, identifying a druggable downstream dependency.

    Evidence shRNA and re-expression with mTORC1/cap-dependent translation readouts and rapamycin panel plus xenografts

    PMID:19451229

    Open questions at the time
    • Molecular step linking merlin to mTORC1 not resolved
  7. 2010 High

    Demonstrated tissue-context specificity by showing Nf2-driven liver progenitor overgrowth is EGFR-driven and YAP-independent, cautioning against a single universal effector.

    Evidence Liver-specific conditional Nf2 knockout with EGFR inhibitor rescue

    PMID:20675406

    Open questions at the time
    • Why YAP is dispensable here but central elsewhere is unexplained
  8. 2012 High

    Showed merlin restricts cortical Ezrin to control centrosome positioning and spindle orientation, and that Rac1-merlin signaling governs Schwann cell myelination in vivo.

    Evidence Nf2-/- epithelial cells with live imaging/spindle assays; Rac1-CKO rescued by NF2 mutation in vivo

    PMID:23197717 PMID:23249734

    Open questions at the time
    • Mechanistic basis of cortical Ezrin exclusion by merlin only partly defined
  9. 2013 High

    Placed Nf2/Merlin genetically upstream of Lats1/2-YAP in cell-fate determination, cementing its role in the core Hippo pathway during development.

    Evidence Dominant-negative Nf2 with Lats2 rescue and maternal-zygotic Nf2 mutant blastocysts

    PMID:23791728

    Open questions at the time
    • How merlin physically engages the Lats kinases not addressed in this study
  10. 2015 High

    Provided the structural mechanism: an auto-inhibitory tail blocks Lats1/2 binding and angiomotin relieves this auto-inhibition, with S518 phosphorylation and cancer mutations disrupting activation.

    Evidence Crystal structures of the Merlin FERM domain with binding assays, phospho- and cancer-mutant analysis

    PMID:26045165

    Open questions at the time
    • In vivo dynamics of the open/closed transition not directly visualized
  11. 2015 High

    Tied junctional mechanical force to EGFR mobility/internalization via Merlin and Ezrin, and identified FAK dependency as a therapeutic vulnerability of Merlin-negative tumors.

    Evidence FRAP/single-particle tracking of EGFR with Merlin/Ezrin depletion; FAK inhibitor sensitivity in cell panels and xenografts

    PMID:24848258 PMID:26483553

    Open questions at the time
    • Mechanochemical step linking cortical actomyosin to receptor confinement not fully resolved
  12. 2016 High

    Showed Merlin's Hippo control extends to in vivo organ morphogenesis and revealed Hippo-independent (Lin28B-let-7) and density-dependent outputs.

    Evidence Conditional kidney KO with Yap/Taz heterozygous rescue; co-IP and miRNA processing assays with phospho-merlin mutants

    PMID:26997273 PMID:27480037

    Open questions at the time
    • Relative weight of Hippo-dependent vs -independent outputs in tumor suppression unknown
  13. 2019 High

    Connected contact-dependent NF2/Hippo signaling to ferroptosis sensitivity, identifying NF2 loss as a determinant of ferroptosis vulnerability.

    Evidence NF2 inactivation, E-cadherin blocking, ferroptosis and YAP reporter assays, orthotopic mouse model

    PMID:31341276

    Open questions at the time
    • Generality across NF2-mutant tumor types not established
  14. 2020 High

    Defined lipid binding as a requirement for Merlin membrane recruitment and Hippo activation under osmotic stress, mechanistically anchoring Merlin to the plasma membrane.

    Evidence Lipid-binding mutant, PIP5K manipulation, PI(4,5)P2 measurement, LATS/YAP phosphorylation assays

    PMID:32115406

    Open questions at the time
    • How lipid binding integrates with conformational opening not fully resolved
  15. 2020 High

    Resolved the activating ubiquitination event: NEDD4L modifies Merlin at K396 (AMOTL1-scaffolded, dephosphorylation-dependent) to enable Lats1 binding and anti-mitogenic activity.

    Evidence Ubiquitination assays, K396R mutant, NEDD4L depletion, Lats1 binding and functional rescue, patient mutation analysis

    PMID:33058421

    Open questions at the time
    • Integration of K396 ubiquitination with the angiomotin-mediated conformational switch not directly tested
  16. 2024 High

    Showed Merlin forms PI4P-dependent solid-like condensates at the medial apical cortex whose material properties are essential for Hippo activation, adding a biophysical layer to its mechanism.

    Evidence Drosophila live imaging, PI4P manipulation, condensate biophysical characterization, Pez/tension perturbation

    PMID:39116228

    Open questions at the time
    • Whether mammalian Merlin forms comparable condensates not demonstrated
    • Molecular composition of the condensate beyond Merlin/PI4P undefined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple regulatory layers — conformational auto-inhibition, S518 phosphorylation, K396 ubiquitination, lipid binding, and condensate formation — are integrated into a single activation hierarchy in mammalian cells remains unresolved.
  • No unified model ordering the regulatory inputs
  • Tissue-specific selection of effector pathways (Hippo vs EGFR vs mTORC1) not mechanistically explained

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 4 GO:0060089 molecular transducer activity 3 GO:0098772 molecular function regulator activity 3 GO:0008289 lipid binding 2
Localization
GO:0005856 cytoskeleton 4 GO:0005886 plasma membrane 3 GO:0005815 microtubule organizing center 1
Pathway
R-HSA-162582 Signal Transduction 6 R-HSA-1500931 Cell-Cell communication 3 R-HSA-1266738 Developmental Biology 2 R-HSA-5357801 Programmed Cell Death 1
Partners
AMOTL1ERBINEZRLATS1LRP6NEDD4LPAK2PIKE-L

Evidence

Reading pass · 40 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 Merlin was placed in a signaling pathway downstream of the small GTPase Rac: activated Rac induces phosphorylation of merlin and decreases its association with the cytoskeleton; merlin overexpression inhibits Rac-induced signaling in a phosphorylation-dependent manner; and Nf2-/- cells exhibit characteristics of cells expressing activated Rac alleles. Cell-based signaling assays, phosphorylation studies, Nf2-/- mouse cells, overexpression of activated Rac Developmental cell High 11703924
2001 p21-activated kinase (PAK), a common downstream effector of Rac and Cdc42, directly phosphorylates merlin at serine 518; this phosphorylation affects merlin activity and localization. In vivo and in vitro kinase assays, expression of activated Rac/Cdc42, PAK overexpression in mammalian cells The Journal of biological chemistry High 11719502
2002 PAK2 specifically phosphorylates merlin at serine 518; this phosphorylation causes dramatic relocalization of the merlin protein, demonstrated by biochemical fractionation, active/dominant-negative PAK2 mutants, immunodepletion, and phospho-directed antibodies. Biochemical fractionation, active and dominant-negative PAK2 mutants, immunodepletion, phospho-specific antibodies, wild-type and mutant merlin constructs The Journal of biological chemistry High 11782491
2003 Nf2 deficiency in primary cells causes an inability to undergo contact-dependent growth arrest and to form stable cadherin-containing adherens junctions (AJs); merlin colocalizes and interacts with AJ components in confluent wild-type cells, indicating merlin is required for AJ assembly and contact-dependent growth arrest. Nf2-/- primary cells, colocalization imaging, co-immunoprecipitation with AJ components Genes & development High 12695331
2004 Merlin inhibits phosphatidylinositol 3-kinase (PI3K) activity by binding to PIKE-L; wild-type merlin (but not patient-derived mutant L64P) binds PIKE-L and disrupts PIKE-L interaction with PI3K; knockdown of PIKE-L abolishes merlin's tumor-suppressive activity. Binding assays, PI3K activity assay, PIKE-L point mutant (P187L), RNA interference knockdown, cell growth assays Proceedings of the National Academy of Sciences of the United States of America High 15598747
2004 Phosphorylation of merlin at S518 (mimicked by S518D mutation) abrogates merlin's ability to suppress cell growth and motility, whereas the non-phosphorylatable S518A mutant functions equivalently to wild-type; phosphorylation at the analogous ERM site T576 had no effect on merlin function. Doxycycline-inducible merlin mutant (S518D, S518A, T576 mutants) expression in RT4 schwannoma cells, cell growth and motility assays Oncogene High 14724586
2006 Re-expression of merlin in NF2-deficient mesothelioma cells inhibits cell motility, spreading, and invasiveness; merlin expression attenuates FAK phosphorylation at Tyr397 and disrupts FAK interactions with Src and p85 (PI3K regulatory subunit). Merlin re-expression by adenoviral vector, siRNA knockdown in MEFs, cell invasion/motility assays, co-immunoprecipitation of FAK/Src/p85 Oncogene High 16652148
2006 Drosophila Merlin and Expanded cooperatively regulate the steady-state levels of signaling and adhesion receptors; loss of both proteins causes upregulation of Notch at the plasma membrane due to a defect in receptor clearance/endocytosis from the cell surface. Drosophila imaginal disc genetics, pulse-chase receptor labeling in living tissues, Mer;ex double mutant analysis Current biology : CB High 16581517
2007 Merlin directly interacts with microtubules through two tubulin-binding sites (N-terminal FERM domain and C-terminal domain); merlin's intramolecular association and S518 phosphorylation regulate the merlin-tubulin interaction; merlin promotes tubulin polymerization in vitro and in vivo, and loss of merlin alters Schwann cell microtubule organization. In vitro tubulin-binding assays, merlin mutant constructs, immunofluorescence colocalization, primary Schwann cells from merlin-deficient mice Human molecular genetics High 17566081
2007 Schwannomin/merlin interacts with NF2-interacting protein HEI10 (a cyclin B-binding cell cycle regulator); the interaction requires the alpha-helical domain of merlin and the coiled-coil domain of HEI10, and requires conformational opening of merlin; this interaction links merlin to cell cycle control machinery. Yeast two-hybrid screen, co-immunoprecipitation, domain-mapping with deletion mutants, subcellular colocalization, Schwann cell vs. schwannoma comparison Oncogene Medium 16532029
2009 Loss of merlin activates integrin-dependent mTORC1 signaling and cap-dependent mRNA translation (including cyclin D1); depletion of merlin rescues mTORC1 signaling in anchorage-deprived cells; merlin-negative mesothelioma lines are rapamycin-sensitive; re-expression of merlin confers partial rapamycin resistance. shRNA knockdown, recombinant merlin re-expression, mTORC1 and cap-dependent translation assays, rapamycin sensitivity panel, xenograft models Molecular and cellular biology High 19451229
2009 Erbin, an epithelial-enriched protein, controls merlin tumor suppressor function by switching the functional valence of PAK2 binding: in epithelial cells, Erbin/Merlin complexes bind and inactivate GTPase-bound PAK2, preventing its phosphorylation and inactivation of merlin. Co-immunoprecipitation, TGF-β signaling assays in epithelial vs. mesenchymal cells, PAK2 kinase assays, dominant-negative constructs Developmental cell Medium 19289088
2010 In Nf2-deficient liver, overproliferation of liver progenitors is driven by aberrant EGFR activity; pharmacologic inhibition of EGFR blocks proliferation of Nf2-/- liver progenitors in vitro and in vivo; Merlin was found NOT to be a major regulator of YAP in liver progenitors in this context. Liver-specific conditional Nf2 knockout mouse, EGFR inhibitor treatment in vitro and in vivo, molecular pathway analysis Genes & development High 20675406
2012 Rac1 controls Schwann cell myelination through NF2/merlin: Rac1 knockout reduces PAK phosphorylation and NF2/merlin phosphorylation; mutation of NF2/merlin rescues the myelin deficit in Rac1-CKO mice; cAMP levels and E-cadherin expression downstream of Rac1 are restored by NF2/merlin mutation. Rac1 conditional knockout mice, in vivo NF2 mutant rescue experiment, cAMP measurement, E-cadherin immunostaining, rolipram treatment The Journal of neuroscience : the official journal of the Society for Neuroscience High 23197717
2012 Merlin restricts the cortical distribution of the actin regulator Ezrin; in the absence of Merlin, ectopic cortical Ezrin yields mispositioned centrosomes, misoriented spindles, and aberrant epithelial architecture; in tumor cells with centrosome amplification, failure to restrict cortical Ezrin abolishes centrosome clustering, causing multipolar mitoses. Nf2-/- epithelial cells, live imaging, centrosome positioning assay, 3D organotypic cultures, spindle orientation analysis Genes & development High 23249734
2013 Nf2/Merlin is required upstream of Lats1/2-dependent YAP phosphorylation in the preimplantation embryo; injection of dominant-negative Nf2 causes YAP mislocalization and ectopic Cdx2 expression, rescued by Lats2 kinase overexpression; maternal-zygotic Nf2 mutant embryos fail to establish a pluripotent ICM and form excess TE. Dominant-negative Nf2 mRNA injection, Lats2 overexpression rescue, maternal-zygotic Nf2 mutant blastocysts, immunofluorescence for YAP and Cdx2 Current biology : CB High 23791728
2015 Crystal structures show that the Lats1/2-binding site on the Merlin FERM domain is physically blocked by Merlin's auto-inhibitory tail; angiomotin binding releases this auto-inhibition and promotes Merlin binding to Lats1/2; S518 phosphorylation prevents angiomotin from binding Merlin; cancer-causing mutations in the angiomotin-binding domain impair angiomotin-mediated Merlin activation. High-resolution crystal structures of Merlin FERM domain, binding assays, phospho-mimetic/deficient mutants, cancer mutation analysis Cell research High 26045165
2015 Merlin and Ezrin are essential components of a mechanism whereby mechanical forces associated with cell-cell junction establishment are transduced via cortical actomyosin to control lateral mobility and activity of EGFR; Merlin inhibits EGFR internalization in a contact-dependent manner requiring cortical cytoskeleton localization. Fluorescence recovery after photobleaching (FRAP), single-particle tracking, Merlin/Ezrin depletion, live imaging, cortical actomyosin perturbation The Journal of cell biology High 26483553
2015 Merlin inhibits Wnt/β-catenin signaling by directly binding LRP6 and blocking LRP6 phosphorylation required for Wnt signal transduction; Wnt3a treatment activates PAK1 in a PIP2-dependent manner, phosphorylating Merlin at S518, causing dissociation from LRP6 and allowing LRP6 phosphorylation. Co-immunoprecipitation, LRP6 phosphorylation assays, PAK1 inhibitor/overexpression, PIP2 manipulation, NF2 patient tissue analysis Cell death and differentiation Medium 27285107
2016 Merlin triggers AMOTL1 proteasomal degradation mediated by NEDD family ubiquitin ligases through direct interaction with AMOTL1. Co-immunoprecipitation, proteasome inhibitor treatment, ubiquitination assays Neoplasia (New York, N.Y.) Medium 26806348
2016 Merlin regulates NF2/Merlin-Lin28B-let-7 tumor-suppressive signaling in a Hippo-independent, cell-density-dependent manner: at high cell density, dephosphorylated Merlin sequesters Lin28B in the cytoplasm permitting pri-let-7 miRNA maturation; at low density, phosphorylated Merlin does not bind Lin28B, allowing nuclear Lin28B to inhibit let-7 maturation. Co-immunoprecipitation, cell density manipulation, phospho-mimetic merlin mutants, miRNA processing assays, Lin28B localization Cell reports Medium 26997273
2016 NF2 and Lats1/2 are required for branching morphogenesis in the mouse kidney ureteric bud; removal of Nf2 or Lats1/2 causes loss of branching, rescued by loss of one copy of Yap/Taz; YAP suppresses RET signaling and tip identity downstream of NF2. Conditional knockout mice (ureteric bud lineage), genetic epistasis (Yap/Taz heterozygous rescue), mosaic analysis Nature communications High 27480037
2017 In Drosophila, Merlin and Kibra activate Hippo signaling in parallel to Expanded at a spatially distinct cellular domain (medial apical cortex); Merlin and Kibra together recruit Salvador, which recruits the core kinase Hippo. Drosophila genetics, live imaging, domain-specific immunofluorescence, epistasis analysis Developmental cell High 28292426
2019 In epithelial cells, E-cadherin-mediated intercellular contact suppresses ferroptosis by activating intracellular NF2 and Hippo signaling; YAP (when NF2/Hippo is inactive) promotes ferroptosis by upregulating ACSL4 and TFRC; NF2 genetic inactivation renders cancer cells more sensitive to ferroptosis. NF2 genetic inactivation (siRNA and KO), E-cadherin blocking antibodies, ferroptosis assays (lipid peroxidation), YAP reporter assays, orthotopic mouse model Nature High 31341276
2019 NF2/Merlin regulates TEAD palmitoylation and stability in a cell-density-dependent manner; Merlin suppresses fatty acid synthase (FASN) and acetyl-CoA carboxylase (ACC) expression (involved in de novo palmitate biosynthesis), leading to TEAD depalmitoylation by APT2/ABHD17A and subsequent proteasomal degradation via E3 ligase CHIP. NF2 knockdown/overexpression, FASN/ACC expression assays, palmitoylation assays, proteasome inhibitor treatment, TEAD stability assays Proceedings of the National Academy of Sciences of the United States of America Medium 31043565
2019 BRCA1/BARD1 ubiquitinates NF2, leading to NF2 destabilization, which turns off the Hippo pathway and stabilizes YAP1; in BRCA1-deficient cells the Hippo pathway is activated. BRCA1 knockout cells, co-immunoprecipitation, ubiquitination assay, YAP1 phosphorylation assays, YAP1 mutant (5SA) rescue Proceedings of the National Academy of Sciences of the United States of America Medium 30918126
2020 NF2's lipid-binding ability is required for Hippo pathway activation in response to osmotic stress; osmotic stress induces PI(4,5)P2 plasma membrane enrichment via PIP5K family activation, allowing NF2 membrane recruitment and downstream LATS/YAP phosphorylation; NF2 mutant deficient in lipid binding cannot activate the Hippo pathway. NF2 lipid-binding mutant, PIP5K manipulation, PI(4,5)P2 measurement, LATS and YAP phosphorylation assays under osmotic stress Genes & development High 32115406
2020 NEDD4L-mediated ubiquitination of Merlin at lysine 396 is required to activate Merlin in the Hippo pathway; ubiquitination is promoted by S518 dephosphorylation; AMOTL1 scaffolds NEDD4L to Merlin; ubiquitinated Merlin binds Lats1 and activates Lats1; the K396R mutation or NEDD4L depletion disrupts Lats1 binding and activation and abolishes anti-mitogenic activity. Ubiquitination assays, NEDD4L overexpression/depletion, Merlin K396R mutant, Lats1 binding assays, anti-mitogenic functional assays, NF2-patient mutation analysis EMBO reports High 33058421
2024 In Drosophila epithelia, Merlin forms solid-like condensates at the medial apical cortex (distinct from cell junctions); condensate formation requires phosphatidylinositol-4-phosphate (PI4P)-mediated plasma membrane targeting and is antagonistically controlled by Pez and cytoskeletal tension through PI4P regulation; solid-like material properties of Merlin condensates are essential for Hippo pathway activation. Drosophila live imaging, PI4P manipulation, condensate biophysical characterization, genetic manipulation of Pez and cytoskeletal tension Science (New York, N.Y.) High 39116228
2000 Merlin isoform I and isoform II both interact with ezrin through a head-to-tail orientation (N-terminal half of one protein with C-terminal half of the other); isoform I binds only open-conformation ezrin while isoform II binds regardless of conformation; merlin homodimerization is stronger than merlin-ezrin interaction and can inhibit merlin-ezrin binding. Co-immunoprecipitation, yeast two-hybrid assays, domain-mapping experiments Journal of neuroscience research Medium 11070492
2005 Layilin (a cell-surface hyaluronan receptor) interacts with full-length merlin and its N-terminal FERM domain independently of phospholipids; layilin antibody can co-immunoprecipitate merlin, confirming in vivo association; both proteins show similar subcellular localization in ruffling membranes. Co-immunoprecipitation, GST-pulldown assays, immunofluorescence colocalization Experimental cell research Medium 15913605
2002 Schwannomin/merlin and HRS (hepatocyte growth factor-regulated tyrosine kinase substrate) cooperatively inhibit Stat3 and Stat5 activation; a pathogenic missense mutation Q538P in schwannomin fails to bind HRS and does not inhibit Stat5 phosphorylation. Co-immunoprecipitation, STAT phosphorylation assays, schwannomin mutant (Q538P), IGF-I stimulation in human schwannoma cells Human molecular genetics Medium 12444102
2007 Merlin phosphorylation at S518 affects its interaction with tubulin: merlin's intramolecular association and S518 phosphorylation regulate the merlin-tubulin interaction; merlin promotes tubulin polymerization in vitro. In vitro tubulin polymerization assay, phospho-mimetic/deficient merlin mutants, primary Schwann cells from merlin-deficient mice Human molecular genetics Medium 17566081
2007 Merlin inhibits neurite outgrowth through a mechanism dependent on S518 phosphorylation and involving inactivation of Rac GTPase; overexpression of merlin in cerebellar cultures and P19 neurogenic cells decreases neurite outgrowth; merlin inhibition increases process formation. Merlin overexpression/knockdown in cerebellar cultures and P19 cells, S518 phosphorylation mutants, neurite length quantification The Journal of neuroscience : the official journal of the Society for Neuroscience Medium 20668201
2007 Akt phosphorylates merlin at T230 and S315; this phosphorylation abolishes merlin's folded conformation, inhibits its association with PIKE-L, promotes merlin polyubiquitination, and leads to proteasome-mediated degradation, providing a negative feedback loop from merlin/PIKE-L/PI3K to Akt. In vitro Akt kinase assay, phospho-site mutagenesis, co-immunoprecipitation, ubiquitination assay, proteasome inhibitor treatment Cell adhesion & migration Medium 19262146
2000 Calpain (a calcium-dependent cysteine protease) cleaves and degrades merlin; marked calpain system activation results in merlin degradation in some schwannomas and meningiomas lacking NF2 mutations. Calpain cleavage assays, tumor tissue analysis for calpain activity and merlin levels Neuropathology : official journal of the Japanese Society of Neuropathology Medium 11132929
2015 Merlin-deficient cells show increased dependence on FAK signaling (synthetic lethal relationship); weak cell-cell adhesions in Merlin-negative MPM cells underlie greater dependence on cell-ECM-induced FAK signaling, explaining FAK inhibitor vulnerability. Cancer cell line panel, cell-cell/ECM contact blocking antibodies, FAK inhibitor (VS-4718) sensitivity assays, xenograft models Science translational medicine Medium 24848258
2015 Merlin suppresses FOXM1 protein stability, which plays a critical role in nuclear translocation of β-catenin; by destabilizing FOXM1, Merlin suppresses Wnt/β-catenin signaling and downstream target gene expression. Merlin overexpression/knockdown, FOXM1 protein stability assays, β-catenin nuclear localization, FOXM1 overexpression rescue Cancer research Medium 26483206
2003 NF2/merlin re-expression in schwannoma cells inhibits cell proliferation under serum-free conditions; merlin accelerates PDGFR internalization, inhibits PDGF-induced MAPK and PI3K signaling (pErk1/2, pAkt), and promotes PDGFR degradation. Adenoviral NF2 overexpression in HEI193 schwannoma cells, proliferation assays, receptor internalization assay, Western blotting for signaling International journal of oncology Medium 14612918
2012 Merlin/NF2 regulates angiogenesis in schwannomas through Rac1; loss of merlin downregulates semaphorin 3F (SEMA3F) expression through Rac1; re-introduction of SEMA3F normalized tumor blood vessels and reduced tumor burden in vivo. RNA interference, chemical inhibitors for Rac1, SEMA3F re-expression in NF2-null cells, intracranial tumor models in nude mice Neoplasia (New York, N.Y.) Medium 22431917

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 ERM proteins and merlin: integrators at the cell cortex. Nature reviews. Molecular cell biology 1121 12154370
2019 Intercellular interaction dictates cancer cell ferroptosis via NF2-YAP signalling. Nature 918 31341276
2013 Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO. Science (New York, N.Y.) 721 23348505
2010 Dinaciclib (SCH 727965), a novel and potent cyclin-dependent kinase inhibitor. Molecular cancer therapeutics 458 20663931
2009 Neurofibromatosis type 2 (NF2): a clinical and molecular review. Orphanet journal of rare diseases 360 19545378
2015 Role of Merlin/NF2 inactivation in tumor biology. Oncogene 346 25893302
2001 The Nf2 tumor suppressor, merlin, functions in Rac-dependent signaling. Developmental cell 286 11703924
2003 NF2 deficiency promotes tumorigenesis and metastasis by destabilizing adherens junctions. Genes & development 255 12695331
2010 Nf2/Merlin controls progenitor homeostasis and tumorigenesis in the liver. Genes & development 223 20675406
2001 p21-activated kinase links Rac/Cdc42 signaling to merlin. The Journal of biological chemistry 218 11719502
2014 Merlin deficiency predicts FAK inhibitor sensitivity: a synthetic lethal relationship. Science translational medicine 215 24848258
1996 Type of mutation in the neurofibromatosis type 2 gene (NF2) frequently determines severity of disease. American journal of human genetics 212 8755919
2005 Membrane organization and tumorigenesis--the NF2 tumor suppressor, Merlin. Genes & development 206 16204178
2002 Merlin phosphorylation by p21-activated kinase 2 and effects of phosphorylation on merlin localization. The Journal of biological chemistry 192 11782491
1994 Exon scanning for mutation of the NF2 gene in schwannomas. Human molecular genetics 190 8012353
2013 The Hippo pathway member Nf2 is required for inner cell mass specification. Current biology : CB 172 23791728
2006 The tumor suppressors Merlin and Expanded function cooperatively to modulate receptor endocytosis and signaling. Current biology : CB 170 16581517
2009 Merlin and the ERM proteins--regulators of receptor distribution and signaling at the cell cortex. Trends in cell biology 160 19345106
2014 Molecular insights into NF2/Merlin tumor suppressor function. FEBS letters 154 24726726
2008 Molecular characterisation of SMARCB1 and NF2 in familial and sporadic schwannomatosis. Journal of medical genetics 152 18285426
2009 Loss of the tumor suppressor gene NF2, encoding merlin, constitutively activates integrin-dependent mTORC1 signaling. Molecular and cellular biology 141 19451229
2006 Re-expression of the tumor suppressor NF2/merlin inhibits invasiveness in mesothelioma cells and negatively regulates FAK. Oncogene 141 16652148
1994 Frequent NF2 gene transcript mutations in sporadic meningiomas and vestibular schwannomas. American journal of human genetics 129 7911002
2004 Neurofibromatosis 2 (NF2) tumor suppressor merlin inhibits phosphatidylinositol 3-kinase through binding to PIKE-L. Proceedings of the National Academy of Sciences of the United States of America 124 15598747
2015 Angiomotin binding-induced activation of Merlin/NF2 in the Hippo pathway. Cell research 120 26045165
1994 An anti-Ras function of neurofibromatosis type 2 gene product (NF2/Merlin). The Journal of biological chemistry 119 8089100
2012 Merlin: a tumour suppressor with functions at the cell cortex and in the nucleus. EMBO reports 109 22482125
2007 Nf2/Merlin: a coordinator of receptor signalling and intercellular contact. British journal of cancer 100 17971776
1990 Flanking markers bracket the neurofibromatosis type 2 (NF2) gene on chromosome 22. American journal of human genetics 98 2105641
2017 Kibra and Merlin Activate the Hippo Pathway Spatially Distinct from and Independent of Expanded. Developmental cell 96 28292426
2007 Shedding light on Merlin's wizardry. Trends in cell biology 93 17442573
2018 NF2/Merlin Inactivation and Potential Therapeutic Targets in Mesothelioma. International journal of molecular sciences 90 29587439
1999 Merlin: the neurofibromatosis 2 tumor suppressor. Biochimica et biophysica acta 89 10214350
2021 Neurofibromatosis Type 2 (NF2) and the Implications for Vestibular Schwannoma and Meningioma Pathogenesis. International journal of molecular sciences 86 33445724
2020 Distinct genomic subclasses of high-grade/progressive meningiomas: NF2-associated, NF2-exclusive, and NF2-agnostic. Acta neuropathologica communications 85 33087175
2004 Effect of merlin phosphorylation on neurofibromatosis 2 (NF2) gene function. Oncogene 82 14724586
2017 Timing of Smarcb1 and Nf2 inactivation determines schwannoma versus rhabdoid tumor development. Nature communications 79 28824165
2003 Overexpression of the NF2 gene inhibits schwannoma cell proliferation through promoting PDGFR degradation. International journal of oncology 78 14612918
2019 Cell contact and Nf2/Merlin-dependent regulation of TEAD palmitoylation and activity. Proceedings of the National Academy of Sciences of the United States of America 77 31043565
2021 MEF2C silencing downregulates NF2 and E-cadherin and enhances Erastin-induced ferroptosis in meningioma. Neuro-oncology 67 33984142
2007 The merlin interacting proteins reveal multiple targets for NF2 therapy. Biochimica et biophysica acta 67 17980164
1998 NF2 gene in neurofibromatosis type 2 patients. Human molecular genetics 66 9817927
2011 Inactivation of Merlin in malignant mesothelioma cells and the Hippo signaling cascade dysregulation. Pathology international 65 21615608
2019 The Role of Merlin/NF2 Loss in Meningioma Biology. Cancers 61 31652973
2005 Genetic and epigenetic alteration of the NF2 gene in sporadic meningiomas. Genes, chromosomes & cancer 61 15609345
1998 Induction of oxidative stress in rat brain by acrylonitrile (ACN). Toxicological sciences : an official journal of the Society of Toxicology 58 10048137
2009 The neurofibromatoses. Part 2: NF2 and schwannomatosis. Reviews in neurological diseases 57 19898272
2012 Rac1 controls Schwann cell myelination through cAMP and NF2/merlin. The Journal of neuroscience : the official journal of the Society for Neuroscience 56 23197717
2013 Neurofibromatosis type 2 (NF2): diagnosis and management. Handbook of clinical neurology 55 23931824
2020 Critical roles of phosphoinositides and NF2 in Hippo pathway regulation. Genes & development 54 32115406
2012 Merlin/ERM proteins establish cortical asymmetry and centrosome position. Genes & development 54 23249734
2016 A critical role for NF2 and the Hippo pathway in branching morphogenesis. Nature communications 53 27480037
2015 Alterations in the NF2/LATS1/LATS2/YAP Pathway in Schwannomas. Journal of neuropathology and experimental neurology 52 26360373
2015 NF2/Merlin mediates contact-dependent inhibition of EGFR mobility and internalization via cortical actomyosin. The Journal of cell biology 52 26483553
2005 Layilin, a cell surface hyaluronan receptor, interacts with merlin and radixin. Experimental cell research 51 15913605
2014 Analyses of merlin/NF2 connection to FAK inhibitor responsiveness in serous ovarian cancer. Gynecologic oncology 49 24786638
2015 Merlin/NF2 Suppresses Pancreatic Tumor Growth and Metastasis by Attenuating the FOXM1-Mediated Wnt/β-Catenin Signaling. Cancer research 48 26483206
2012 Merlin, a multi-suppressor from cell membrane to the nucleus. FEBS letters 48 22595235
2003 NF2: the wizardry of merlin. Genes, chromosomes & cancer 48 14566860
2007 The Nf2 tumor suppressor regulates cell-cell adhesion during tissue fusion. Proceedings of the National Academy of Sciences of the United States of America 46 17360635
1994 The murine NF2 homologue encodes a highly conserved merlin protein with alternative forms. Human molecular genetics 45 8012352
2014 NF2/merlin in hereditary neurofibromatosis 2 versus cancer: biologic mechanisms and clinical associations. Oncotarget 44 24393766
2013 Merlin, the NF2 gene product. Pathology oncology research : POR 44 23666797
2000 Interaction between two isoforms of the NF2 tumor suppressor protein, merlin, and between merlin and ezrin, suggests modulation of ERM proteins by merlin. Journal of neuroscience research 44 11070492
2012 Merlin/NF2 regulates angiogenesis in schwannomas through a Rac1/semaphorin 3F-dependent mechanism. Neoplasia (New York, N.Y.) 43 22431917
2002 Neurofibromatosis 2 (NF2) tumor suppressor schwannomin and its interacting protein HRS regulate STAT signaling. Human molecular genetics 42 12444102
1995 Expression of the neurofibromatosis 2 (NF2) gene isoforms during rat embryonic development. Human molecular genetics 42 7795605
2009 Erbin and the NF2 tumor suppressor Merlin cooperatively regulate cell-type-specific activation of PAK2 by TGF-beta. Developmental cell 41 19289088
2008 Nf2/merlin regulates hematopoietic stem cell behavior by altering microenvironmental architecture. Cell stem cell 41 18682243
2016 Neurofibromatosis 2 (NF2) controls the invasiveness of glioblastoma through YAP-dependent expression of CYR61/CCN1 and miR-296-3p. Biochimica et biophysica acta 39 26923924
2016 Childhood neurofibromatosis type 2 (NF2) and related disorders: from bench to bedside and biologically targeted therapies. Acta otorhinolaryngologica Italica : organo ufficiale della Societa italiana di otorinolaringologia e chirurgia cervico-facciale 39 27958595
2012 Genetic and epigenetic alterations of the NF2 gene in sporadic vestibular schwannomas. PloS one 39 22295085
2020 Merlin regulates signaling events at the nexus of development and cancer. Cell communication and signaling : CCS 38 32299434
2007 The tumor suppressor merlin interacts with microtubules and modulates Schwann cell microtubule cytoskeleton. Human molecular genetics 37 17566081
2016 Crizotinib inhibits NF2-associated schwannoma through inhibition of focal adhesion kinase 1. Oncotarget 36 27363027
2016 Merlin inhibits Wnt/β-catenin signaling by blocking LRP6 phosphorylation. Cell death and differentiation 33 27285107
2017 Ponatinib promotes a G1 cell-cycle arrest of merlin/NF2-deficient human schwann cells. Oncotarget 32 28427224
2016 AMOTL1 Promotes Breast Cancer Progression and Is Antagonized by Merlin. Neoplasia (New York, N.Y.) 32 26806348
2012 Merlin: the wizard requires protein stability to function as a tumor suppressor. Biochimica et biophysica acta 29 22750751
2000 Calpain-dependent proteolysis of NF2 protein: involvement in schwannomas and meningiomas. Neuropathology : official journal of the Japanese Society of Neuropathology 27 11132929
2017 Differential Expression of NF2 in Neuroepithelial Compartments Is Necessary for Mammalian Eye Development. Developmental cell 26 29249622
2006 Angucyclines Sch 47554 and Sch 47555 from Streptomyces sp. SCC-2136: cloning, sequencing, and characterization. Molecules and cells 26 17085966
2020 NEDD4L-mediated Merlin ubiquitination facilitates Hippo pathway activation. EMBO reports 25 33058421
2016 Merlin/NF2-Lin28B-let-7 Is a Tumor-Suppressive Pathway that Is Cell-Density Dependent and Hippo Independent. Cell reports 25 26997273
2023 NF2 alteration in mesothelioma. Frontiers in toxicology 24 37180489
2014 Oncogenic role of Merlin/NF2 in glioblastoma. Oncogene 24 25043298
2013 Neurofibromatosis type 2 protein, NF2: an uncoventional cell cycle regulator. Anticancer research 24 23267122
2010 Merlin inhibits neurite outgrowth in the CNS. The Journal of neuroscience : the official journal of the Society for Neuroscience 24 20668201
2007 Phosphorylation of merlin regulates its stability and tumor suppressive activity. Cell adhesion & migration 24 19262146
2006 A functional association between merlin and HEI10, a cell cycle regulator. Oncogene 24 16532029
2003 Chromosome 22q alterations and expression of the NF2 gene product, merlin, in gastrointestinal stromal tumors. Human pathology 24 14562282
2020 Therapy of Sporadic and NF2-Related Vestibular Schwannoma. Cancers 23 32244314
2024 NF2: An underestimated player in cancer metabolic reprogramming and tumor immunity. NPJ precision oncology 22 38879686
2016 Merlin, the product of NF2 gene, is associated with aromatase expression and estrogen formation in human liver tissues and liver cancer cells. The Journal of steroid biochemistry and molecular biology 22 27289045
2016 Merlin, a regulator of Hippo signaling, regulates Wnt/β-catenin signaling. BMB reports 22 27345717
2014 A neuronal function of the tumor suppressor protein merlin. Acta neuropathologica communications 22 25012216
2010 Schwannomin/merlin promotes Schwann cell elongation and influences myelin segment length. Molecular and cellular neurosciences 22 21182951
2019 BRCA1/BARD1-dependent ubiquitination of NF2 regulates Hippo-YAP1 signaling. Proceedings of the National Academy of Sciences of the United States of America 21 30918126
2002 Analysis of the NF2 gene in oligodendrogliomas and ependymomas. Cancer genetics and cytogenetics 21 11996787
2024 PI4P-mediated solid-like Merlin condensates orchestrate Hippo pathway regulation. Science (New York, N.Y.) 20 39116228

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