Affinage

MSX2

Homeobox protein MSX-2 · UniProt P35548

Length
267 aa
Mass
28.9 kDa
Annotated
2026-04-28
100 papers in source corpus 31 papers cited in narrative 31 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MSX2 is a homeodomain transcription factor that integrates BMP, FGF, Wnt, and vitamin K/PXR signaling to control the balance between progenitor cell proliferation and differentiation in skeletal, vascular, and neural crest tissues. MSX2 functions primarily as a transcriptional repressor—occupying target promoters such as osteocalcin in proliferating osteoblasts and recruiting a TLE1/HDAC1 co-repressor complex to suppress Runx2-dependent gene activation—but also directly activates specific targets including Osterix, Atoh1, and Stra8 via homeodomain binding (PMID:15456894, PMID:15060165, PMID:18703512, PMID:24715462). Its pro-osteogenic functions require DNA-binding activity, whereas suppression of adipogenesis occurs through DNA-binding-independent protein–protein interaction with C/EBPα, and MSX2 protein stability is controlled by FBXW2-mediated ubiquitination (facilitated by VRK2 phosphorylation) and by CLU-dependent mitophagic clearance, both of which regulate nuclear MSX2 levels to modulate SOX2 transcription (PMID:12925529, PMID:31548378, PMID:36779631). A gain-of-function P148H homeodomain mutation that enhances DNA-binding affinity causes autosomal dominant Boston-type craniosynostosis by expanding osteogenic progenitors at calvarial suture fronts (PMID:8106171, PMID:9917362).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1993 High

    Identification of the MSX2 P148H gain-of-function mutation established that enhanced DNA-binding affinity of a homeodomain transcription factor can cause craniosynostosis, providing the first direct link between MSX2 dosage and cranial suture biology.

    Evidence Genetic mapping and sequencing of a Boston-type craniosynostosis kindred combined with DNA-binding assays of the mutant homeodomain

    PMID:8106171

    Open questions at the time
    • Mechanism by which enhanced DNA binding causes premature suture fusion was not defined
    • Target genes of MSX2 in suture mesenchyme were unknown
  2. 1996 High

    Demonstration that MSX2 represses transcription independently of its consensus DNA-binding site, with repressor activity mapping N-terminal to the homeodomain, revealed that MSX2 operates through both DNA-dependent and protein–protein interaction mechanisms.

    Evidence Deletion mutagenesis, in vitro DNA binding assays, and transcriptional reporter assays

    PMID:8861098

    Open questions at the time
    • Identity of co-repressor partners mediating DNA-binding-independent repression was unknown
    • In vivo relevance of the two repression modes was not tested
  3. 1999 High

    Bidirectional manipulation of Msx2 in osteoblasts and transgenic mice established that Msx2 dosage controls the proliferative osteogenic progenitor pool: overexpression maintains proliferation and prevents differentiation, while loss depletes progenitors, unifying the craniosynostosis gain-of-function and knockout phenotypes.

    Evidence Retroviral sense/antisense expression in primary chick calvarial osteoblasts; tissue-specific Msx2 transgenic mice with BrdU incorporation and histomorphometry

    PMID:10328922 PMID:9917362

    Open questions at the time
    • Downstream transcriptional targets maintaining the progenitor state were not identified
    • Relationship to BMP signaling in vivo was correlative
  4. 1999 High

    Identification of MINT as a direct MSX2-binding nuclear co-repressor that occupies osteocalcin promoter elements provided the first molecular partner explaining MSX2's repressive function on osteoblast-specific genes.

    Evidence Far-Western expression cloning, GST pulldown, EMSA on osteocalcin G/T-rich elements, reporter assays in MC3T3E1 cells

    PMID:10451362

    Open questions at the time
    • Whether MINT is required for all MSX2 repressive functions or only osteocalcin regulation was unknown
    • In vivo validation of the MINT-MSX2 complex at endogenous chromatin was lacking
  5. 2000 High

    Msx2 knockout mice confirmed that Msx2 is essential for both intramembranous and endochondral ossification, with calvarial foramina, defective osteoprogenitor proliferation, and reduced Pth/Pthrp receptor signaling establishing its non-redundant skeletal functions.

    Evidence Msx2-null mouse analysis with histomorphometry, BrdU assay, gene expression, and Msx1/Msx2 genetic epistasis

    PMID:10742104

    Open questions at the time
    • Whether Msx2 directly regulates Pthrp receptor transcription was not determined
    • Cell-autonomous versus non-autonomous roles in endochondral bone were not resolved
  6. 2003 High

    Structure–function dissection in mesenchymal cells demonstrated that MSX2's pro-osteogenic activity requires DNA binding whereas its anti-adipogenic activity operates through DNA-binding-independent interaction with C/EBPα, mechanistically separating two lineage-determination functions within a single transcription factor.

    Evidence MSX2 DNA-binding mutants (P148H, T147A) tested for osteogenesis and adipogenesis in primary aortic myofibroblasts and C3H10T1/2 cells

    PMID:12925529

    Open questions at the time
    • Structural basis of the MSX2–C/EBPα interaction was not resolved
    • Whether the same separation of function applies in vivo was untested
  7. 2003 High

    BMP2 and Wnt signaling were shown to converge on the Msx2 promoter via cooperative Smad4 and Lef1 binding, placing Msx2 as an integrative node downstream of two major morphogenetic pathways.

    Evidence Promoter-reporter assays, ChIP for Smad4 and Lef1, and analysis in Smad4-deficient ES cells

    PMID:14551209

    Open questions at the time
    • Whether additional signaling inputs regulate the Msx2 promoter was not explored
    • Chromatin context and enhancer regulation in vivo were not addressed
  8. 2004 High

    ChIP across the osteoblast differentiation time-course revealed that MSX2 occupies the osteocalcin promoter during proliferation and is replaced by Dlx3/Dlx5 post-mitotically, establishing a homeodomain transcription factor switching mechanism that gates osteoblast gene activation.

    Evidence Sequential ChIP with staged osteoblast cultures, transcriptional reporters, and RNA interference

    PMID:15456894

    Open questions at the time
    • What triggers MSX2 eviction from the promoter was unknown
    • Whether this switch operates genome-wide or is osteocalcin-specific was not tested
  9. 2004 High

    Discovery that MSX2 recruits a TLE1/HDAC1 co-repressor complex to suppress Runx2 transcriptional activity identified the enzymatic mechanism (histone deacetylation) underlying MSX2-mediated repression at osteoblast gene promoters.

    Evidence Co-immunoprecipitation of MSX2–TLE1–HDAC1, stable knockdown/overexpression in periodontal ligament cells, mineralization and HDAC activity assays

    PMID:15060165

    Open questions at the time
    • Genome-wide extent of TLE1/HDAC1 co-recruitment by MSX2 was not mapped
    • Relationship between MINT and TLE1/HDAC1 co-repressor usage was unclear
  10. 2007 Medium

    MSX2 was positioned as a mediator of BMP4-induced epithelial–mesenchymal transition in cancer cells, expanding its functional repertoire beyond skeletal development to include E-cadherin repression and Twist1 upregulation.

    Evidence siRNA knockdown abolishing BMP4-induced EMT markers in Panc-1 cells; MSX2 overexpression inducing Twist1 confirmed by microarray and reversal by siRNA

    PMID:17516553 PMID:18349132

    Open questions at the time
    • Whether MSX2 directly binds Twist1 or E-cadherin regulatory elements was not tested
    • Generalizability beyond pancreatic cancer cells was not established
  11. 2008 High

    Identification of Osterix as a direct MSX2 target activated independently of Runx2 revealed a parallel BMP2-to-osteoblast differentiation pathway, demonstrating that MSX2 can function as a transcriptional activator, not solely a repressor.

    Evidence MSX2 overexpression in Runx2-deficient mesenchymal cells induces Osterix; MSX2 knockdown blocks BMP2-induced Osterix

    PMID:18703512

    Open questions at the time
    • Whether MSX2 directly binds the Osterix promoter was not shown by ChIP
    • How the activator versus repressor mode is selected was unknown
  12. 2008 High

    The P148H mutant was found to have accelerated proteasomal degradation mediated by the Praja1 E3 ligase and to act as a dominant-negative by promoting ubiquitylation of wild-type MSX2, revealing that ubiquitin-dependent turnover modulates MSX2 function in craniosynostosis.

    Evidence Pulse-chase, ubiquitylation assays, Praja1 overexpression, cyclin D1 reporter in suture mesenchymal cells

    PMID:18786927

    Open questions at the time
    • Reconciliation with earlier data showing P148H as a simple gain-of-function was unresolved
    • In vivo relevance of Praja1-mediated degradation was not tested
  13. 2014 High

    In vivo ChIP and double-knockout phenotyping established that Msx1/Msx2 directly activate Atoh1 and Stra8 transcription via homeodomain sites in their enhancers, demonstrating MSX2's role as a direct transcriptional activator in neural tube patterning and meiosis initiation.

    Evidence Msx1/Msx2 double-mutant mouse phenotyping, ChIP at Atoh1 3′ enhancer and Stra8 regulatory regions, reporter assays with homeodomain site mutations

    PMID:22071108 PMID:24715462

    Open questions at the time
    • Whether MSX2 alone is sufficient or always acts redundantly with MSX1 at these targets was not resolved
    • Genome-wide catalog of MSX2 activator versus repressor targets was lacking
  14. 2014 Medium

    Conditional deletion of Msx1/Msx2 in vascular smooth muscle cells reduced aortic calcification and stiffness in diabetic mice, establishing MSX2 as a driver of vascular osteogenesis through maintenance of Wnt2/Wnt5a signaling in adventitial myofibroblasts.

    Evidence SM22-Cre conditional Msx1fl/fl;Msx2fl/fl;LDLR−/− mice, pulse wave velocity, aortic calcium quantification, RNAi in primary myofibroblasts

    PMID:25056439

    Open questions at the time
    • Individual contributions of Msx1 versus Msx2 to vascular calcification were not fully separated
    • Direct binding of MSX2 to Wnt2/Wnt5a promoters was not shown
  15. 2019 High

    Identification of FBXW2 as the principal E3 ubiquitin ligase for MSX2—with VRK2-mediated phosphorylation as the signal for FBXW2 recognition under hypoxia—established a complete phospho-degron pathway controlling MSX2 stability and downstream SOX2 derepression.

    Evidence Co-IP, ubiquitylation assays, pulse-chase, VRK2 kinase assay, SOX2 reporter, and in vivo tumor models

    PMID:31548378

    Open questions at the time
    • Specific phosphorylation sites on MSX2 targeted by VRK2 were not fully mapped
    • Relationship between FBXW2 and Praja1-mediated degradation pathways was not addressed
  16. 2023 Medium

    CLU-dependent mitophagy was shown to clear MSX2 from the cytoplasm, preventing its nuclear translocation and thereby relieving SOX2 suppression, revealing a non-proteasomal, autophagy-based mechanism for MSX2 turnover linked to cancer stemness.

    Evidence CLU gain/loss-of-function, mitophagy assays, subcellular fractionation, AKT/DNM1L phosphorylation, tumor sphere and cisplatin sensitivity assays

    PMID:36779631

    Open questions at the time
    • How MSX2 is targeted to mitochondria for mitophagic degradation is unknown
    • Whether mitophagic clearance of MSX2 operates in non-cancer contexts is untested
    • Integration of proteasomal (FBXW2) and mitophagic (CLU) degradation pathways has not been resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • A genome-wide map of MSX2 binding sites distinguishing direct activator versus repressor targets, the structural basis for its dual transcriptional modes, and the integration of its proteasomal and mitophagic degradation pathways remain unresolved.
  • No genome-wide ChIP-seq for MSX2 has been reported in the timeline
  • Structural basis for activator-to-repressor switching is unknown
  • Relationship between FBXW2/Praja1 proteasomal and CLU-mitophagic degradation is not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 10 GO:0003677 DNA binding 7
Localization
GO:0005634 nucleus 5
Pathway
R-HSA-74160 Gene expression (Transcription) 11 R-HSA-1266738 Developmental Biology 7 R-HSA-162582 Signal Transduction 7 R-HSA-392499 Metabolism of proteins 3
Partners
CEBPAFBXW2HDAC1SPENTBX2TBX5TLE1VRK2
Complex memberships
MSX2–MINT co-repressor complexMSX2–TLE1–HDAC1 co-repressor complex

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 A Pro-to-His substitution at position 7 of the MSX2 homeodomain (P7H, equivalent to P148H) enhances DNA binding affinity and causes autosomal dominant Boston-type craniosynostosis via a gain-of-function mechanism. Genetic mapping, sequencing of affected kindred, murine Msx2 in situ hybridization in calvarial sutures Cell High 8106171
1996 MSX2 functions as a transcriptional repressor independently of its consensus DNA binding site, and this repressor activity maps to sequences N-terminal to the homeodomain; MSX2 has higher apparent DNA-binding affinity than MSX1. In vitro DNA binding assays, transcriptional reporter assays, deletion mutagenesis Mechanisms of development High 8861098
1997 BMP4 induces programmed cell death via an Msx2-mediated pathway; constitutive Msx2 expression in P19 cells increases apoptosis upon aggregation, and BMP4 does not further increase cell death in Msx2-expressing cells, placing Msx2 downstream of BMP4 in a cell-death pathway. Stable transfection/overexpression, aggregation assay, BMP4 treatment, apoptosis quantification Developmental biology Medium 9205134
1999 Msx2 overexpression prevents osteoblastic differentiation and mineralization while maintaining cell proliferation; antisense Msx2 decreases proliferation and accelerates differentiation, indicating Msx2 acts to maintain an undifferentiated, proliferative state in osteogenic cells. Retroviral-mediated overexpression (sense and antisense), primary chick calvarial osteoblast culture, alkaline phosphatase assay, mineralization assay Developmental biology High 10328922
1999 Msx2 gene dosage controls the number of proliferative osteogenic cells at the calvarial osteogenic front; the gain-of-function P148H variant enhances DNA binding and increases BrdU-positive osteoblastic cells, causing craniosynostosis by expanding the progenitor pool. Tissue-specific Msx2 transgenic mice, BrdU incorporation assay, histomorphometry Developmental biology High 9917362
1999 MINT (Msx2-interacting nuclear target protein) physically binds Msx2 via the core suppressor domain of Msx2, co-localizes with Msx2 in chromatin/nuclear matrix fractions, and the MINT RRM domain binds the osteocalcin promoter G/T-rich elements, acting as a co-repressor of osteocalcin transcription. Far-Western expression cloning, GST pulldown, Western blot of fractionated extracts, gel-shift (EMSA), transcriptional reporter assays in MC3T3E1 cells Biochemistry High 10451362
2000 Msx2-deficient mice show defective proliferation of osteoprogenitors at the osteogenic front, calvarial foramen, and defects in endochondral bone; reduced Pth/Pthrp receptor signaling accompanies post-natal skeletal deficits, demonstrating Msx2 is required for both chondrogenesis and osteogenesis. Msx2 knockout mouse analysis, histomorphometry, BrdU proliferation assay, gene expression analysis, genetic epistasis with Msx1 null Nature genetics High 10742104
2000 BMP4-induced chondrogenesis in mandibular explants is positively regulated by Sox9 and negatively regulated by Msx2; adenoviral overexpression of Msx2 in the proximal mandible inhibits BMP4-induced chondrogenesis and downregulates type II collagen. BMP4 bead implantation in mandibular explants, adenoviral Msx2 overexpression, in situ hybridization Developmental dynamics Medium 10767084
2001 MSX2 represses transcription from the Dlx2 promoter and competes with PITX2 for binding to a bicoid/homeodomain element, antagonizing PITX2-mediated Dlx2 activation. Luciferase reporter assays, EMSA with homeodomain binding elements, Western blot Gene expression Medium 11763998
2003 BMP2-Msx2 signaling in aortic myofibroblasts promotes osteogenic differentiation (alkaline phosphatase, mineralization) and suppresses adipogenesis; osteogenic actions require Msx2 DNA binding (P148H enhances, T147A abrogates), whereas adipogenesis suppression occurs via protein-protein interaction with C/EBPα independently of DNA binding. Viral transduction of primary aortic myofibroblasts and C3H10T1/2 cells, alkaline phosphatase assay, mineralized nodule formation, Pparg expression, Msx2 DNA-binding mutants The Journal of biological chemistry High 12925529
2003 BMP2 signaling activates the Msx2 promoter via cooperative binding of Smad4 at two Smad binding elements and Lef1 at two Lef1/TCF sites; Wnt/β-catenin can activate Msx2 via Lef1 independently of BMP, but requires Smad4 (not Smad1) for this response. Promoter-reporter assays in embryonic stem cells, chromatin immunoprecipitation (ChIP), Smad4-deficient ES cells, BMP antagonist treatment The Journal of biological chemistry High 14551209
2004 Msx2 occupies the osteocalcin (OC) gene promoter chromatin in proliferating osteoblasts (transcriptionally repressed state), and is replaced post-proliferatively by Dlx3, Dlx5, and Runx2 to initiate transcription, establishing a temporal molecular switch in homeodomain protein occupancy during osteoblast differentiation. Chromatin immunoprecipitation (ChIP) during staged osteoblast differentiation, transcriptional reporter assays, RNA interference Molecular and cellular biology High 15456894
2004 Msx2 inhibits PPARγ transcriptional activity and blocks adipocyte differentiation induced by PPARγ, C/EBPα, C/EBPβ, or C/EBPδ overexpression, acting via inhibition of the C/EBP transcription factor family. Stable and transient transfection in C3H10T1/2, C2C12, 3T3-F442A cells, adipogenesis assay, luciferase reporter assays, Runx2-deficient mesenchymal cells The Journal of biological chemistry High 15175325
2004 Msx2 co-localizes with Runx2 in periodontal ligament cells and suppresses Runx2 transcriptional activity by forming a complex with the co-repressor TLE1 that recruits histone deacetylase 1 (HDAC1); knockdown of Msx2 in PDL-L2 cells induces osteoblastic differentiation and matrix mineralization. Co-immunoprecipitation, stable Msx2 knockdown and overexpression, HDAC activity assay, mineralization assay, RT-PCR, in situ hybridization Molecular and cellular biology High 15060165
2003 Fibroblast growth factor signaling (FGF2 most potently) upregulates Msx2 expression in calvarial sutures, decreases cell proliferation, and causes suture obliteration, placing Msx2 downstream of FGF receptor signaling in craniosynostosis. Heparin-acrylic bead FGF delivery to mouse calvaria, in situ hybridization, cell proliferation assay, histology Journal of bone and mineral research Medium 12674336
2007 BMP4 induces epithelial-mesenchymal transition (EMT) in Panc-1 pancreatic cancer cells through induction of MSX2 expression via ERK, p38 MAPK and Smad signaling pathways; siRNA knockdown of MSX2 abolishes BMP4-induced E-cadherin repression, vimentin induction, and enhanced cell migration. BMP4 treatment, siRNA knockdown, signaling pathway inhibitors (ERK, p38, Smad), Western blot, migration assay Journal of cellular physiology Medium 17516553
2007 Vitamin K2 (MK4) activates Msx2 transcription through pregnane X receptor (PXR)/RXRα binding to a PXR-responsive element in the Msx2 promoter; PXR recruits p300 co-activator to this element, and knockdown of PXR or Msx2 attenuates MK4-induced osteoblast differentiation. Promoter deletion/reporter assay, ChIP, PXR/Msx2 siRNA knockdown, osteoblast differentiation assay in MC3T3-E1 cells Molecular and cellular biology Medium 17875939
2008 BMP2 regulates Osterix expression via an Msx2-dependent, Runx2-independent pathway in mesenchymal cells; Msx2 overexpression induces Osterix in Runx2-deficient cells, and Msx2 knockdown inhibits BMP2-induced Osterix induction. Msx2 overexpression and siRNA knockdown in Runx2-deficient mesenchymal cells, alkaline phosphatase assay, microarray, qPCR The Journal of biological chemistry High 18703512
2008 Msx2 promotes chondrocyte maturation through upregulation of Indian hedgehog (Ihh) expression; constitutively active Msx2 stimulates hypertrophic chondrocyte markers (alkaline phosphatase, collagen X) in a BMP2/Smad-dependent manner, and cyclopamine (hedgehog inhibitor) blocks Msx2-induced chondrogenesis. Primary chondrocyte overexpression, embryonic metatarsal organ culture, cyclopamine inhibitor, Smad overexpression/dominant-negative, knockdown The Journal of biological chemistry Medium 18682398
2008 Msx1 and Msx2 physically interact with cardiac T-box proteins Tbx2, Tbx3, and Tbx5 through their homeodomain and T-box domains respectively; together with Tbx2/Tbx3, Msx proteins suppress Connexin43 (Cx43) promoter activity, and Msx1 binds the Cx43 promoter at a conserved homeodomain site. Yeast two-hybrid screen, in vitro pulldown, luciferase reporter assay, ChIP in rat heart-derived cell line Cardiovascular research Medium 18285513
2008 The Boston-type craniosynostosis MSX2 P148H mutant has enhanced susceptibility to ubiquitin-mediated proteasomal degradation via Praja1 E3 ligase, resulting in shorter protein half-life; wild-type MSX2 stimulates suture mesenchymal cell proliferation and cyclin D1 expression, while P148H fails to do so and acts as a dominant-negative by increasing ubiquitylation of wild-type MSX2. Pulse-chase experiment, ubiquitylation assay, Praja1 overexpression, cyclin D1 reporter/Western, cell proliferation assay The Journal of biological chemistry High 18786927
2008 MSX2 upregulates Twist1 expression in pancreatic cancer cells (shown by microarray and confirmed by siRNA reversal), and siRNA knockdown of MSX2 reduces Twist1 and reverses EMT-associated phenotypes including E-cadherin relocalization. Stable MSX2 overexpression, siRNA knockdown, microarray, Western blot, orthotopic xenograft The American journal of pathology Medium 18349132
2011 MINT (Msx2-interacting nuclear target protein) forms a high-affinity complex with CSL (RBP-J), the nuclear effector of Notch signaling, and this interaction antagonizes Notch-dependent transcriptional activation; specific domains of MINT and CSL necessary and sufficient for the interaction were delineated. Isothermal titration calorimetry (ITC), deletion mutagenesis, transcriptional reporter assay in cultured cells The Journal of biological chemistry High 21372128
2011 Msx1 and Msx2 directly activate Stra8 transcription by binding homeodomain binding sites in the Stra8 regulatory sequences; in Msx1/Msx2 double mutants, Stra8 is not fully activated and meiosis initiation in the fetal ovary is impaired. Msx1/Msx2 double-mutant analysis, ChIP, Msx1 overexpression reporter assay in F9 cells Development Medium 22071108
2012 MSX2 cooperates with SP1 to transcriptionally regulate ABCG2 expression via SP1 binding elements in the ABCG2 promoter; MSX2 expression level correlates with ABCG2 expression, and siRNA knockdown of MSX2 reduces ABCG2, linking MSX2 to chemoresistance. Overexpression, siRNA knockdown, promoter-reporter assay with SP1 binding element mutations, correlation analysis across cell lines Journal of cellular physiology Medium 21465479
2014 In human embryonic stem cells, BMP4-induced MSX2 expression promotes mesodermal commitment and preferential cardiovascular differentiation; Smad1/5/8 phosphorylation and SLUG act upstream of MSX2 in BMP4-induced epithelial-mesenchymal transition. BMP4 treatment of hESCs, shRNA knockdown of SLUG, ChIP (phospho-Smad1/5/8 on SLUG promoter), differentiation marker analysis Stem cells Medium 24549638
2014 Msx1 and Msx2 directly activate Atoh1 transcription by binding homeodomain sites in the Atoh1 3′ enhancer; in Msx1/Msx2 double-mutant spinal cord, Atoh1-positive dorsal progenitors are absent, and ChIP confirms Msx1 binding to the Atoh1 enhancer in vivo. Msx1/Msx2 double-mutant mouse analysis, ChIP, in vitro transcriptional reporter assay with homeodomain site mutations, cell lineage analysis Development High 24715462
2014 In aortic endothelial cells, Msx2 and Wnt7b maintain EC differentiation markers and oppose endothelial-mesenchymal transition; conditional deletion of EC Wnt7b in vivo upregulates osteogenic genes including Msx2 and increases aortic collagen and calcium. Adenoviral transduction of primary aortic ECs, conditional Cdh5-Cre Wnt7b deletion in LDLR-/- mice, immunofluorescence, Western blot Arteriosclerosis, thrombosis, and vascular biology Medium 23685555
2014 SM22-Cre-mediated deletion of Msx1+Msx2 in vascular myofibroblasts/smooth muscle cells reduces aortic calcium and pulse wave velocity in diabetic LDLR-/- mice; RNA interference reveals Msx2 selectively sustains Wnt2, Wnt5a, and Sca1 expression while Msx1 selectively maintains Shh and Msx2 sustains Wnt2/Wnt5a in aortic adventitial myofibroblasts. Conditional SM22-Cre Msx1fl/fl Msx2fl/fl LDLR-/- mouse model, pulse wave velocity, aortic calcium quantification, RNA interference in primary myofibroblasts, gene expression profiling Diabetes Medium 25056439
2019 MSX2 is a substrate of FBXW2 E3 ubiquitin ligase; FBXW2 binds MSX2, promotes its ubiquitylation and proteasomal degradation, and shortens its half-life; hypoxia induces VRK2 kinase to phosphorylate MSX2, facilitating FBXW2-MSX2 binding and degradation; MSX2 represses SOX2 transcription, and its degradation leads to SOX2 induction. Co-immunoprecipitation, ubiquitylation assay, pulse-chase, FBXW2 overexpression and knockdown, VRK2 kinase assay, SOX2 reporter assay, in vivo tumor model Proceedings of the National Academy of Sciences of the United States of America High 31548378
2023 CLU-mediated mitophagy promotes mitophagic degradation of MSX2, preventing its nuclear translocation; nuclear MSX2 suppresses SOX2 activity and cancer stemness; CLU activates AKT to phosphorylate DNM1L/Drp1 at Ser616, initiating mitochondrial fission required for this mitophagic clearance. CLU gain/loss-of-function, mitophagy assays, subcellular fractionation, AKT/DNM1L phosphorylation Western blot, SOX2 reporter, tumor sphere formation, cisplatin sensitivity assay Autophagy Medium 36779631

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 Msx2 deficiency in mice causes pleiotropic defects in bone growth and ectodermal organ formation. Nature genetics 596 10742104
1993 A mutation in the homeodomain of the human MSX2 gene in a family affected with autosomal dominant craniosynostosis. Cell 563 8106171
2008 BMP2 regulates Osterix through Msx2 and Runx2 during osteoblast differentiation. The Journal of biological chemistry 425 18703512
2003 MSX2 promotes osteogenesis and suppresses adipogenic differentiation of multipotent mesenchymal progenitors. The Journal of biological chemistry 282 12925529
2004 Dlx3 transcriptional regulation of osteoblast differentiation: temporal recruitment of Msx2, Dlx3, and Dlx5 homeodomain proteins to chromatin of the osteocalcin gene. Molecular and cellular biology 229 15456894
2003 Smad4 and beta-catenin co-activators functionally interact with lymphoid-enhancing factor to regulate graded expression of Msx2. The Journal of biological chemistry 173 14551209
1999 Msx2 gene dosage influences the number of proliferative osteogenic cells in growth centers of the developing murine skull: a possible mechanism for MSX2-mediated craniosynostosis in humans. Developmental biology 157 9917362
2005 Combined deficiencies of Msx1 and Msx2 cause impaired patterning and survival of the cranial neural crest. Development (Cambridge, England) 154 16221730
2004 Reciprocal roles of MSX2 in regulation of osteoblast and adipocyte differentiation. The Journal of biological chemistry 152 15175325
1997 Msx2 is a transcriptional regulator in the BMP4-mediated programmed cell death pathway. Developmental biology 131 9205134
2007 Vascular Bmp Msx2 Wnt signaling and oxidative stress in arterial calcification. Annals of the New York Academy of Sciences 119 18056036
1996 Comparison of MSX-1 and MSX-2 suggests a molecular basis for functional redundancy. Mechanisms of development 117 8861098
1991 Cloning and evolutionary analysis of msh-like homeobox genes from mouse, zebrafish and ascidian. Gene 115 1673109
1989 UVB-induced melanogenesis may be mediated through the MSH-receptor system. The Journal of investigative dermatology 115 2497190
2005 Analysis of Msx1; Msx2 double mutants reveals multiple roles for Msx genes in limb development. Development (Cambridge, England) 113 15930102
2007 Concerted action of Msx1 and Msx2 in regulating cranial neural crest cell differentiation during frontal bone development. Mechanisms of development 110 17693062
1981 Chemistry and biosynthesis of pro-opiomelanocortin. ACTH, MSH's, endorphins and their related peptides. Molecular and cellular biochemistry 108 6262628
2000 Vnd/nkx, ind/gsh, and msh/msx: conserved regulators of dorsoventral neural patterning? Current opinion in neurobiology 107 10679430
2008 Redirection of flux through the FPP branch-point in Saccharomyces cerevisiae by down-regulating squalene synthase. Biotechnology and bioengineering 105 18175359
2006 The fluorescence protease protection (FPP) assay to determine protein localization and membrane topology. Nature protocols 102 17406244
1999 Ectopic Msx2 overexpression inhibits and Msx2 antisense stimulates calvarial osteoblast differentiation. Developmental biology 100 10328922
1998 Expression of Msx-2 during development, regeneration, and wound healing in axolotl limbs. The Journal of experimental zoology 100 9846383
1998 Human pigmentation phenotype: a point mutation generates nonfunctional MSH receptor. Biochemical and biophysical research communications 98 9571181
2013 Dkk1 and MSX2-Wnt7b signaling reciprocally regulate the endothelial-mesenchymal transition in aortic endothelial cells. Arteriosclerosis, thrombosis, and vascular biology 97 23685555
1997 Perinatal lethality and multiple craniofacial malformations in MSX2 transgenic mice. Human molecular genetics 96 9147639
2000 Positionally-dependent chondrogenesis induced by BMP4 is co-regulated by Sox9 and Msx2. Developmental dynamics : an official publication of the American Association of Anatomists 91 10767084
1998 Does alpha-MSH have a role in regulating skin pigmentation in humans? Pigment cell research 90 9877097
2019 The FBXW2-MSX2-SOX2 axis regulates stem cell property and drug resistance of cancer cells. Proceedings of the National Academy of Sciences of the United States of America 88 31548378
2004 Homeobox protein MSX2 acts as a molecular defense mechanism for preventing ossification in ligament fibroblasts. Molecular and cellular biology 88 15060165
2007 Bone morphogenetic protein 4 induces epithelial-mesenchymal transition through MSX2 induction on pancreatic cancer cell line. Journal of cellular physiology 84 17516553
1999 The RRM domain of MINT, a novel Msx2 binding protein, recognizes and regulates the rat osteocalcin promoter. Biochemistry 83 10451362
2000 The role of alpha-MSH as a modulator of cutaneous inflammation. Annals of the New York Academy of Sciences 76 11268349
2014 BMP4 promotes EMT and mesodermal commitment in human embryonic stem cells via SLUG and MSX2. Stem cells (Dayton, Ohio) 72 24549638
2007 Msx2 -/- transgenic mice develop compound amelogenesis imperfecta, dentinogenesis imperfecta and periodental osteopetrosis. Bone 72 17878071
2015 60 YEARS OF POMC: From POMC and α-MSH to PAM, molecular oxygen, copper, and vitamin C. Journal of molecular endocrinology 71 26667899
2008 Msx1 and Msx2 are required for endothelial-mesenchymal transformation of the atrioventricular cushions and patterning of the atrioventricular myocardium. BMC developmental biology 70 18667074
2007 Vitamin K induces osteoblast differentiation through pregnane X receptor-mediated transcriptional control of the Msx2 gene. Molecular and cellular biology 70 17875939
1999 alpha-MSH and the regulation of melanocyte function. Annals of the New York Academy of Sciences 70 10816655
1988 Radioreceptor assay for alpha-MSH using mouse B16 melanoma cells+. Journal of receptor research 70 2838620
2008 Msx1 and Msx2 are functional interacting partners of T-box factors in the regulation of Connexin43. Cardiovascular research 69 18285513
2022 Pituitary hormone α-MSH promotes tumor-induced myelopoiesis and immunosuppression. Science (New York, N.Y.) 68 35926007
2014 Targeted reduction of vascular Msx1 and Msx2 mitigates arteriosclerotic calcification and aortic stiffness in LDLR-deficient mice fed diabetogenic diets. Diabetes 66 25056439
1999 UV light and MSH receptors. Annals of the New York Academy of Sciences 66 10816644
2008 Up-regulation of MSX2 enhances the malignant phenotype and is associated with twist 1 expression in human pancreatic cancer cells. The American journal of pathology 65 18349132
2019 Inhibition of farnesyl pyrophosphate (FPP) and/or geranylgeranyl pyrophosphate (GGPP) biosynthesis and its implication in the treatment of cancers. Critical reviews in biochemistry and molecular biology 64 30773935
2001 Antagonistic regulation of Dlx2 expression by PITX2 and Msx2: implications for tooth development. Gene expression 62 11763998
2011 Msx1 and Msx2 promote meiosis initiation. Development (Cambridge, England) 58 22071108
2011 Apelin and the proopiomelanocortin system: a new regulatory pathway of hypothalamic α-MSH release. American journal of physiology. Endocrinology and metabolism 55 21846903
2008 Preclinical evidence for nitrogen-containing bisphosphonate inhibition of farnesyl diphosphate (FPP) synthase in the kidney: implications for renal safety. Toxicology in vitro : an international journal published in association with BIBRA 53 18325729
2012 The neuroendocrine circuitry controlled by POMC, MSH, and AGRP. Handbook of experimental pharmacology 52 22249810
2000 Identification of peroxisomal targeting signals in cholesterol biosynthetic enzymes. AA-CoA thiolase, hmg-coa synthase, MPPD, and FPP synthase. Journal of lipid research 49 11108725
1982 Central nervous system and peripheral effects of ACTH, MSH, and related neuropeptides. Peptides 49 6289280
2017 The interaction of MC3R and MC4R with MRAP2, ACTH, α-MSH and AgRP in chickens. The Journal of endocrinology 48 28512117
2003 Fibroblast growth factors lead to increased Msx2 expression and fusion in calvarial sutures. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 48 12674336
2003 Microphthalmia resulting from MSX2-induced apoptosis in the optic vesicle. Investigative ophthalmology & visual science 46 12766037
2011 Transcriptional repression in the Notch pathway: thermodynamic characterization of CSL-MINT (Msx2-interacting nuclear target protein) complexes. The Journal of biological chemistry 45 21372128
2004 Msx-1 and Msx-2 in mammary gland development. Journal of mammary gland biology and neoplasia 45 15300013
2005 Melanocortin-4 receptors, beta-MSH and leptin: key elements in the satiety pathway. Peptides 42 16290320
1997 Binding of cyclic and linear MSH core peptides to the melanocortin receptor subtypes. European journal of pharmacology 42 9042613
2011 Msx1 and Msx2 in limb mesenchyme modulate digit number and identity. Developmental dynamics : an official publication of the American Association of Anatomists 39 21465616
2008 Regulation of feeding and anxiety by alpha-MSH reactive autoantibodies. Psychoneuroendocrinology 38 18842346
2004 Alx4 and Msx2 play phenotypically similar and additive roles in skull vault differentiation. Journal of anatomy 37 15198690
1997 Gestational exposure to ethanol suppresses msx2 expression in developing mouse embryos. Proceedings of the National Academy of Sciences of the United States of America 37 9207129
2005 Novel 3D pharmacophore of alpha-MSH/gamma-MSH hybrids leads to selective human MC1R and MC3R analogues. Journal of medicinal chemistry 36 15771429
2000 Craniofacial disorders caused by mutations in homeobox genes MSX1 and MSX2. Journal of craniofacial genetics and developmental biology 36 10879654
2012 The homeobox gene MSX2 determines chemosensitivity of pancreatic cancer cells via the regulation of transporter gene ABCG2. Journal of cellular physiology 35 21465479
2013 Mechanisms by which the orexigen NPY regulates anorexigenic α-MSH and TRH. American journal of physiology. Endocrinology and metabolism 34 23321476
2013 ARP101 inhibits α-MSH-stimulated melanogenesis by regulation of autophagy in melanocytes. FEBS letters 34 24188823
2013 IFN-γ inhibits basal and α-MSH-induced melanogenesis. Pigment cell & melanoma research 34 24267286
2005 Design of cyclic and other templates for potent and selective peptide alpha-MSH analogues. Current opinion in chemical biology 34 16023401
2000 The homeobox genes MSX2 and MOX2 are candidates for regulating epithelial-mesenchymal cell interactions in the human placenta. Placenta 34 10831122
2000 The neuropeptide alpha-MSH in host defense. Annals of the New York Academy of Sciences 33 11268348
2008 MSX2 stimulates chondrocyte maturation by controlling Ihh expression. The Journal of biological chemistry 32 18682398
2006 MSX2 promotes vaginal epithelial differentiation and wolffian duct regression and dampens the vaginal response to diethylstilbestrol. Molecular endocrinology (Baltimore, Md.) 32 16513791
2001 Calcitonin, angiotensin II and FPP significantly modulate mouse sperm function. Molecular human reproduction 30 11228244
1993 B16-G4F mouse melanoma cells: an MSH receptor-deficient cell clone. FEBS letters 30 8482388
2023 CLU (clusterin) promotes mitophagic degradation of MSX2 through an AKT-DNM1L/Drp1 axis to maintain SOX2-mediated stemness in oral cancer stem cells. Autophagy 29 36779631
2010 Applications of the role of α-MSH in ocular immune privilege. Advances in experimental medicine and biology 29 21222267
1988 MSG effects on beta-endorphin and alpha-MSH in the hypothalamus and caudal medulla. Peptides 29 2852357
2015 MSX2 in ameloblast cell fate and activity. Frontiers in physiology 28 25601840
2013 Alpha-MSH signalling via melanocortin 5 receptor promotes lipolysis and impairs re-esterification in adipocytes. Biochimica et biophysica acta 28 24046867
1989 Adrenalectomy and response to corticosterone and MSH in the genetically obese yellow mouse. The American journal of physiology 28 2916701
2008 Isoprenoid quantitation in human brain tissue: a validated HPLC-fluorescence detection method for endogenous farnesyl- (FPP) and geranylgeranylpyrophosphate (GGPP). Analytical and bioanalytical chemistry 27 18690423
1998 FPP modulates mammalian sperm function via TCP-11 and the adenylyl cyclase/cAMP pathway. Molecular reproduction and development 27 9820206
2016 α-MSH and Foxc2 promote fatty acid oxidation through C/EBPβ negative transcription in mice adipose tissue. Scientific reports 26 27819350
2006 Functional interactions between Dlx2 and lymphoid enhancer factor regulate Msx2. Nucleic acids research 26 17068080
2005 Formation of the CRS2-CAF2 group II intron splicing complex is mediated by a 22-amino acid motif in the COOH-terminal region of CAF2. The Journal of biological chemistry 26 16379013
2008 The Boston-type craniosynostosis mutation MSX2 (P148H) results in enhanced susceptibility of MSX2 to ubiquitin-dependent degradation. The Journal of biological chemistry 25 18786927
2002 Msx2 and p21(CIP1/WAF1) mediate the proapoptotic effects of bone morphogenetic protein-4 on ventricular zone progenitor cells. Journal of neuroscience research 25 12205674
2020 Anti-inflammatory effects of α-MSH through p-CREB expression in sarcoidosis like granuloma model. Scientific reports 24 32350353
2016 Msx1 and Msx2 function together in the regulation of primordial germ cell migration in the mouse. Developmental biology 24 27435625
2004 alpha-MSH and gamma-MSH inhibit IL-1beta induced activation of the hypothalamic-pituitary-adrenal axis through central melanocortin receptors. Regulatory peptides 24 15491790
1999 Agouti antagonism of melanocortin-4 receptor: greater effect with desacetyl-alpha-melanocyte-stimulating hormone (MSH) than with alpha-MSH. Endocrinology 24 10218968
2014 Msx1 and Msx2 act as essential activators of Atoh1 expression in the murine spinal cord. Development (Cambridge, England) 23 24715462
2014 α-Melanocyte stimulating hormone (MSH) and prostaglandin E2 (PGE2) drive melanosome transfer by promoting filopodia delivery and shedding spheroid granules: Evidences from atomic force microscopy observation. Journal of dermatological science 23 25445925
2007 Conditional alleles of Msx1 and Msx2. Genesis (New York, N.Y. : 2000) 23 17654563
2006 Msx1 and Msx2 have shared essential functions in neural crest but may be dispensable in epidermis and axis formation in Xenopus. The International journal of developmental biology 23 16586351
1992 Melanotropic activity of gamma MSH peptides in melanoma cells. Life sciences 23 1556905
2006 Antimicrobial properties of alpha-MSH and related synthetic melanocortins. TheScientificWorldJournal 22 17028769
2003 alpha-MSH and desacetyl-alpha-MSH signaling through melanocortin receptors. Annals of the New York Academy of Sciences 22 12851298