Affinage

MAFA

Killer cell lectin-like receptor subfamily G member 1 · UniProt Q96E93

Length
195 aa
Mass
21.8 kDa
Annotated
2026-06-10
100 papers in source corpus 43 papers cited in narrative 43 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

MAFA is a beta cell-enriched basic leucine zipper transcription factor that serves as a master regulator of adult beta cell identity and glucose-stimulated insulin secretion (PMID:12011435, PMID:12368292, PMID:15923615). Originally purified as the RIPE3b1 activity that binds the RIPE3b/C1 enhancer element of the insulin gene, it is the only known beta cell-specific factor capable of inducing endogenous insulin transcription in non-beta cells (PMID:12011435, PMID:12368292, PMID:14973194), and it activates insulin transcription synergistically with PDX-1 and BETA2/NeuroD through physical complex formation on the proximal promoter (PMID:15665000, PMID:15993959). MAFA functions at the apex of a beta cell transcriptional network: it directly drives Pdx1 transcription through the Area II control region (PMID:12551916, PMID:18522939) while itself being a target of upstream regulators including FoxA2, Nkx2.2, PDX-1, Nkx6.1, and Pax6 that confer beta cell-specific expression (PMID:16847327, PMID:20584984). Beyond insulin, MAFA directly transactivates a broad beta cell functional program — glucose-sensing and metabolic genes (PMID:17149590), the voltage-gated calcium channel subunit CaVbeta4 governing Ca2+ entry and exocytosis (PMID:30911681), autonomic neurotransmitter receptors (nicotinic ChrnB2/B4 and adrenergic Adra2A) (PMID:26904947), monoamine oxidases MaoA/MaoB (PMID:26546820), and exocytosis machinery (PMID:34978761), and associates with the ~1.5 MDa MLL3/MLL4 H3K4 methyltransferase complexes to activate these target programs at the chromatin level (PMID:26180087). MAFA activity and abundance are governed by an intricate post-translational network: multi-site N-terminal phosphorylation by ERK2, p38 MAPK, and GSK3 is required for dimerization, DNA binding, and transactivation, with Ser65 phosphorylation priming polyubiquitination and proteasomal degradation, the latter facilitated by the proteasome activator PA28gamma (PMID:11416124, PMID:19004825, PMID:20208071, PMID:21646385); p38 MAPK-mediated phosphorylation at Thr134 selectively drives MAFA degradation under oxidative stress (PMID:19407223, PMID:23660596), while SUMOylation at Lys32 dampens its transactivation (PMID:19029092, PMID:20718938). MAFA is required for postnatal beta cell proliferation through the prolactin receptor and cyclin D2 (PMID:25126749) and for maintaining differentiated beta cell identity, since its loss causes beta cell dedifferentiation and conversion toward glucagon/MafB-expressing states (PMID:25500951). A heterozygous MAFA p.Ser64Phe missense mutation that impairs transactivation-domain phosphorylation and stabilizes the protein causes familial insulinomatosis or diabetes (PMID:29339498).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2001 High

    Before MAFA's beta cell role was known, its avian ortholog established that transactivation-domain phosphorylation is a prerequisite for Maf transcriptional and differentiation activity, defining the regulatory principle that would later govern MAFA function.

    Evidence In vitro ERK2 kinase assay with S14A/S65A mutagenesis and in ovo electroporation differentiation assay

    PMID:11416124

    Open questions at the time
    • Did not address mammalian beta cell context
    • Kinases acting in vivo not identified
  2. 2002 High

    Identifying the long-sought RIPE3b1 insulin enhancer activity as the mammalian MAFA established it as a beta cell-selective insulin transcription factor and the molecular basis of glucose-responsive insulin gene control.

    Evidence Biochemical purification, EMSA, reporter assay, RT-PCR, plus glucose-dependent binding and dominant-negative inhibition in beta cell lines

    PMID:12011435 PMID:12368292

    Open questions at the time
    • In vivo requirement not yet demonstrated
    • Mechanism of glucose responsiveness unresolved
  3. 2004 High

    Demonstrating that MAFA alone induces endogenous insulin in non-beta cells and is absent in Nkx6.1-null pancreata positioned it as a uniquely sufficient, developmentally regulated beta cell determinant.

    Evidence Ectopic expression in non-beta lines and Nkx6.1-/- mouse with immunostaining

    PMID:14973194

    Open questions at the time
    • Direct vs indirect downstream of Nkx6.1 not separated at this stage
  4. 2005 High

    Establishing physical and functional synergy of MAFA with PDX-1 and BETA2, and the in vivo diabetic phenotype of MafA-deficient mice, defined MAFA as a non-redundant node coordinating the insulin transcription complex and glucose-stimulated secretion.

    Evidence Co-IP/GST pull-down with reporter mutagenesis, plus knockout mouse with glucose tolerance and insulin secretion assays

    PMID:15665000 PMID:15923615 PMID:15993959

    Open questions at the time
    • Stoichiometry and architecture of the trimeric complex unresolved
    • Distinction between secretory and transcriptional contributions to phenotype incomplete
  5. 2006 High

    Mapping the beta cell-specific MafA promoter to a FoxA2/Nkx2.2/PDX-1-bound conserved region placed MAFA within a transcriptional hierarchy and connected its glucose induction to the hexosamine/O-GlcNAc pathway.

    Evidence ChIP, EMSA, reporter mutagenesis, Nkx2.2 knockout, and pharmacological hexosamine pathway dissection

    PMID:16847327 PMID:17142462 PMID:17149590

    Open questions at the time
    • Direct O-GlcNAc modification of MAFA itself not established
    • Promoter-level regulators incompletely enumerated
  6. 2008 High

    Resolving the Ser65-primed phosphorylation/ubiquitination cascade and Lys32 SUMOylation revealed how kinase signaling and SUMO converge to tune MAFA stability and transcriptional output as a glucose- and stress-responsive rheostat.

    Evidence Site-directed mutagenesis (S65 variants, K32R), ubiquitination/degradation assays, reporter assays, and GSK3 pharmacology

    PMID:17682063 PMID:19004825 PMID:19029092

    Open questions at the time
    • E3 ligase mediating C-terminal ubiquitination not identified
    • SUMO ligase/protease not defined
  7. 2010 High

    Demonstrating that N-terminal phosphorylation is required for C-terminal dimerization and DNA binding uncovered a MAFA-unique structural mechanism coupling signaling to DNA occupancy.

    Evidence Mass spectrometry site mapping, MafA/MafB chimeras, dephosphorylation assay, EMSA

    PMID:20208071 PMID:20584984 PMID:20718938

    Open questions at the time
    • Structural basis of phosphorylation-dependent dimerization not solved
    • Which physiological kinase sets the DNA-binding-competent state in beta cells unclear
  8. 2011 High

    Identifying PA28gamma as the activator coupling GSK3-phosphorylated MAFA to proteasomal degradation, and ATF2 as a partner enhancing insulin promoter synergy, expanded both the destruction and the assembly arms of MAFA regulation.

    Evidence Co-IP, proteasome degradation assays, phosphosite mutagenesis (PA28gamma); Co-IP, EMSA, RNAi (ATF2)

    PMID:21278380 PMID:21646385

    Open questions at the time
    • Whether PA28gamma acts ubiquitin-dependently or independently not fully resolved
    • ATF2 contribution in vivo untested
  9. 2013 High

    Defining thyroid hormone as a direct upstream input to the Mafa promoter and Thr134-specific p38 phosphorylation as the oxidative-stress degradation trigger linked MAFA to functional maturation signals and stress vulnerability.

    Evidence ChIP/EMSA/reporter with dominant-negative epistasis in neonatal rats; T134A/T57A mutagenesis with Co-IP and insulin secretion assays

    PMID:23305647 PMID:23660596

    Open questions at the time
    • Crosstalk between maturation signals and stress-driven degradation not integrated
    • p38 upstream activators in beta cells not defined
  10. 2014 High

    Knockout studies established that MAFA is required to maintain differentiated beta cell identity and to drive postnatal beta cell replication, extending its role from gene activation to cell-fate stability and proliferation.

    Evidence MafA knockout mice with lineage tracing, transcriptome analysis; Prlr promoter reporter and BrdU proliferation assays

    PMID:25126749 PMID:25500951

    Open questions at the time
    • Mechanism converting beta cells toward glucagon/MafB states incompletely defined
    • Direct vs indirect control of proliferation machinery partially resolved
  11. 2015 High

    Discovering MAFA association with MLL3/MLL4 H3K4 methyltransferase complexes and the HMGA1 coactivator provided the chromatin-level mechanism by which MAFA broadly activates beta cell gene programs.

    Evidence Unbiased mass spectrometry, size-fractionation Co-IP, NCOA6 knockdown/knockout; Co-IP, GST pull-down, ChIP for HMGA1

    PMID:25628604 PMID:26180087

    Open questions at the time
    • Genome-wide MAFA-dependent H3K4 methylation landscape not mapped
    • Recruitment determinants of MLL3/4 by MAFA unknown
  12. 2018 High

    Identifying the MAFA p.Ser64Phe mutation that impairs phosphorylation and stabilizes the protein causally linked MAFA dysregulation to a human Mendelian disease spectrum of insulinomatosis and diabetes.

    Evidence Exome sequencing in two families, phosphorylation and protein stability assays, reporter assays in beta cell lines

    PMID:29339498

    Open questions at the time
    • Why the same mutation causes opposite phenotypes (insulinomatosis vs diabetes) unresolved at this stage
  13. 2019 High

    Mapping direct MAFA targets to calcium-channel, monoamine oxidase, and autonomic neurotransmitter receptor genes mechanistically connected MAFA to the secretory coupling machinery beyond insulin gene transcription.

    Evidence ChIP and beta cell-specific MafA knockout mice with patch-clamp/Ca2+ imaging, Mao inhibition, and insulin secretion assays

    PMID:26546820 PMID:26904947 PMID:30911681

    Open questions at the time
    • Relative contribution of each target to overall secretory defect not quantified
    • Direct ChIP for all targets not uniformly established
  14. 2022 Medium

    Demonstrating MAFA control of exocytosis genes and PPP1R1A, its stabilization by Kindlin-2, m6A-dependent MafA mRNA control by METTL3, and S64F-driven senescence built a layered picture of MAFA regulation spanning mRNA stability, protein stability, secretory effectors, and beta cell aging.

    Evidence siRNA in human/mouse islets and cell lines, RNAseq, Co-IP/domain mapping, m6A and mRNA stability assays, S64F knock-in mouse with senescence assays

    PMID:31980627 PMID:33631146 PMID:34644565 PMID:34978761 PMID:35872977

    Open questions at the time
    • Several effector links rest on single-lab loss-of-function without orthogonal in vivo confirmation
    • Sex-dependence of S64F senescence mechanism not fully explained

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple converging post-translational inputs (ERK2, p38, GSK3, PA28gamma, SUMO, Kindlin-2) and upstream signals are integrated in vivo to set MAFA dosage during health, stress, and the divergent S64F disease outcomes remains unresolved.
  • No integrated quantitative model of MAFA stability control
  • E3 ligase and SUMO enzymes for MAFA unidentified
  • Genome-wide direct target/chromatin map in primary human beta cells incomplete

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 7 GO:0003677 DNA binding 5
Localization
GO:0005634 nucleus 2
Pathway
R-HSA-74160 Gene expression (Transcription) 4 R-HSA-1266738 Developmental Biology 3 R-HSA-1643685 Disease 2 R-HSA-4839726 Chromatin organization 1
Partners
ATF2FERMT2HMGA1MAPK14NCOA6NEUROD1PA28GAMMAPDX1
Complex memberships
MAFA-PDX-1-BETA2/NeuroD insulin promoter complexMLL3/MLL4 H3K4 methyltransferase complex

Evidence

Reading pass · 43 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 MAFA (RIPE3b1) was identified as the mammalian homologue of avian MafA/L-Maf by biochemical purification and shown to specifically bind the insulin enhancer element RIPE3b and activate insulin gene expression; it is selectively expressed in pancreatic beta cells but not alpha cells. Biochemical purification, DNA binding assay (EMSA), reporter gene assay, RT-PCR Proceedings of the National Academy of Sciences of the United States of America High 12011435 12368292
2002 MafA protein and mRNA are up-regulated by glucose in pancreatic beta cells, and MafA binds the RIPE3b element in a glucose-dependent manner; dominant-negative MafA inhibits insulin promoter activity in beta cell lines. RT-PCR, EMSA, transient transfection reporter assay, dominant-negative construct The Journal of biological chemistry High 12368292
2004 MafA selectively induces endogenous insulin transcription in non-beta cells, making it the only beta cell-specific activator of the insulin gene; MafA expression is first detected during the second principal phase of beta cell differentiation and is absent in Nkx6.1-null pancreata. Ectopic expression in non-beta cell lines, in vivo mouse genetic model (Nkx6.1-/-), immunostaining Proceedings of the National Academy of Sciences of the United States of America High 14973194
2005 MafA physically interacts with endogenous PDX-1 and BETA2 (NeuroD) in beta cells, and together these three factors synergistically activate insulin promoter activity; synergy requires MafA transactivation and DNA-binding activity. Co-immunoprecipitation, GST pull-down, transfection reporter assay, dominant-negative and siRNA knockdown The Journal of biological chemistry High 15665000
2005 MafA-deficient mice display glucose intolerance and develop diabetes mellitus with severely impaired glucose-, arginine-, and KCl-stimulated insulin secretion, reduced Pdx1, Beta2, Glut-2, and insulin transcripts, demonstrating MafA is a key in vivo regulator of glucose-stimulated insulin secretion. Knockout mouse model, glucose tolerance test, insulin secretion assay, RT-PCR Molecular and cellular biology High 15923615
2005 FoxO1 protects beta cells against oxidative stress by forming a complex with PML and SIRT1 to activate MafA (and NeuroD) expression; hyperglycemia suppresses MafA expression in vivo and this can be prevented by constitutively nuclear FoxO1. Coimmunoprecipitation (FoxO1-Pml-Sirt1 complex), acetylation-defective/mimicking mutants, transgenic mouse model, in vivo glucose manipulation Cell metabolism High 16154098
2001 Phosphorylation of MafA at serines 14 and 65 (located in the transcriptional activating domain) is essential for its transcriptional activity and biological functions including induction of differentiation programs; these residues are phosphorylated by ERK2 in vitro. In vitro kinase assay (ERK2), site-directed mutagenesis (S14A, S65A), reporter gene assay, in ovo electroporation differentiation assay Molecular and cellular biology High 11416124
2006 FoxA2, Nkx2.2, and PDX-1 bind in vivo to conserved region 3 (bp -8118 to -7750) of the mafA promoter to drive beta cell-specific mafA transcription; Nkx2.2-null animals lack MafA expression in the pancreatic epithelium, and PDX-1 knockdown decreases mafA mRNA. Chromatin immunoprecipitation (ChIP), EMSA, site-directed mutagenesis, reporter assay, siRNA knockdown, Nkx2.2 knockout mouse Molecular and cellular biology High 16847327
2006 MAFA overproduction enhances and dominant-negative MAFA diminishes binding to the insulin promoter, correlating with insulin mRNA and protein levels; MAFA also positively regulates glucokinase, Glut2, PDX1, NKX6-1, GLP1R, PCSK1, and pyruvate carboxylase expression in beta cell lines. Inducible stable cell lines (overexpression and dominant-negative), EMSA, RT-PCR, Western blot, insulin secretion assay Diabetologia High 17149590
2007 MafA protein stability is regulated by glycogen synthase kinase 3 (GSK3): GSK3 constitutively phosphorylates the MafA N-terminal region at multiple sites, and this phosphorylation is a prerequisite for rapid MafA protein degradation under low-glucose conditions. Mutational analysis of MafA phosphorylation sites, pharmacological GSK3 inhibition in MIN6 beta cells, pulse-chase/degradation assay Molecular and cellular biology High 17682063
2008 Phosphorylation at Ser65 of MafA controls both protein stability and transactivation potential; phosphorylation at Ser65 is the initial degradation signal, with ubiquitination occurring in the C-terminus; phosphorylation at Ser65 acts as primer for subsequent GSK3-mediated phosphorylation at neighboring N-terminal residues; Ser65 phosphorylation is required for polyubiquitination. Site-directed mutagenesis (S65E, S65D, S65A), ubiquitination assay, proteasome degradation assay, reporter assay The Journal of biological chemistry High 19004825
2008 Sumoylation of MafA at Lys32 reduces its transcriptional activity toward the insulin gene promoter and increases repression of the CHOP-10 promoter; low glucose and hydrogen peroxide increase endogenous MafA sumoylation; sumoylation does not affect nuclear localization or ubiquitin-dependent degradation. SUMO modification assay, site-directed mutagenesis (K32R), reporter gene assay, beta cell treatment with glucose/H2O2 The Journal of biological chemistry High 19029092
2009 p38 MAPK directly binds to MafA and regulates MafA protein stability under both basal and oxidative stress conditions; under oxidative stress p38 MAPK-mediated phosphorylation at threonine 57 and threonine 134 drives MafA degradation via the ubiquitin-proteasomal pathway; inhibiting p38 MAPK (but not GSK3) prevents oxidative stress-dependent MafA degradation. p38 MAPK inhibitor treatment, site-directed mutagenesis (T57A, T134A), Co-IP (p38-MafA binding), protein stability assay, isolated mouse islets Molecular endocrinology High 19407223
2010 Phosphorylation within the MafA N-terminal transactivation domain (aa 1-72) is required for C-terminal dimerization and DNA binding; dephosphorylation precludes detection of MafA dimers and dramatically reduces DNA binding; this phosphorylation dependency is unique to MafA and not shared by MafB. Mass spectrometry (phosphorylation site mapping), MafA/MafB chimeric proteins, dephosphorylation assay, EMSA The Journal of biological chemistry High 20208071
2003 The islet beta cell-enriched RIPE3b1/MafA transcription factor binds to sequence blocks 4 and 5 (B4/5) within the pdx-1 gene Area II control region and activates pdx-1 transcription; ChIP confirmed MafA occupancy at the endogenous pdx-1 Area II region. EMSA, reporter assay with mutagenesis, chromatin immunoprecipitation (ChIP) The Journal of biological chemistry High 12551916
2005 MafA, PDX-1, and BETA2 synergistically activate the insulin promoter; mutagenesis shows at least GG2, C1, and E1 elements (within -150 to -100 bp) are necessary for synergy; neither MafB nor c-Maf shows the same synergistic activation with PDX-1 and BETA2. Transient transfection reporter assay, promoter deletion and mutagenesis Biochimica et biophysica acta Medium 15993959
2005 MafA phosphorylation by p38 MAP kinase occurs at threonine 113, threonine 57, and serine 272; mutation of these residues severely impairs MafA biological activity; p38 also phosphorylates MafB and c-Maf. Western blot, mass spectrometry, in vitro kinase assay, site-directed mutagenesis, reporter/biological activity assay FEBS letters High 15963504
2006 Glucose-induced MafA expression in beta cells requires flux through the hexosamine biosynthetic pathway and O-linked glycosylation by UDP-N-acetylglucosaminyl transferase; glucosamine stimulates MafA expression in the absence of high glucose, and inhibition of the hexosamine pathway abolishes glucose-induced MafA induction. Pharmacological inhibition (glucosamine supplementation, hexosamine pathway inhibitors, OGT inhibitor/activator), RT-PCR, Western blot in beta cell lines The Journal of biological chemistry Medium 17142462
2008 MafA and MafB regulate Pdx1 transcription exclusively through the Area II control region; in adult islets only MafA is bound to Area II by quantitative ChIP; both MafA and MafB are bound to Area II at E18.5 during development; MafB-/- mice show severely compromised Pdx1 Area I/II transgene expression. Transfection reporter assay, quantitative ChIP, MafB knockout mouse model The Journal of biological chemistry High 18522939
2010 Region 3 (bp -8118 to -7750) of the mafA promoter is necessary but not sufficient for beta cell-specific in vivo expression; full promoter (R1-6) is required including region 3; Nkx6.1 and Pax6 (but not NeuroD1) bind to and activate MafA through region 3 in ChIP and transfection assays and in vivo knockout models. Transgenic reporter mice (R3, R1-6, R1-6ΔR3), ChIP, EMSA, transfection assay, mouse knockout models Molecular and cellular biology High 20584984
2011 ATF2 forms a complex with MafA and acquires the capacity to bind the C1/RIPE3b element; co-expression of ATF2, MafA, PDX-1, and BETA2 produces synergistic activation of the insulin promoter; RNAi knockdown of ATF2 or MafA decreases endogenous insulin mRNA in MIN6 cells. Co-immunoprecipitation, EMSA, reporter assay, RNAi knockdown, immunohistochemistry The Journal of biological chemistry High 21278380
2011 Proteasome activator PA28γ binds to GSK3-phosphorylated MAFA, stimulates its proteasomal degradation, and attenuates MAFA-driven insulin promoter activity; MAFA phosphorylation-site mutants (alanine substitutions at Ser49, Thr53, Thr57, Ser61, Ser65) do not bind PA28γ and are resistant to degradation; PA28γ degrades MAFA through a mechanism distinct from p21 degradation. Co-immunoprecipitation (PA28γ-MAFA), proteasome degradation assay, site-directed mutagenesis, reporter assay, PA28γ mutant analysis Journal of molecular endocrinology High 21646385
2010 SUMOylation at a conserved lysine residue in the MafA N-terminal transactivator domain negatively regulates its transcriptional and oncogenic activities; a SUMOylation-deficient mutant (K32R) shows enhanced transactivation of crystallin and insulin promoters and enhanced colony formation. SUMO modification assay, site-directed mutagenesis (K32R), reporter gene assay, in ovo electroporation, colony formation assay Genes to cells High 20718938
2015 MafA associates with the MLL3 and MLL4 histone H3K4 methyltransferase complexes (~1.5 MDa) in beta cell extracts; all subunits of MLL3/4 complexes were identified by unbiased mass spectrometry; NCOA6 knockdown (a core MLL3/4 subunit) reduces expression of a subset of MafA target genes in mouse and human beta cell lines. In-cell biochemistry/mass spectrometry (unbiased pulldown), size-fractionation Co-IP, siRNA knockdown, islet-specific NCoA6 knockout mouse Diabetes High 26180087
2013 Thyroid hormone (T3) has a direct receptor-ligand interaction with the Mafa promoter (shown by ChIP and EMSA) and this interaction is functional in a luciferase reporter assay; dominant-negative Mafa abolishes T3-enhanced glucose-responsive insulin secretion, placing Mafa downstream of thyroid hormone signaling for beta cell functional maturation. Chromatin immunoprecipitation, EMSA, luciferase reporter assay, dominant-negative Mafa, in vivo T3 supplementation/inhibition in neonatal rats Diabetes High 23305647
2018 A missense MAFA mutation (p.Ser64Phe) impairs phosphorylation within the transactivation domain, profoundly increases MAFA protein stability under both high and low glucose, and enhances transactivation potential in beta cell lines, causing familial insulinomatosis or diabetes. Exome sequencing (disease mutation identification), phosphorylation assay, protein stability assay in beta cell lines, reporter assay Proceedings of the National Academy of Sciences of the United States of America High 29339498
2021 The MAFA S64F mutation causes accelerated cellular senescence and increased senescence-associated secretory proteins in male human beta cells; male MafAS64F/+ mice show transiently higher MafA protein levels, sex-dependent changes in Ca2+ signaling, DNA damage, and aging genes preceding glucose intolerance. S64F MafA knock-in mouse model, human beta cell expression system, senescence assays, gene expression profiling Cell reports High 34644565
2013 p38 MAPK directly binds to MafA and promotes its degradation through the ubiquitin proteasomal pathway under oxidative stress; degradation under oxidative stress depends specifically on p38 MAPK-mediated phosphorylation at T134 (not T57); expression of T134A-MafA but not T57A-MafA reduces oxidative stress-mediated loss of glucose-stimulated insulin secretion; PA28γ expression is reduced under oxidative stress, explaining the dominance of p38 MAPK over GSK3 in this context. Site-directed mutagenesis (T134A, T57A), Co-IP (p38-MafA), ubiquitin assay, insulin secretion assay, Western blot Molecular endocrinology High 23660596
2016 MAFA controls ANS-mediated insulin secretion by activating transcription of nicotinic receptor genes (ChrnB2, ChrnB4) and adrenergic receptor gene (Adra2A) in beta cells; acetylcholine-mediated insulin secretion requires nicotinic signaling; shown in MafA-deficient mouse model and human islet correlation studies. MafA-deficient mouse model, ChIP, reporter assay, insulin secretion assay with nicotinic/adrenergic agonists, human islet gene expression analysis Cell reports High 26904947
2019 MafA directly binds to transcriptional control sequences of MaoA and MaoB genes (monoamine oxidases) in beta cells, activating their expression; MaoB expression is reduced in MafA-deficient mouse islets; inhibition of Mao activity reduces insulin secretion. ChIP (MafA binding to MaoA/MaoB promoters), MafA knockout mouse, pharmacological Mao inhibition, insulin secretion assay Biochemical and biophysical research communications High 26546820
2019 MafA controls expression of the calcium channel subunit CaVγ4, as verified by ChIP and experiments in beta cell-specific MafA knockout mice; reduced CaVγ4 leads to decreased CaV1.2 and CaV1.3 expression and suppresses voltage-gated Ca2+ entry and glucose-stimulated insulin exocytosis. ChIP (MafA at CaVγ4 locus), beta cell-specific MafA knockout mouse, patch-clamp/Ca2+ imaging, insulin exocytosis assay Communications biology High 30911681
2021 MafA regulates expression of the PPP1R1A (protein phosphatase 1 inhibitor protein 1A) gene in beta cells; PPP1R1A silencing impairs GLP1-mediated glucose-stimulated insulin secretion amplification, PKA-target protein phosphorylation, and mitochondrial coupling efficiency, and causes beta cell dedifferentiation. MafA knockout mouse (gene expression profiling), siRNA knockdown of PPP1R1A, insulin secretion assay, PKA phosphorylation assay, mitochondrial coupling assay Metabolism: clinical and experimental Medium 33631146
2022 MAFA and MAFB regulate exocytosis-related genes in human beta cells including STX1A, SYT7, and STXBP1; MAFA/MAFB silencing impairs insulin secretion and reduces STX1A, SYT7, and STXBP1 mRNA; STX1A and STXBP1 protein expression is impaired in islets from T2D donors lacking MAFA. RNAseq (MafA-/- mouse islets), MAFA/MAFB siRNA knockdown in human islets and EndoC-βH1 cells, insulin secretion assay, Western blot Acta physiologica Medium 34978761
2020 Kindlin-2 binds to MafA through its C-terminal region, stabilizes MafA protein, and thereby activates insulin expression; Kindlin-2 loss decreases MafA levels and impairs insulin secretion; Kindlin-2 loss also activates GSK-3β and downregulates β-catenin, reducing beta cell proliferation. Conditional beta cell-specific Kindlin-2 knockout mouse, Co-IP (Kindlin-2-MafA), domain mapping, protein stability assay, Ca2+ imaging, insulin secretion assay Nature communications High 31980627
2022 METTL3-mediated m6A methylation regulates MafA mRNA stability and expression; METTL3 silencing reduces m6A levels, MafA mRNA stability, and MafA protein; MafA overexpression rescues the impaired glucose-stimulated insulin secretion caused by METTL3 silencing. METTL3 siRNA knockdown, m6A measurement, mRNA stability assay, MafA overexpression rescue, insulin secretion assay in NIT-1 and β-TC-6 cells Frontiers in endocrinology Medium 35872977
2014 Loss of MafA in knockout mice reduces the beta-to-alpha cell ratio and leads to beta cell dedifferentiation, including reduced/lost insulin expression and conversion of a minority of beta cells to glucagon-expressing cells; re-expression of Mafb (an immature beta cell marker) is observed in dedifferentiated beta cells in MafA KO and diabetic mouse models. MafA knockout mouse, lineage tracing, transcriptome analysis, immunostaining Diabetologia High 25500951
2014 MafA regulates postnatal beta cell replication through the prolactin receptor (Prlr) and cyclin D2 (Ccnd2); MafA directly transactivates the Prlr promoter; loss of MafA reduces Prlr and Ccnd2 expression and impairs beta cell proliferation at 4 weeks of age. MafA knockout mouse, transcriptome analysis, reporter assay (Prlr promoter), siRNA knockdown, BrdU proliferation assay, Western blot PloS one High 25126749
2009 Expression of MafA in Pdx1+ pancreatic progenitors reduces pancreatic mass and proliferation of progenitors, at least partially through induction of cyclin kinase inhibitors p27 and p57, and disproportionately inhibits formation of endocrine cells. Conditional MafA transgene expression in Pdx1+ progenitors (in vivo mouse), cell cycle analysis, immunostaining for p27/p57 Developmental biology Medium 19576197
2003 MafA is able to bind MARE sequences and heterodimerize with v-Maf, MafB, Jun, and Fos, but not with small Maf proteins (MafF, MafK); increased expression of mafA in neuroretina induces sustained proliferation of postmitotic cells. EMSA, co-immunoprecipitation (heterodimerization), overexpression in QNR cells (proliferation assay) Oncogene Medium 9674710
2003 MafA cell-transforming ability is correlated with its DNA-binding domain (from chimeric MafA/MafB analysis); transactivation and transformation by MafA are controlled by phosphorylation of two conserved serine residues in the transactivation domain; MafA is a weaker transactivator than MafB or c-Maf but the strongest inducer of cellular transformation. Reporter assay, chicken embryo fibroblast transformation assay, MafA/MafB chimeric proteins, site-directed mutagenesis, MafA-estrogen receptor fusion Oncogene Medium 12970735
2010 c-Jun expression is increased in diabetic db/db islets and directly suppresses MafA expression; adenoviral overexpression of c-Jun in MIN6 cells and isolated islets significantly decreases MafA expression and insulin expression; MafA overexpression restores insulin promoter activity suppressed by c-Jun. db/db mouse model (immunohistochemistry, Western blot), adenoviral overexpression of c-Jun, reporter assay, MafA rescue experiment Diabetes Medium 20424231
2015 HMGA1 physically interacts with PDX-1 and MafA both in vitro and in vivo; HMGA1 overexpression enhances the transactivating activity of PDX-1 and MafA on insulin promoters; HMGA1 knockdown decreases this activity; glucose increases HMGA1 binding to the insulin gene promoter. Co-immunoprecipitation, GST pull-down, reporter assay (overexpression and knockdown), ChIP Frontiers in endocrinology Medium 25628604
2010 MafA regulates intrathymic insulin (Ins2) expression; MafA knockout mice show reduced thymic Ins2 expression and develop autoantibodies against pancreatic islets; MafA expression in thymus correlates with Ins2 expression in NOD mice. MafA knockout mouse, RT-PCR (thymic Ins2), autoantibody measurement, reporter assay for MafA polymorphisms Diabetes Medium 20682694

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 FoxO1 protects against pancreatic beta cell failure through NeuroD and MafA induction. Cell metabolism 496 16154098
2005 MafA is a key regulator of glucose-stimulated insulin secretion. Molecular and cellular biology 399 15923615
2002 Identification of beta-cell-specific insulin gene transcription factor RIPE3b1 as mammalian MafA. Proceedings of the National Academy of Sciences of the United States of America 268 12011435
2002 MafA is a glucose-regulated and pancreatic beta-cell-specific transcriptional activator for the insulin gene. The Journal of biological chemistry 252 12368292
2006 A switch from MafB to MafA expression accompanies differentiation to pancreatic beta-cells. Developmental biology 240 16580660
2017 PDX1, Neurogenin-3, and MAFA: critical transcription regulators for beta cell development and regeneration. Stem cell research & therapy 233 29096722
2004 The MafA transcription factor appears to be responsible for tissue-specific expression of insulin. Proceedings of the National Academy of Sciences of the United States of America 225 14973194
2010 MafA and MafB regulate genes critical to beta-cells in a unique temporal manner. Diabetes 198 20627934
2011 MafA and MafB activity in pancreatic β cells. Trends in endocrinology and metabolism: TEM 172 21719305
2006 MAFA controls genes implicated in insulin biosynthesis and secretion. Diabetologia 167 17149590
2005 The islet beta cell-enriched MafA activator is a key regulator of insulin gene transcription. The Journal of biological chemistry 155 15665000
2009 beta-Cell-specific overexpression of glutathione peroxidase preserves intranuclear MafA and reverses diabetes in db/db mice. Endocrinology 152 19819955
1995 The reduction of insulin gene transcription in HIT-T15 beta cells chronically exposed to high glucose concentration is associated with the loss of RIPE3b1 and STF-1 transcription factor expression. Molecular endocrinology (Baltimore, Md.) 142 7491105
2010 Mafa expression enhances glucose-responsive insulin secretion in neonatal rat beta cells. Diabetologia 132 21190012
2007 PDX-1 and MafA play a crucial role in pancreatic beta-cell differentiation and maintenance of mature beta-cell function. Endocrine journal 127 17938503
1996 Chronic exposure of betaTC-6 cells to supraphysiologic concentrations of glucose decreases binding of the RIPE3b1 insulin gene transcription activator. The Journal of clinical investigation 127 8613527
2013 Thyroid hormone promotes postnatal rat pancreatic β-cell development and glucose-responsive insulin secretion through MAFA. Diabetes 121 23305647
2014 MafA is critical for maintenance of the mature beta cell phenotype in mice. Diabetologia 113 25500951
2012 MicroRNA-30d induces insulin transcription factor MafA and insulin production by targeting mitogen-activated protein 4 kinase 4 (MAP4K4) in pancreatic β-cells. The Journal of biological chemistry 113 22733810
2005 A crucial role of MafA as a novel therapeutic target for diabetes. The Journal of biological chemistry 107 15664997
2014 The MafA transcription factor becomes essential to islet β-cells soon after birth. Diabetes 106 24520122
2006 FoxA2, Nkx2.2, and PDX-1 regulate islet beta-cell-specific mafA expression through conserved sequences located between base pairs -8118 and -7750 upstream from the transcription start site. Molecular and cellular biology 102 16847327
2020 Mobile health technology-supported atrial fibrillation screening and integrated care: A report from the mAFA-II trial Long-term Extension Cohort. European journal of internal medicine 99 33067121
2009 Low-threshold mechanoreceptor subtypes selectively express MafA and are specified by Ret signaling. Neuron 92 20064392
2012 Reprogramming of pancreatic exocrine cells towards a beta (β) cell character using Pdx1, Ngn3 and MafA. The Biochemical journal 88 22150363
2023 Mobile Health-Technology-Integrated Care for Atrial Fibrillation: A Win Ratio Analysis from the mAFA-II Randomized Clinical Trial. Thrombosis and haemostasis 85 37247623
2010 Regulation of MafA expression in pancreatic beta-cells in db/db mice with diabetes. Diabetes 85 20424231
2001 Phosphorylation of MafA is essential for its transcriptional and biological properties. Molecular and cellular biology 85 11416124
2007 MafA regulates expression of genes important to islet beta-cell function. Molecular endocrinology (Baltimore, Md.) 83 17636040
2018 MAFA missense mutation causes familial insulinomatosis and diabetes mellitus. Proceedings of the National Academy of Sciences of the United States of America 81 29339498
2005 Relative contribution of PDX-1, MafA and E47/beta2 to the regulation of the human insulin promoter. The Biochemical journal 81 15862113
2005 Synergistic activation of the insulin gene promoter by the beta-cell enriched transcription factors MafA, Beta2, and Pdx1. Biochimica et biophysica acta 79 15993959
2000 NK cell expression of the killer cell lectin-like receptor G1 (KLRG1), the mouse homolog of MAFA, is modulated by MHC class I molecules. European journal of immunology 77 10741410
2007 MafA stability in pancreatic beta cells is regulated by glucose and is dependent on its constitutive phosphorylation at multiple sites by glycogen synthase kinase 3. Molecular and cellular biology 70 17682063
2007 Roles and regulation of transcription factor MafA in islet beta-cells. Endocrine journal 66 17785922
2013 Ebselen treatment prevents islet apoptosis, maintains intranuclear Pdx-1 and MafA levels, and preserves β-cell mass and function in ZDF rats. Diabetes 63 23801580
2015 Preserving Mafa expression in diabetic islet β-cells improves glycemic control in vivo. The Journal of biological chemistry 62 25645923
1995 The role of the insulin control element and RIPE3b1 activators in glucose-stimulated transcription of the insulin gene. Molecular endocrinology (Baltimore, Md.) 62 8584024
2021 PDX1LOW MAFALOW β-cells contribute to islet function and insulin release. Nature communications 61 33514698
2017 Mafa Enables Pdx1 to Effectively Convert Pancreatic Islet Progenitors and Committed Islet α-Cells Into β-Cells In Vivo. Diabetes 56 28223284
2003 Mouse MafA, homologue of zebrafish somite Maf 1, contributes to the specific transcriptional activity through the insulin promoter. Biochemical and biophysical research communications 56 14680841
2021 The Effects of Implementing a Mobile Health-Technology Supported Pathway on Atrial Fibrillation-Related Adverse Events Among Patients With Multimorbidity: The mAFA-II Randomized Clinical Trial. JAMA network open 55 34932104
2003 The islet beta cell-enriched RIPE3b1/Maf transcription factor regulates pdx-1 expression. The Journal of biological chemistry 54 12551916
1998 mafA, a novel member of the maf proto-oncogene family, displays developmental regulation and mitogenic capacity in avian neuroretina cells. Oncogene 54 9674710
2015 MLL3 and MLL4 Methyltransferases Bind to the MAFA and MAFB Transcription Factors to Regulate Islet β-Cell Function. Diabetes 53 26180087
2018 Long Noncoding RNA Meg3 Regulates Mafa Expression in Mouse Beta Cells by Inactivating Rad21, Smc3 or Sin3α. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 52 29529600
1998 MAFA-L, an ITIM-containing receptor encoded by the human NK cell gene complex and expressed by basophils and NK cells. European journal of immunology 51 9842918
2006 Glucose induces MafA expression in pancreatic beta cell lines via the hexosamine biosynthetic pathway. The Journal of biological chemistry 47 17142462
2015 Cooperation between HMGA1, PDX-1, and MafA is Essential for Glucose-Induced Insulin Transcription in Pancreatic Beta Cells. Frontiers in endocrinology 43 25628604
2012 Combined transfection of the three transcriptional factors, PDX-1, NeuroD1, and MafA, causes differentiation of bone marrow mesenchymal stem cells into insulin-producing cells. Experimental diabetes research 42 22761608
2003 MafA has strong cell transforming ability but is a weak transactivator. Oncogene 42 12970735
2021 Sex-biased islet β cell dysfunction is caused by the MODY MAFA S64F variant by inducing premature aging and senescence in males. Cell reports 41 34644565
2020 Kindlin-2 modulates MafA and β-catenin expression to regulate β-cell function and mass in mice. Nature communications 41 31980627
2012 Beta cell nuclear musculoaponeurotic fibrosarcoma oncogene family A (MafA) is deficient in type 2 diabetes. Diabetologia 40 22847061
2010 Islet beta-cell-specific MafA transcription requires the 5'-flanking conserved region 3 control domain. Molecular and cellular biology 40 20584984
2008 MafA is a dedicated activator of the insulin gene in vivo. The Journal of endocrinology 40 18515495
2008 Sumoylation regulates the transcriptional activity of MafA in pancreatic beta cells. The Journal of biological chemistry 40 19029092
2015 MAFA and T3 Drive Maturation of Both Fetal Human Islets and Insulin-Producing Cells Differentiated From hESC. The Journal of clinical endocrinology and metabolism 39 26207953
2009 Combination of MafA, PDX-1 and NeuroD is a useful tool to efficiently induce insulin-producing surrogate beta-cells. Current medicinal chemistry 39 19689288
2006 MafA expression and insulin promoter activity are induced by nicotinamide and related compounds in INS-1 pancreatic beta-cells. Diabetes 39 16505238
2005 MafA transcription factor is phosphorylated by p38 MAP kinase. FEBS letters 39 15963504
2007 Role of PDX-1 and MafA as a potential therapeutic target for diabetes. Diabetes research and clinical practice 38 17449132
2022 Role of the Transcription Factor MAFA in the Maintenance of Pancreatic β-Cells. International journal of molecular sciences 37 35562869
2009 Role of MafA in pancreatic beta-cells. Advanced drug delivery reviews 37 19393272
2009 p38 MAPK is a major regulator of MafA protein stability under oxidative stress. Molecular endocrinology (Baltimore, Md.) 37 19407223
2008 The stability and transactivation potential of the mammalian MafA transcription factor are regulated by serine 65 phosphorylation. The Journal of biological chemistry 37 19004825
2013 Reprogramming of various cell types to a beta-like state by Pdx1, Ngn3 and MafA. PloS one 35 24312421
2008 MafA and MafB regulate Pdx1 transcription through the Area II control region in pancreatic beta cells. The Journal of biological chemistry 32 18522939
2002 An unusual inhibitory receptor--the mast cell function-associated antigen (MAFA). Molecular immunology 32 12217400
1996 Proximity relationships between the type I receptor for Fc epsilon (Fc epsilon RI) and the mast cell function-associated antigen (MAFA) studied by donor photobleaching fluorescence resonance energy transfer microscopy. European journal of immunology 32 8566088
2016 MafA-Controlled Nicotinic Receptor Expression Is Essential for Insulin Secretion and Is Impaired in Patients with Type 2 Diabetes. Cell reports 31 26904947
2009 Expression of MafA in pancreatic progenitors is detrimental for pancreatic development. Developmental biology 31 19576197
2000 The RIPE3b1 activator of the insulin gene is composed of a protein(s) of approximately 43 kDa, whose DNA binding activity is inhibited by protein phosphatase treatment. The Journal of biological chemistry 31 10744746
2021 The MafA-target gene PPP1R1A regulates GLP1R-mediated amplification of glucose-stimulated insulin secretion in β-cells. Metabolism: clinical and experimental 30 33631146
2011 ATF2 interacts with beta-cell-enriched transcription factors, MafA, Pdx1, and beta2, and activates insulin gene transcription. The Journal of biological chemistry 30 21278380
2022 MafA Regulation in β-Cells: From Transcriptional to Post-Translational Mechanisms. Biomolecules 29 35454124
2012 The combined expression of Pdx1 and MafA with either Ngn3 or NeuroD improves the differentiation efficiency of mouse embryonic stem cells into insulin-producing cells. Cell transplantation 28 22776709
2010 Insulin transactivator MafA regulates intrathymic expression of insulin and affects susceptibility to type 1 diabetes. Diabetes 28 20682694
2006 MafA differentiates rat intestinal cells into insulin-producing cells. Biochemical and biophysical research communications 28 16934222
2011 MafA promotes the reprogramming of placenta-derived multipotent stem cells into pancreatic islets-like and insulin+ cells. Journal of cellular and molecular medicine 26 20158571
2011 Proteasome activator PA28{gamma} stimulates degradation of GSK3-phosphorylated insulin transcription activator MAFA. Journal of molecular endocrinology 26 21646385
2007 Inhibition of MafA transcriptional activity and human insulin gene transcription by interleukin-1beta and mitogen-activated protein kinase kinase kinase in pancreatic islet beta cells. Diabetologia 26 17583797
2010 Phosphorylation within the MafA N terminus regulates C-terminal dimerization and DNA binding. The Journal of biological chemistry 25 20208071
2009 Neither MafA/L-Maf nor MafB is essential for lens development in mice. Genes to cells : devoted to molecular & cellular mechanisms 25 19624757
2002 Clustering the mast cell function-associated antigen (MAFA) leads to tyrosine phosphorylation of p62Dok and SHIP and affects RBL-2H3 cell cycle. Immunology letters 25 12008030
2019 The calcium channel subunit gamma-4 is regulated by MafA and necessary for pancreatic beta-cell specification. Communications biology 24 30911681
2013 Preventing p38 MAPK-mediated MafA degradation ameliorates β-cell dysfunction under oxidative stress. Molecular endocrinology (Baltimore, Md.) 24 23660596
2007 Islet cell differentiation in liver by combinatorial expression of transcription factors neurogenin-3, BETA2, and RIPE3b1. Biochemical and biophysical research communications 24 17239820
2009 Definition of Mafa-A and -B haplotypes in pedigreed cynomolgus macaques (Macaca fascicularis). Immunogenetics 23 19937015
2022 The m6A Methyltransferase METTL3 Ameliorates Methylglyoxal-Induced Impairment of Insulin Secretion in Pancreatic β Cells by Regulating MafA Expression. Frontiers in endocrinology 22 35872977
2019 MafB Is Important for Pancreatic β-Cell Maintenance under a MafA-Deficient Condition. Molecular and cellular biology 22 31208980
2019 Transcriptome analysis of human brain microvascular endothelial cells response to Neisseria meningitidis and its antigen MafA using RNA-seq. Scientific reports 22 31822804
2014 MafA is required for postnatal proliferation of pancreatic β-cells. PloS one 22 25126749
2013 Generation of functional insulin-producing cells from neonatal porcine liver-derived cells by PDX1/VP16, BETA2/NeuroD and MafA. PloS one 22 24260156
2012 Memory immune responses against pandemic (H1N1) 2009 influenza virus induced by a whole particle vaccine in cynomolgus monkeys carrying Mafa-A1*052:02. PloS one 22 22623997
2015 Islet-specific monoamine oxidase A and B expression depends on MafA transcriptional activity and is compromised in type 2 diabetes. Biochemical and biophysical research communications 21 26546820
2014 Differentiation of iPSCs into insulin-producing cells via adenoviral transfection of PDX-1, NeuroD1 and MafA. Diabetes research and clinical practice 21 24794627
2013 Both PAX4 and MAFA are expressed in a substantial proportion of normal human pancreatic alpha cells and deregulated in patients with type 2 diabetes. PloS one 21 24013263
2022 MAFA and MAFB regulate exocytosis-related genes in human β-cells. Acta physiologica (Oxford, England) 19 34978761
2010 SUMOylation negatively regulates transcriptional and oncogenic activities of MafA. Genes to cells : devoted to molecular & cellular mechanisms 19 20718938

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