MAFA (v-maf musculoaponeurotic fibrosarcoma oncogene homolog A (avian))

2009-03-01   Celio Pouponnot , Alain Eychène 

Institut Curie, CNRS UMR 146, F-91405 Orsay, France





The MAFA open reading frame is encoded by a unique exon. The entire genomic organization and the putative existence of non-coding exons remain unknown.


MAFA displays a restricted expression pattern. It is notably expressed in pancreas (in beta-cells) and lens.





Maf oncoproteins are b-ZIP transcription factors that belong to the AP-1 super-family, which notably includes JUN and FOS. The Maf family contains seven members, which can be subdivided into two groups; the large and small Maf proteins. While the small Maf proteins, MAFF, MAFG and MAFK, are essentially composed of a b-Zip domain, the large Maf proteins, MAFA/L-MAF, MAFB, MAF/c-MAF and NRL contain an additional amino-terminal transactivation domain. MAFA was initially cloned in quail and chicken species and named MAFA and L-MAF, respectively. More recently, mammalian MAFA was cloned and identified as an essential component of the RIPE3b1 complex, which binds the insulin promoter.
Atlas Image
Schematic representation of the MAFA protein structure. Critical residues involved in post-translational modifications are indicated by the color code. The kinases responsible for S14 and S65 phosphorylation in MAFA remain to be identified. GSK-3 phosphorylates the transactivation domain of MAFA, thereby inducing its ubiquitination and proteasome-dependent degradation. This is linked to an increase in MAFA transactivation. These phosphorylations are required for MAFA transforming activity. In contrast, sumoylation of MAFA transactivation domain decreases its transactivation activity.


MAFA, like all large Maf proteins, contains an amino-terminal transactivation domain and a carboxy-terminal b-ZIP DNA binding domain. Large Maf proteins stimulate transcription of their target genes through their binding to two types of palindromic sequences called TRE- or CRE- type MARE (Maf Responsive Element) (TGCTGAC(G)TCAGCA). The leucine zipper domain allows the formation of homo- or hetero- dimers, an absolute pre-requisite for DNA binding. As homodimers, these proteins recognize palindromic sequences, with the basic domain contacting DNA directly. Among the AP-1 family, the Maf proteins are defined by the presence of an additional homologous domain, called the Extended Homology Region (EHR) or ancillary domain, which also contacts DNA. Consequently, they recognize a longer palindromic sequence than other AP-1 family members. The MARE sequence is composed of a TRE or CRE core contacted by the basic domain and a TGC flanking sequence, which is recognized by the EHR domain. While the TGC motif is crucial for Maf binding, the TRE/CRE core can be more degenerate. MAFA transactivation activity and stability is regulated by post-translational modifications (phosphorylation, ubiquitylation and sumoylation) mostly occuring on the transactivation domain. GSK-3 was identified as the major protein kinase regulating MAFA activity and oncogenic properties.


Endogenous MAFA protein is detected and phosphorylated in pancreatic beta cells.




During development, Maf proteins are involved early in specification and later in terminal differentiation. MAFA is involved in the regulation of insulin gene expression in pancreatic beta cells. Accordingly, MAFA ablation in mice leads to diabetes.
Besides their roles during development, large Maf proteins, MAFA, MAFB, and MAF/c-MAF are also involved in oncogenesis.


MAFB and MAF/c-MAF are the closest MAFA homologs. The MAFA entire protein sequence shares 52%, 48% and 40% identity with those of MAFB, MAF/c-MAF and NRL, respectively. MAFA DNA binding domain (EHR + b-ZIP) shares 82%, 83%, 64% and 55-60% identity with those of MAFB, MAF/c-MAF, NRL and small MAFs, respectively. MAFA and JUN share 30% sequence identity in their b-ZIP domain (20% identity in their entire sequence).

Implicated in

Entity name
Hybrid gene
Two cases reported translocations of MAFA to the immunoglobulin heavy-chain (IgH) locus, juxtaposing the MAFA gene with the strong enhancers of the IgH locus (meeting report, accurate description lacking).
Large Maf proteins, MAFA, MAFB, and MAF/c-MAF are bona fide oncogenes as demonstrated in tissue culture, animal models and in human cancers. MAFA displays the strongest transforming activity, in vitro. In human, MAF/c-MAF, MAFB and MAFA genes are translocated to the immunoglobulin heavy chain (IgH) locus in 8-10% of multiple myelomas. MAFA translocations are present in less than 1% of multiple myelomas. MAF/C-MAF overexpression plays a causative role in multiple myeloma by promoting proliferation and pathological interactions with bone marrow stroma.
The transforming activity of Maf proteins is context dependent and they can occasionally display tumor suppressor-like activity in specific cellular settings. Their transforming activity relies on overexpression and does not require an activating mutation (no activating mutation has been identified to be associated with human cancers). It is regulated by post-translational modifications, notably phosphorylation.


Pubmed IDLast YearTitleAuthors
114161242001Phosphorylation of MafA is essential for its transcriptional and biological properties.Benkhelifa S et al
180707072007Genetic events in the pathogenesis of multiple myeloma.Chng WJ et al
191430532008A new MAFia in cancer.Eychène A et al
176820632007MafA stability in pancreatic beta cells is regulated by glucose and is dependent on its constitutive phosphorylation at multiple sites by glycogen synthase kinase 3.Han SI et al
123682922002MafA is a glucose-regulated and pancreatic beta-cell-specific transcriptional activator for the insulin gene.Kataoka K et al
129173292003Members of the large Maf transcription family regulate insulin gene transcription in islet beta cells.Matsuoka TA et al
129707352003MafA has strong cell transforming ability but is a weak transactivator.Nishizawa M et al
95258571998Induction of lens differentiation by activation of a bZIP transcription factor, L-Maf.Ogino H et al
120114352002Identification of beta-cell-specific insulin gene transcription factor RIPE3b1 as mammalian MafA.Olbrot M et al
162474502006Cell context reveals a dual role for Maf in oncogenesis.Pouponnot C et al
180424542007GSK-3-mediated phosphorylation enhances Maf-transforming activity.Rocques N et al
190290922009Sumoylation regulates the transcriptional activity of MafA in pancreatic beta cells.Shao C et al
159635042005MafA transcription factor is phosphorylated by p38 MAP kinase.Sii-Felice K et al
159236152005MafA is a key regulator of glucose-stimulated insulin secretion.Zhang C et al

Other Information

Locus ID:

NCBI: 389692
MIM: 610303
HGNC: 23145
Ensembl: ENSG00000182759


dbSNP: 389692
ClinVar: 389692
TCGA: ENSG00000182759


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Type II diabetes mellitusKEGGko04930
Maturity onset diabetes of the youngKEGGko04950
Type II diabetes mellitusKEGGhsa04930
Maturity onset diabetes of the youngKEGGhsa04950
Developmental BiologyREACTOMER-HSA-1266738
Regulation of beta-cell developmentREACTOMER-HSA-186712
Regulation of gene expression in beta cellsREACTOMER-HSA-210745


Entity IDNameTypeEvidenceAssociationPKPDPMIDs


Pubmed IDYearTitleCitations
238636252013Inactivation of specific β cell transcription factors in type 2 diabetes.162
180424542007GSK-3-mediated phosphorylation enhances Maf-transforming activity.48
159939592005Synergistic activation of the insulin gene promoter by the beta-cell enriched transcription factors MafA, Beta2, and Pdx1.29
290967222017PDX1, Neurogenin-3, and MAFA: critical transcription regulators for beta cell development and regeneration.24
194072232009p38 MAPK is a major regulator of MafA protein stability under oxidative stress.19
289337842017Inhibition of the deubiquitinase USP5 leads to c-Maf protein degradation and myeloma cell apoptosis.17
185086682008PDX-1 functions as a master factor in the pancreas.16
227616082012Combined transfection of the three transcriptional factors, PDX-1, NeuroD1, and MafA, causes differentiation of bone marrow mesenchymal stem cells into insulin-producing cells.16
212783802011ATF2 interacts with beta-cell-enriched transcription factors, MafA, Pdx1, and beta2, and activates insulin gene transcription.13
185229392008MafA and MafB regulate Pdx1 transcription through the Area II control region in pancreatic beta cells.11


Celio Pouponnot ; Alain Eychène

MAFA (v-maf musculoaponeurotic fibrosarcoma oncogene homolog A (avian))

Atlas Genet Cytogenet Oncol Haematol. 2009-03-01

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