Disease relevance of MAFA

• AIMS/HYPOTHESIS: Effects of the transcription factor v-maf musculoaponeurotic fibrosarcoma oncogene homologue A (MAFA) on the regulation of beta cell gene expression and function were investigated [1].

High impact information on MAFA

• Here we report that a prototype inhibitory receptor, the mast cell function-associated antigen (MAFA), selectively regulates the FcvarepsilonRI stimulus-response coupling network and the subsequent de novo production and secretion of inflammatory mediators [2].
• Here, we report cloning of the human mafA (hMafA) and demonstrate that it can specifically bind the insulin enhancer element RIPE3b and activate insulin-gene expression [3].
• The cytoplasmic tail of MAFA contains a YXXL (YSTL) motif, which is conserved among related C-type lectins and is an essential element in the immunoreceptor tyrosine-based activation motifs [4].
• Here we report that the MAFA is expressed as both a monomer and a homodimer [4].
• However, we found that mutations in either the ICE or the RIPE3b1 element reduced glucose-responsive expression from transfected 5'-flanking rat insulin II gene constructs [5].

Biological context of MAFA

• MAFA thus qualifies as a master regulator of beta-cell-specific gene expression and function [1].
• There may exist a RIPE3b1 activator binding site in the glucose-responsive element from -1138 to -880 bp [6].
• The DNA binding activity of the RIPE3b1 transcription factor of insulin appears to be influenced by tyrosine phosphorylation [7].
• Our in vitro study provides molecular targets that explain the phenotype of recently reported Mafa-null mice [1].
• We have also shown that mannose, a sugar that can be metabolized by the beta cell, mimics the effects of glucose in the in vivo transfection assays and the in vitro RIPE3b1 binding assays [5].

Anatomical context of MAFA

• This glycoprotein, named mast cell function-associated antigen (MAFA), was also shown to interfere with the coupling cascade of the type 1 Fc epsilon receptor upstream to phospholipase C gamma 1 activation by protein-tyrosine kinases [4].
• Islet cell differentiation in liver by combinatorial expression of transcription factors Neurogenin-3, BETA2, and RIPE3b1 [8].
• Taken together, these results of distinct methodologies suggest that MAFA functions within raft microdomains of the RBL-2H3 cell membrane and thus in close proximity to the FcepsilonRI which themselves signal from within the raft environment [9].
• Compartmentalization of the Type I Fcepsilon receptor and MAFA on mast cell membranes [9].

Associations of MAFA with chemical compounds

• Glucose influenced DNA-binding activity of MAFA in rat islets in a bell-shaped manner [1].
• We used cholera toxin B subunit (CTB) to cluster the raft component ganglioside GM1 and studied the effects of this perturbation on rotation of FcepsilonRI and MAFA by time-resolved phosphorescence anisotropy of erythrosin-conjugated probes [9].
• Evaluation of raft localization of FcepsilonRI and MAFA using sucrose gradient ultracentrifugation of Triton X-100 treated membrane fragments demonstrates that a significant fraction of MAFA molecules sediments with rafts when FcepsilonRI is clustered by antigen or when MAFA itself is clustered by mAb G63 [9].
• Collectively, the data suggested that removal of a tyrosine(s) within RIPE3b1 prevented activator binding to insulin C1 control element sequences [7].
• The loss in RIPE3b1 binding activity was prevented by inhibitors of tyrosine phosphatases (sodium orthovanadate and sodium molybdate) but not by inhibitors of serine/threonine phosphatases (sodium fluoride, okadaic acid, and microcystin LR) [7].

Other interactions of MAFA

• In fragment D, cotransfection of oligonucleotide that confers RIPE3b1 activator decreased the glucose-stimulated promoter activity, but the other oligonucleotide that confers STF-1 did not [6].

Analytical, diagnostic and therapeutic context of MAFA

• We discuss how tyrosine phosphorylation, a very rare and highly significant regulatory modification, may control RIPE3b1 activator function [7].
• The gel mobility shift assay was used to determine whether the formation of the ICE- and RIPE3b1-specific factor-DNA element complexes were affected in glucose-treated beta-cell extracts [5].

References