MafA Stability in Pancreatic β Cells Is Regulated by Glucose and Is Dependent on Its Constitutive Phosphorylation at Multiple Sites by Glycogen Synthase Kinase 3

Han, Song‐iee; Aramata, Shinsaku; Yasuda, Kazuaki; Kataoka, Kohsuke

doi:10.1128/mcb.01573-06

Cited by 73 publications

(127 citation statements)

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“…For example, casein kinase I phosphorylation of ␤-catenin primes it for subsequent GSK3␤ phosphorylation at multiple sites at the N terminus, leading to the recognition by ␤-transducin repeat containing E3 ubiquitin protein ligase and rapid degradation by the 26 S proteasome (10). Also, phosphorylation by GSK3 induces both activation and degradation of MafA, SRC-3, and BCL-3 (11)(12)(13)(14).…”

mentioning

confidence: 99%

GSK3 Protein Positively Regulates Type I Insulin-like Growth Factor Receptor through Forkhead Transcription Factors FOXO1/3/4

Huo

Liu

Shao

et al. 2014

Journal of Biological Chemistry

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Background: Glycogen synthase kinase-3 (GSK3) and the O subfamily of forkhead/winged helix transcription factors (FOXO) have pro-tumor or anti-tumor roles in human cancers. Results: GSK3 up-regulates type I insulin-like growth factor receptor (IGF-IR) expression and IGF-I-induced hepatoma cell proliferation through FOXO1/3/4. Conclusion: GSK3 and FOXO promote hepatoma cell proliferation through IGF-IR. Significance: These findings inform how GSK3 and FOXO promote cell proliferation.

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confidence: 99%

GSK3 Protein Positively Regulates Type I Insulin-like Growth Factor Receptor through Forkhead Transcription Factors FOXO1/3/4

Huo

Liu

Shao

et al. 2014

Journal of Biological Chemistry

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“…We transfected NIH3T3 cells with a constant amount of this plasmid together with an increasing amount of an expression plasmid for FLAG-tagged PA28g (F-PA28g). NIH3T3 was used as a recipient cell for this assay because HA-MAFA protein is relatively stable in this cell line (Han et al 2007, see also Fig. 3C).…”

Section: Pa28g Reduces the Amount Of Mafa Proteinmentioning

confidence: 99%

“…The mammalian expression vector for hemagglutinin (HA)-tagged mouse Mafa (pHygEF2/HA-m-MafA) and its derivatives (IRES-EGFP fusions and amino acid substitution mutants) were described previously (Han et al 2007).…”

Section: Plasmidsmentioning

confidence: 99%

“…Thr57 and Ser65 can also be phosphorylated by ERK and/or p38 MAP kinase (Benkhelifa et al 2001, Ochi et al 2003, Sii-Felice et al 2005. Phosphorylation at these sites is required for proteasomal degradation of MAFA protein (Ochi et al 2003, Han et al 2007, Rocques et al 2007, and mutations at these phosphorylation sites influence the transforming and differentiation-inducing activities of MAFA (Benkhelifa et al 2001, Nishizawa et al 2003, Ochi et al 2003, Pouponnot et al 2006, Rocques et al 2007). However, the molecular mechanism by which phosphorylated MAFA is degraded is unknown.…”

Section: Introductionmentioning

confidence: 99%

“…The amino-terminal domain of MAFA is first phosphorylated by an unidentified priming kinase at Ser65 and then sequentially by GSK3 at Ser61, Thr57, Thr53, and Ser49 (Han et al 2007, Rocques et al 2007). Thr57 and Ser65 can also be phosphorylated by ERK and/or p38 MAP kinase (Benkhelifa et al 2001, Ochi et al 2003, Sii-Felice et al 2005.…”

Section: Introductionmentioning

confidence: 99%

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Proteasome activator PA28γ stimulates degradation of GSK3-phosphorylated insulin transcription activator MAFA

Kanai¹,

Aramata²,

Katakami³

et al. 2011

Journal of Molecular Endocrinology

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MAFA is a member of the MAF family of basic leucine zipper transcription factors and is a critical regulator of insulin gene expression and islet b-cell function. To be degraded by the proteasome, MAFA must be phosphorylated by GSK3 and MAP kinases at multiple serine and threonine residues (Ser49, Thr53, Thr57, Ser61, and Ser65) within its amino-terminal domain. In this study, we report that MAFA degradation is stimulated by PA28g (REGg and PSME3), a member of a family of proteasome activators that bind and activate the 20S proteasome. To date, only a few PA28g-proteasome pathway substrates have been identified, including steroid receptor coactivator 3 (SRC3) and the cell cycle inhibitor p21 (CIP1). PA28g binds to MAFA, induces its proteasomal degradation, and thereby attenuates MAFA-driven transcriptional activation of the insulin promoter. Co-expression of GSK3 enhanced the PA28g-mediated degradation of MAFA, but mutants that contained alanine substitutions at the MAFA phosphorylation sites did not bind PA28g and were resistant to degradation. We also found that a PA28g mutant (N151Y) that did not stimulate p21 degradation enhanced MAFA degradation, and another mutant (K188D) that promoted greater p21 degradation did not enhance MAFA degradation. These results suggest that PA28g stimulates MAFA degradation through a novel molecular mechanism that is distinct from that for the degradation of p21.

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Generation and mutational analysis of a transgenic murine model of the human MAF mutation

Fujino

Ojima

Ishibashi

et al. 2023

American J of Med Genetics Pt A

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Aymé-Gripp syndrome is an autosomal dominant multisystem disorder. The major clinical features of this syndrome include congenital cataracts, sensorineural hearing loss, intellectual disability, and a distinctive flat facial appearance. MAF has been identified as a causative gene of the syndrome, and heterozygous variants owing to impairment in glycogen synthase kinase 3 (GSK3)-mediated MAF phosphorylation shows related disorders. However, the underlying mechanisms of these types of disorders in affected individuals remain poorly understood. To explore the underlying mechanisms and discover new phenotypes, a murine model with a Maf mutation on a GSK3 phosphorylation motif, p.Thr58Ile, was generated using CRISPR-Cas9 gene editing. This is a homologous mutation to that in human patients. Our murine model exhibited similar phenotypes to those in humans, such as lens abnormalities, short stature, growth retardation, and abnormal skull morphology. The murine model showed decreased brain volume and malocclusion. Considering the sequencing and genotyping data, our models were successfully generated for the first time (to the best of our knowledge). Therefore, this study offers new and unique functional insights into human and murine MAF and novel clinical values of MAF pathogenic variants associated with changes in the functions of several organs based on a viable murine model.

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MafA Stability in Pancreatic β Cells Is Regulated by Glucose and Is Dependent on Its Constitutive Phosphorylation at Multiple Sites by Glycogen Synthase Kinase 3

Cited by 73 publications

References 58 publications

GSK3 Protein Positively Regulates Type I Insulin-like Growth Factor Receptor through Forkhead Transcription Factors FOXO1/3/4

GSK3 Protein Positively Regulates Type I Insulin-like Growth Factor Receptor through Forkhead Transcription Factors FOXO1/3/4

Proteasome activator PA28γ stimulates degradation of GSK3-phosphorylated insulin transcription activator MAFA

Generation and mutational analysis of a transgenic murine model of the human MAF mutation

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