FoxO1a-cyclic GMP-dependent kinase I interactions orchestrate myoblast fusion.
The regulatory circuits that orchestrate mammalian myoblast cell fusion during myogenesis are poorly understood. The transcriptional activity of FoxO1a directly regulates this process, yet the molecular mechanisms governing FoxO1a activity during muscle cell differentiation remain unknown. Here we show an autoregulatory loop in which FoxO1a directly activates transcription of the cyclic GMP-dependent protein kinase I (cGKI) gene and where the ensuing cGKI activity phosphorylates FoxO1a and abolishes its DNA binding activity. These findings establish the FoxO1a-to-cGKI pathway as a novel feedback loop that allows the precise tuning of myoblast fusion. Interestingly, this pathway appears to operate independently of muscle cell differentiation programs directed by myogenic transcription factors.
Bois
Philippe R J
PR
Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Brochard
Vanessa F
VF
Salin-Cantegrel
Adèle V A
AV
Cleveland
John L
JL
Grosveld
Gerard C
GC
D000595:Amino Acid Sequence; D000818:Animals; D002454:Cell Differentiation; D002459:Cell Fusion; D002478:Cells, Cultured; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D032446:Myoblasts / Q000166:cytology* / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D016415:Sequence Alignment; D015398:Signal Transduction; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics
D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D014157:Transcription Factors; D004247:DNA; D017869:Cyclic GMP-Dependent Protein Kinases