Regulation of BMAL1 Protein Stability and Circadian Function by GSK3β-Mediated Phosphorylation
Copyright policy )Regulation of BMAL1 Protein Stability and Circadian Function by GSK3β-Mediated Phosphorylation
Circadian rhythms govern a large array of physiological and metabolic functions. To achieve plasticity in circadian regulation, proteins constituting the molecular clock machinery undergo various post-translational modifications (PTMs), which influence their activity and intracellular localization. The core clock protein BMAL1 undergoes several PTMs. Here we report that the Akt-GSK3beta signaling pathway regulates BMAL1 protein stability and activity.GSK3beta phosphorylates BMAL1 specifically on Ser 17 and Thr 21 and primes it for ubiquitylation. In the absence of GSK3beta-mediated phosphorylation, BMAL1 becomes stabilized and BMAL1 dependent circadian gene expression is dampened. Dopamine D2 receptor mediated signaling, known to control the Akt-GSK3beta pathway, influences BMAL1 stability and in vivo circadian gene expression in striatal neurons.These findings uncover a previously unknown mechanism of circadian clock control. The GSK3beta kinase phosphorylates BMAL1, an event that controls the stability of the protein and the amplitude of circadian oscillation. BMAL1 phosphorylation appears to be an important regulatory step in maintaining the robustness of the circadian clock.
Threonine, Dopamine, Messenger, glycogen-synthase kinase-3-beta, receptors, Sequence Homology, Glycogen Synthase Kinase 3, Mice, Serine, Phosphorylation, Cells, Cultured, Cultured, Q, R, ARNTL Transcription Factors, inhibition, Circadian Rhythm, Amino Acid, Medicine, transcription, Sleep Research, Research Article, Signal Transduction, mice, kinase, General Science & Technology, 1.1 Normal biological development and functioning, Cells, Science, Molecular Sequence Data, mammalian clock, Underpinning research, component, ubiquitin, Genetics, Animals, Humans, Amino Acid Sequence, RNA, Messenger, Protein Processing, Glycogen Synthase Kinase 3 beta, Sequence Homology, Amino Acid, Neurosciences, Post-Translational, Ubiquitination, RNA, activation, Generic health relevance, Protein Processing, Post-Translational
Threonine, Dopamine, Messenger, glycogen-synthase kinase-3-beta, receptors, Sequence Homology, Glycogen Synthase Kinase 3, Mice, Serine, Phosphorylation, Cells, Cultured, Cultured, Q, R, ARNTL Transcription Factors, inhibition, Circadian Rhythm, Amino Acid, Medicine, transcription, Sleep Research, Research Article, Signal Transduction, mice, kinase, General Science & Technology, 1.1 Normal biological development and functioning, Cells, Science, Molecular Sequence Data, mammalian clock, Underpinning research, component, ubiquitin, Genetics, Animals, Humans, Amino Acid Sequence, RNA, Messenger, Protein Processing, Glycogen Synthase Kinase 3 beta, Sequence Homology, Amino Acid, Neurosciences, Post-Translational, Ubiquitination, RNA, activation, Generic health relevance, Protein Processing, Post-Translational
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