Regulation of Pgc1a expression by a Gsk3b-Tfeb signaling axis in skeletal muscle (Mus musculus)

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Nucleus3251, 25Skeletal muscle cellInteraction Legend:Transcription/TranslationTranslocationDirect or IndirectmechanismInhibitionMitochondrial biogenesis14-3-3 protein familyCHIR99021Gsk-3βTfebPTfeb4, 5PPARGC1A promotor55Pgc-1αTfebTfebPPost TranslationalModificationDirect Stimulation(In)DirectStimulation


In (skeletal) muscle cells, PGC-1 signaling controls mitochondrial biogenesis and oxidative substrate metabolism. PGC-1 signaling disturbance in skeletal muscle is linked to several chronic diseases. This pathway depicts the mechanism in which inhibition of GSK-3β increases Pgc-1α abundance, through dephosphorylation of Tfeb Theeuwes et al, 2019. This reaction allows Tfeb to translocate to the nucleus, where it stimulates the transcription of the PPARGC1A gene to the Pgc-1α protein. Phosphorylation of Tfeb leads to binding with members of the 14-3-3 protein family, which disables transport into the nucleus. If the dephosphorylation of Tfeb through Gsk-3β is a direct or indirect reaction is as of yet unknown.

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  1. Xu Y, Ren J, He X, Chen H, Wei T, Feng W; ''YWHA/14-3-3 proteins recognize phosphorylated TFEB by a noncanonical mode for controlling TFEB cytoplasmic localization.''; Autophagy, 2019 PubMed Europe PMC Scholia
  2. Marchand B, Arsenault D, Raymond-Fleury A, Boisvert FM, Boucher MJ; ''Glycogen synthase kinase-3 (GSK3) inhibition induces prosurvival autophagic signals in human pancreatic cancer cells.''; J Biol Chem, 2015 PubMed Europe PMC Scholia
  3. Ring DB, Johnson KW, Henriksen EJ, Nuss JM, Goff D, Kinnick TR, Ma ST, Reeder JW, Samuels I, Slabiak T, Wagman AS, Hammond ME, Harrison SD; ''Selective glycogen synthase kinase 3 inhibitors potentiate insulin activation of glucose transport and utilization in vitro and in vivo.''; Diabetes, 2003 PubMed Europe PMC Scholia
  4. Li Y, Xu M, Ding X, Yan C, Song Z, Chen L, Huang X, Wang X, Jian Y, Tang G, Tang C, Di Y, Mu S, Liu X, Liu K, Li T, Wang Y, Miao L, Guo W, Hao X, Yang C; ''Protein kinase C controls lysosome biogenesis independently of mTORC1.''; Nat Cell Biol, 2016 PubMed Europe PMC Scholia
  5. Theeuwes WF, Gosker HR, Schols AMWJ, Langen RCJ, Remels AHV; ''Regulation of PGC-1α expression by a GSK-3β-TFEB signaling axis in skeletal muscle.''; Biochim Biophys Acta Mol Cell Res, 2019 PubMed Europe PMC Scholia


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108519view21:01, 29 December 2019AlexanderPicoModified title
108444view12:16, 20 December 2019DeSlTest
108436view12:40, 19 December 2019DeSlModified description
108435view12:38, 19 December 2019DeSlAdded lit. refs for specific interactions (provided by W. Theeuwes).
108430view16:00, 18 December 2019DeSlTextual update in legend.
108426view14:26, 18 December 2019DeSlAdded legend to describe interactions.
108425view14:18, 18 December 2019DeSlModified description
108424view14:16, 18 December 2019DeSlModified description
108423view14:14, 18 December 2019DeSlOntology Term : 'peroxisome proliferator-activated receptor signaling pathway' added !
108422view14:12, 18 December 2019DeSlOntology Term : 'skeletal muscle fiber' added !
108421view14:12, 18 December 2019DeSlModified description
108420view14:10, 18 December 2019DeSlModified description
108419view13:58, 18 December 2019DeSlUpdated layout
108418view13:49, 18 December 2019DeSlNew pathway

External references


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NameTypeDatabase referenceComment
14-3-3 protein familyProteinIPR000308 (InterPro)
CHIR99021Metabolite9956119 (PubChem-compound)
Gsk-3βProteinQ9WV60 (Uniprot-TrEMBL) AKA glycogen synthase kinase (GSK)-3β (Human Uniprot: P49841)
Mitochondrial biogenesisPathway


GeneProduct19017 (Entrez Gene) (Human Entrez Gene: 10891)
Pgc-1αProteinO70343 (Uniprot-TrEMBL) (Human Uniprot: Q9UBK2)
TfebProteinQ9R210 (Uniprot-TrEMBL) transcription factor EB (TFEB)

Annotated Interactions

No annotated interactions

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