Endocr J 2009,
PMID: 18946175
Takemori, Hiroshi; Katoh Hashimoto, Yoshiko; Nakae, Jun; Olson, Eric N; Okamoto, Mitsuhiro
Salt inducible kinase (SIK) 1, a member of the AMP-activated kinase (AMPK) family, is activated by the AMPK-activator LKB1 which phosphorylates SIK1 at Thr182. The activated SIK1 then auto-phosphorylates its Ser186 located at the +4 position of Thr182. The phospho-Ser186 is essential for sustained activity of SIK1, which is maintained by sequential phosphorylation at Ser186-Thr182 by glycogen synthase kinase (GSK)-3beta. Meanwhile, SIK1 represses the transcription factor cAMP-response element binding protein (CREB) by phosphorylating its co-activator transducer of regulated CREB activity (TORC). Recently, histone deacetylase (HDAC) 5 was identified as a new substrate of SIK1. Inhibition of SIK1 or AMPK results in the stimulation of glyconeogensis in the liver by enhancing dephosphorylation of TORC2 followed by up-regulation of peroxisome proliferator-activated receptor coactivator (PGC)-1alpha gene expression. However, expression of the PGC-1alpha gene has been found to be repressed in LKB1-defective muscle cells. Our findings show that the AMPK agonist 5-aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside (AICAR)-dependent expression of PGC-1alpha is diminished by inhibitors of GSK-3beta or SIKs in C2C12 myoblasts. Treatment with AICAR or the overexpression of SIK1 induces nuclear export of HDAC5 followed by the activation of myogenic transcription factor (MEF)-2C. The levels of phosphorylation at Thr182 and Ser186 of SIK1 in AICAR-treated C2C12 cells are elevated, and GSK-3beta enzyme purified from AICAR-treated cells shows enhanced phosphorylation activity of SIK1 in vitro. These observations suggest that GSK-3 beta and SIK1 may play important roles in the regulation of PGC-1alpha gene expression by inactivating HDAC5 followed by activation of MEF2C.
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Text Mining Data
Salt inducible kinase (SIK) 1 → LKB1: "
Salt inducible kinase (SIK) 1 , a member of the AMP activated kinase (AMPK) family, is
activated by the AMPK-activator
LKB1 which phosphorylates SIK1 at Thr182
"
CREB ⊣ SIK1: "
Meanwhile, SIK1 represses the transcription factor cAMP-response element binding protein ( CREB ) by phosphorylating its co-activator transducer of regulated CREB activity ( TORC )
"
CREB ⊣ SIK1: "
Meanwhile, SIK1 represses the transcription factor cAMP-response element binding protein ( CREB ) by phosphorylating its co-activator transducer of regulated CREB activity ( TORC )
"
PGC-1alpha → GSK-3beta: "
Our findings show that the AMPK agonist 5-aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside ( AICAR ) -dependent expression of PGC-1alpha is diminished by inhibitors of GSK-3beta or SIKs in C2C12 myoblasts
"
PGC-1alpha → HDAC5: "
These observations suggest that GSK-3 beta and SIK1 may play important roles in the regulation of PGC-1alpha gene expression by inactivating HDAC5 followed by activation of MEF2C
"
PGC-1alpha — SIK1: "
These observations suggest that GSK-3 beta and SIK1 may play important roles in the regulation of PGC-1alpha gene expression by inactivating HDAC5 followed by activation of MEF2C
"
PGC-1alpha — GSK-3 beta: "
These observations suggest that GSK-3 beta and SIK1 may play important roles in the regulation of PGC-1alpha gene expression by inactivating HDAC5 followed by activation of MEF2C
"
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