| Project/Area Number |
18390102
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Pathological medical chemistry
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| Research Institution | National Institute of Biomedical Innovation |
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Principal Investigator |
TAKEMORI Hiroshi National Institute of Biomedical Innovation, 基盤的研究部, project leader (90273672)
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| Co-Investigator(Kenkyū-buntansha) |
HATANO Osamu Nara Medical Scool, Medicine, Lecturer (40164850)
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| Project Period (FY) |
2006 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥16,650,000 (Direct Cost: ¥14,700,000、Indirect Cost: ¥1,950,000)
Fiscal Year 2007: ¥8,450,000 (Direct Cost: ¥6,500,000、Indirect Cost: ¥1,950,000)
Fiscal Year 2006: ¥8,200,000 (Direct Cost: ¥8,200,000)
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| Keywords | LKB1 / SIK / CREB / 糖代謝 / 脂肪 |
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| Research Abstract |
Autophosphorylation is an important mechanism by which protein kinases regulate their own biological activities. Salt inducible kinase 1(SIK1) is a regulator in the feedback cascades of cAMP-mediated gene expression, while its kinase domain also features autophosphorylation activity. We provide evidence that Serl86 in the activation loop is the site of autophosphorylation and essential for the kinase activity. Serl86 is located at the +4 position of the critical. Thr residue ThrI82, which is phosphorylated by upstream kinases such as LKB1. The relationship between phosphorylation at Serl86 and at Thrl82 in COS-7 cells indicates that the former is a prerequisite for the latter. Glycogen synthase kinase-3β(GSK-3β) phosphorylates Ser/Thr residues located at the fourth position ahead of the pre-phosphorylated Ser/Thr residues, and inhibitors of GSK-3β reduce the phosphorylation at Thrl82. The results of an in vitro reconstitution assay also indicate that GSK-3β could be the SIK1 kinase. However, overexpression and knockdown of GSK-3β in LKB1-defective HeLa cells suggests that GSK-3β alone may not be able to phosphorylate or activate SIK1, indicating that LKB1 may play a crucial role by phosphorylating SIK1 at Thrl82, possibly as an initiator of the autophosphorylation cascade, and GSK-3β may phosphorylate SIK1 at Thrl82 by recognizing the priming-autophosphorylation at Serl86 in cultured cells. This may also be the case for the other isoform SIK2, but not for SIK3. Using knockout mice of SIK family enzyme, we are investing the details of their physiological roles.
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