Document Detail

Salt-inducible kinase-1 represses cAMP response element-binding protein activity both in the nucleus and in the cytoplasm.
MedLine Citation:
PMID:  15511237     Owner:  NLM     Status:  MEDLINE    
Salt-inducible kinase-1 (SIK1) is phosphorylated at Ser577 by protein kinase A in adrenocorticotropic hormone-stimulated Y1 cells, and the phospho-SIK1 translocates from the nucleus to the cytoplasm. The phospho-SIK1 is dephosphorylated in the cytoplasm and re-enters the nucleus several hours later. By using green-fluorescent protein-tagged SIK1 fragments, we found that a peptide region (586-612) was responsible for the nuclear localization of SIK1. The region was named the 'RK-rich region' because of its Arg- and Lys-rich nature. SIK1s mutated in the RK-rich region were localized mainly in the cytoplasm. Because SIK1 represses cAMP-response element (CRE)-mediated transcription of steroidogenic genes, the mutants were examined for their effect on transcription. To our surprise, the cytoplasmic mutants strongly repressed the CRE-binding protein (CREB) activity, the extent of repression being similar to that of SIK1(S577A), a mutant localized exclusively in the nucleus. Several chimeras were constructed from SIK1 and from its isoform SIK2, which was localized mainly in the cytoplasm, and they were examined for intracellular localization as well as CREB-repression activity. A SIK1-derived chimera, where the RK-rich region had been replaced with the corresponding region of SIK2, was found in the cytoplasm, its CREB-modulating activity being similar to that of wild-type SIK1. On the other hand, a SIK2-derived chimera with the RK-rich region of SIK1 was localized in both the nucleus and the cytoplasm, and had a CREB-repressing activity similar to that of the wild-type SIK2. Green fluorescent protein-fused transducer of regulated CREB activity 2 (TORC2), a CREB-specific co-activator, was localized in the cytoplasm and nucleus of Y1 cells, and, after treatment with adrenocorticotropic hormone, cytoplasmic TORC2 entered the nucleus, activating CREB. The SIK1 mutants, having a strong CRE-repressing activity, completely inhibited the adrenocorticotropic hormone-induced nuclear entry of green fluorescent protein-fused TORC2. This suggests that SIK1 may regulate the intracellular movement of TORC2, and as a result modulates the CREB-dependent transcription activity. Together, these results indicate that the RK-rich region of SIK1 is important for determining the nuclear localization and attenuating CREB-repressing activity, but the degree of the nuclear localization of SIK1 itself does not necessarily reflect the degree of SIK1-mediated CREB repression.
Yoshiko Katoh; Hiroshi Takemori; Li Min; Masaaki Muraoka; Junko Doi; Nanao Horike; Mitsuhiro Okamoto
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  European journal of biochemistry / FEBS     Volume:  271     ISSN:  0014-2956     ISO Abbreviation:  Eur. J. Biochem.     Publication Date:  2004 Nov 
Date Detail:
Created Date:  2004-10-29     Completed Date:  2004-12-17     Revised Date:  2011-11-01    
Medline Journal Info:
Nlm Unique ID:  0107600     Medline TA:  Eur J Biochem     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  4307-19     Citation Subset:  IM    
Department of Biochemistry and Molecular Biology, Graduate School of Medicine (H-1), Osaka University, Japan.
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MeSH Terms
3T3-L1 Cells
Active Transport, Cell Nucleus
Amino Acid Sequence
Arginine / chemistry
Cell Nucleus / metabolism*
Cloning, Molecular
Cyclic AMP Response Element-Binding Protein / antagonists & inhibitors*,  metabolism
Cyclic AMP-Dependent Protein Kinases / metabolism
Cytoplasm / metabolism*
DNA, Complementary / metabolism
Genes, Reporter
Green Fluorescent Proteins / metabolism
Lysine / chemistry
Microscopy, Fluorescence
Models, Genetic
Molecular Sequence Data
Mutagenesis, Site-Directed
Nuclear Localization Signals
Protein Structure, Tertiary
Protein Transport
Protein-Serine-Threonine Kinases / physiology*
Recombinant Fusion Proteins / metabolism
Transcription, Genetic
Reg. No./Substance:
0/Cyclic AMP Response Element-Binding Protein; 0/DNA, Complementary; 0/Nuclear Localization Signals; 0/Recombinant Fusion Proteins; 147336-22-9/Green Fluorescent Proteins; 56-87-1/Lysine; 74-79-3/Arginine; EC Kinases; EC protein, rat; EC AMP-Dependent Protein Kinases

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