PMID- 10347145
OWN - NLM
STAT- MEDLINE
DCOM- 19990701
LR  - 20210209
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 274
IP  - 23
DP  - 1999 Jun 4
TI  - Insulin stimulates phosphorylation of the forkhead transcription factor FKHR on
      serine 253 through a Wortmannin-sensitive pathway.
PG  - 15982-5
AB  - In the nematode Caenorhabditis elegans, mutations of the insulin/insulin-like
      growth factor-1 receptor homologue Daf-2 gene cause developmental arrest at the
      dauer stage. The effect of Daf-2 mutations is counteracted by mutations in the
      Daf-16 gene, suggesting that Daf-16 is required for signaling by Daf-2. Daf-16
      encodes a forkhead transcription factor. Based on sequence similarity, the FKHR
      genes are the likeliest mammalian Daf-16 homologues. FKHR proteins contain
      potential sites for phosphorylation by the serine/threonine kinase Akt. Because
      Akt is phosphorylated in response to insulin and has been implicated in a variety
      of insulin effects, we investigated whether insulin affects phosphorylation of
      FKHR. Insulin stimulated phosphorylation of endogenous FKHR and of a recombinant 
      c-Myc/FKHR fusion protein transiently expressed in murine SV40-transformed
      hepatocytes. The effect of insulin was inhibited by wortmannin treatment,
      suggesting that PI 3-kinase activity is required for FKHR phosphorylation.
      Mutation of serine 253, located in a consensus Akt phosphorylation site at the
      carboxyl-terminal end of the forkhead domain, abolished the effect of insulin on 
      FKHR phosphorylation. In contrast, mutation of two additional Akt phosphorylation
      sites, at amino acids threonine 24 or serine 316, did not abolish insulin-induced
      phosphorylation. These data indicate that FKHR may represent a distal effector of
      insulin action.
FAU - Nakae, J
AU  - Nakae J
AD  - Developmental Endocrinology Branch, NICHD, National Institutes of Health,
      Bethesda, Maryland 20892, USA.
FAU - Park, B C
AU  - Park BC
FAU - Accili, D
AU  - Accili D
LA  - eng
SI  - GENBANK/AF126056
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Androstadienes)
RN  - 0 (Blood Proteins)
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (FOXO4 protein, human)
RN  - 0 (Forkhead Transcription Factors)
RN  - 0 (Insulin)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Transcription Factors)
RN  - 2ZD004190S (Threonine)
RN  - 452VLY9402 (Serine)
RN  - EC 2.7.11.1 (AKT1 protein, human)
RN  - EC 2.7.11.1 (Protein-Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - XVA4O219QW (Wortmannin)
SB  - IM
MH  - Amino Acid Substitution
MH  - Androstadienes/*pharmacology
MH  - Animals
MH  - Blood Proteins/*metabolism
MH  - Cell Cycle Proteins
MH  - Cells, Cultured
MH  - Consensus Sequence
MH  - Enzyme Inhibitors/*pharmacology
MH  - Forkhead Transcription Factors
MH  - Gene Expression Regulation
MH  - Humans
MH  - Insulin/*pharmacology
MH  - Liver/drug effects/metabolism
MH  - Mice
MH  - Molecular Sequence Data
MH  - Mutagenesis, Site-Directed
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Phosphorylation
MH  - Protein-Serine-Threonine Kinases/metabolism
MH  - Proto-Oncogene Proteins/metabolism
MH  - Proto-Oncogene Proteins c-akt
MH  - Serine/metabolism
MH  - Simian virus 40
MH  - Structure-Activity Relationship
MH  - Threonine/metabolism
MH  - *Transcription Factors
MH  - Wortmannin
EDAT- 1999/05/29 00:00
MHDA- 1999/05/29 00:01
CRDT- 1999/05/29 00:00
PHST- 1999/05/29 00:00 [pubmed]
PHST- 1999/05/29 00:01 [medline]
PHST- 1999/05/29 00:00 [entrez]
AID - 10.1074/jbc.274.23.15982 [doi]
AID - S0021-9258(19)72930-5 [pii]
PST - ppublish
SO  - J Biol Chem. 1999 Jun 4;274(23):15982-5. doi: 10.1074/jbc.274.23.15982.