PMID- 10358075
OWN - NLM
STAT- MEDLINE
DCOM- 19990706
LR  - 20191210
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 274
IP  - 24
DP  - 1999 Jun 11
TI  - Phosphorylation of the transcription factor forkhead family member FKHR by
      protein kinase B.
PG  - 17179-83
AB  - Protein kinase B lies "downstream" of phosphatidylinositide (PtdIns) 3-kinase and
      is thought to mediate many of the intracellular actions of insulin and other
      growth factors. Here we show that FKHR, a human homologue of the DAF16
      transcription factor in Caenorhabditis elegans, is rapidly phosphorylated by
      human protein kinase Balpha (PKBalpha) at Thr-24, Ser-256, and Ser-319 in vitro
      and at a much faster rate than BAD, which is thought to be a physiological
      substrate for PKB. The same three sites, which all lie in the canonical PKB
      consensus sequences (Arg-Xaa-Arg-Xaa-Xaa-(Ser/Thr)), became phosphorylated when
      FKHR was cotransfected with either PKB or PDK1 (an upstream activator of PKB).
      All three residues became phosphorylated when 293 cells were stimulated with
      insulin-like growth factor 1 (IGF-1). The IGF-1-induced phosphorylation was
      abolished by the PtdIns 3-kinase inhibitor wortmannin but not by PD 98059 (an
      inhibitor of the mitogen-activated protein kinase cascade) or by rapamycin. These
      results indicate that FKHR is a physiological substrate of PKB and that it may
      mediate some of the physiological effects of PKB on gene expression. DAF16 is
      known to be a component of a signaling pathway that has been partially dissected 
      genetically and includes homologues of the insulin/IGF-1 receptor, PtdIns
      3-kinase and PKB. The conservation of Thr-24, Ser-256, and Ser-319 and the
      sequences surrounding them in DAF16 therefore suggests that DAF16 is also a
      direct substrate for PKB in C. elegans.
FAU - Rena, G
AU  - Rena G
AD  - Department of Biochemistry, Medical Research Council Protein Phosphorylation
      Unit, University of Dundee, Dundee DD1 5EH, Scotland, United Kingdom.
FAU - Guo, S
AU  - Guo S
FAU - Cichy, S C
AU  - Cichy SC
FAU - Unterman, T G
AU  - Unterman TG
FAU - Cohen, P
AU  - Cohen P
LA  - eng
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 (BAD protein, human)
RN  - 0 (Caenorhabditis elegans Proteins)
RN  - 0 (Carrier Proteins)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (FOXO1 protein, human)
RN  - 0 (Forkhead Box Protein O1)
RN  - 0 (Forkhead Transcription Factors)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Recombinant Proteins)
RN  - 0 (Transcription Factors)
RN  - 0 (bcl-Associated Death Protein)
RN  - 1114-81-4 (Phosphothreonine)
RN  - 17885-08-4 (Phosphoserine)
RN  - 2ZD004190S (Threonine)
RN  - 452VLY9402 (Serine)
RN  - 67763-96-6 (Insulin-Like Growth Factor I)
RN  - EC 2.7.11.1 (3-Phosphoinositide-Dependent Protein Kinases)
RN  - EC 2.7.11.1 (PDPK1 protein, human)
RN  - EC 2.7.11.1 (Protein-Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (akt-1 protein, C elegans)
RN  - W36ZG6FT64 (Sirolimus)
RN  - XVA4O219QW (Wortmannin)
SB  - IM
MH  - 3-Phosphoinositide-Dependent Protein Kinases
MH  - Amino Acid Sequence
MH  - Androstadienes/pharmacology
MH  - Antibody Specificity
MH  - Caenorhabditis elegans Proteins
MH  - Carrier Proteins/metabolism
MH  - Consensus Sequence
MH  - DNA-Binding Proteins/genetics/immunology/*metabolism
MH  - Enzyme Activation
MH  - Forkhead Box Protein O1
MH  - Forkhead Transcription Factors
MH  - Humans
MH  - Insulin-Like Growth Factor I/pharmacology
MH  - Molecular Sequence Data
MH  - Phosphoinositide-3 Kinase Inhibitors
MH  - Phosphorylation
MH  - Phosphoserine/immunology
MH  - Phosphothreonine/immunology
MH  - Protein Processing, Post-Translational
MH  - Protein-Serine-Threonine Kinases/genetics/*metabolism
MH  - *Proto-Oncogene Proteins
MH  - Proto-Oncogene Proteins c-akt
MH  - Recombinant Proteins/metabolism
MH  - Serine/metabolism
MH  - Signal Transduction
MH  - Sirolimus/pharmacology
MH  - Threonine/metabolism
MH  - Transcription Factors/genetics/immunology/*metabolism
MH  - Wortmannin
MH  - bcl-Associated Death Protein
EDAT- 1999/06/08 00:00
MHDA- 1999/06/08 00:01
CRDT- 1999/06/08 00:00
PHST- 1999/06/08 00:00 [pubmed]
PHST- 1999/06/08 00:01 [medline]
PHST- 1999/06/08 00:00 [entrez]
AID - 10.1074/jbc.274.24.17179 [doi]
PST - ppublish
SO  - J Biol Chem. 1999 Jun 11;274(24):17179-83. doi: 10.1074/jbc.274.24.17179.