PMID- 10191262
OWN - NLM
STAT- MEDLINE
DCOM- 19990623
LR  - 20181113
IS  - 0264-6021 (Print)
IS  - 0264-6021 (Linking)
VI  - 339 ( Pt 2)
DP  - 1999 Apr 15
TI  - Activation of serum- and glucocorticoid-regulated protein kinase by agonists that
      activate phosphatidylinositide 3-kinase is mediated by
      3-phosphoinositide-dependent protein kinase-1 (PDK1) and PDK2.
PG  - 319-28
AB  - The PtdIns(3,4,5)P3-dependent activation of protein kinase B (PKB) by
      3-phosphoinositide-dependent protein kinases-1 and -2 (PDK1 and PDK2
      respectively) is a key event in mediating the effects of signals that activate
      PtdIns 3-kinase. The catalytic domain of serum- and glucocorticoid-regulated
      protein kinase (SGK) is 54% identical with that of PKB and, although lacking the 
      PtdIns(3,4, 5)P3-binding pleckstrin-homology domain, SGK retains the residues
      that are phosphorylated by PDK1 and PDK2, which are Thr256 and Ser422 in SGK.
      Here we show that PDK1 activates SGK in vitro by phosphorylating Thr256. We also 
      show that, in response to insulin-like growth factor-1 (IGF-1) or hydrogen
      peroxide, transfected SGK is activated in 293 cells via a PtdIns
      3-kinase-dependent pathway that involves the phosphorylation of Thr256 and
      Ser422. The activation of SGK by PDK1 in vitro is unaffected by PtdIns(3,4,5)P3, 
      abolished by the mutation of Ser422 to Ala, and greatly potentiated by mutation
      of Ser422 to Asp (although this mutation does not activate SGK itself).
      Consistent with these findings, the Ser422Asp mutant of SGK is activated by
      phosphorylation (probably at Thr256) in unstimulated 293 cells, and activation is
      unaffected by inhibitors of PtdIns 3-kinase. Our results are consistent with a
      model in which activation of SGK by IGF-1 or hydrogen peroxide is initiated by a 
      PtdIns(3,4, 5)P3-dependent activation of PDK2, which phosphorylates Ser422. This 
      is followed by the PtdIns(3,4,5)P3-independent phosphorylation at Thr256 that
      activates SGK, and is catalysed by PDK1. Like PKB, SGK preferentially
      phosphorylates serine and threonine residues that lie in
      Arg-Xaa-Arg-Xaa-Xaa-Ser/Thr motifs, and SGK and PKB inactivate glycogen synthase 
      kinase-3 similarly in vitro and in co-transfection experiments. These findings
      raise the possibility that some physiological roles ascribed to PKB on the basis 
      of the overexpression of constitutively active PKB mutants might be mediated by
      SGK.
FAU - Kobayashi, T
AU  - Kobayashi T
AD  - MRC Protein Phosphorylation Unit, Department of Biochemistry, University of
      Dundee, MSI/WTB Complex, Dow Street, Dundee DD1 5EH, Scotland, UK.
      tkobayashi@bad.dundee.ac.uk
FAU - Cohen, P
AU  - Cohen P
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Biochem J
JT  - The Biochemical journal
JID - 2984726R
RN  - 0 (DNA Primers)
RN  - 0 (Immediate-Early Proteins)
RN  - 0 (Nuclear Proteins)
RN  - 2ZD004190S (Threonine)
RN  - 452VLY9402 (Serine)
RN  - 67763-96-6 (Insulin-Like Growth Factor I)
RN  - BBX060AN9V (Hydrogen Peroxide)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
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 (serum-glucocorticoid regulated kinase)
SB  - IM
MH  - 3-Phosphoinositide-Dependent Protein Kinases
MH  - Amino Acid Sequence
MH  - Base Sequence
MH  - Cell Line
MH  - DNA Primers
MH  - Enzyme Activation
MH  - Humans
MH  - Hydrogen Peroxide/pharmacology
MH  - Immediate-Early Proteins
MH  - Insulin-Like Growth Factor I/pharmacology
MH  - Molecular Sequence Data
MH  - Mutagenesis, Site-Directed
MH  - *Nuclear Proteins
MH  - Phosphatidylinositol 3-Kinases/*metabolism
MH  - Phosphorylation
MH  - Protein-Serine-Threonine Kinases/chemistry/genetics/*metabolism
MH  - Serine/metabolism
MH  - Substrate Specificity
MH  - Threonine/metabolism
MH  - Transfection
PMC - PMC1220160
EDAT- 1999/04/07 00:00
MHDA- 1999/04/07 00:01
CRDT- 1999/04/07 00:00
PHST- 1999/04/07 00:00 [pubmed]
PHST- 1999/04/07 00:01 [medline]
PHST- 1999/04/07 00:00 [entrez]
PST - ppublish
SO  - Biochem J. 1999 Apr 15;339 ( Pt 2):319-28.