Protein kinase B kinases that mediate phosphatidylinositol 3,4,5-trisphosphate-dependent activation of protein kinase B.
Protein kinase B (PKB) is activated in response to phosphoinositide 3-kinases and their lipid products phosphatidylinositol 3,4, 5-trisphosphate [PtdIns(3,4,5)P3] and PtdIns(3,4)P2 in the signaling pathways used by a wide variety of growth factors, antigens, and inflammatory stimuli. PKB is a direct target of these lipids, but this regulation is complex. The lipids can bind to the pleckstrin homologous domain of PKB, causing its translocation to the membrane, and also enable upstream, Thr308-directed kinases to phosphorylate and activate PKB. Four isoforms of these PKB kinases were purified from sheep brain. They bound PtdIns(3,4,5)P3 and associated with lipid vesicles containing it. These kinases contain an NH2-terminal catalytic domain and a COOH-terminal pleckstrin homologous domain, and their heterologous expression augments receptor activation of PKB, which suggests they are the primary signal transducers that enable PtdIns(3,4,5)P3 or PtdIns- (3,4)P2 to activate PKB and hence to control signaling pathways regulating cell survival, glucose uptake, and glycogen metabolism.
Stephens
L
L
Inositide Laboratory, The Babraham Institute, Babraham, Cambridge CB2 4AT, UK.
Anderson
K
K
Stokoe
D
D
Erdjument-Bromage
H
H
Painter
G F
GF
Holmes
A B
AB
Gaffney
P R
PR
Reese
C B
CB
McCormick
F
F
Tempst
P
P
Coadwell
J
J
Hawkins
P T
PT
D064413:3-Phosphoinositide-Dependent Protein Kinases; D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000201:enzymology; D003001:Cloning, Molecular; D018076:DNA, Complementary; D004330:Drosophila; D029721:Drosophila Proteins; D004789:Enzyme Activation; D006801:Humans; D008081:Liposomes / Q000378:metabolism; D008969:Molecular Sequence Data; D016366:Open Reading Frames; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D012756:Sheep; D015398:Signal Transduction
D018076:DNA, Complementary; D029721:Drosophila Proteins; D008081:Liposomes; D018129:Phosphatidylinositol Phosphates; D010982:Platelet-Derived Growth Factor; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; C060974:phosphatidylinositol 3,4,5-triphosphate; C060980:phosphatidylinositol 3,4-diphosphate; D064413:3-Phosphoinositide-Dependent Protein Kinases; C494917:Akt1 protein, Drosophila; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt