Dual role of phosphatidylinositol-3,4,5-trisphosphate in the activation of protein kinase B.
Protein kinase B (PKB) is a proto-oncogene that is activated in signaling pathways initiated by phosphoinositide 3-kinase. Chromatographic separation of brain cytosol revealed a kinase activity that phosphorylated and activated PKB only in the presence of phosphatidylinositol-3,4,5-trisphosphate [PtdIns(3,4,5)P3]. Phosphorylation occurred exclusively on threonine-308, a residue implicated in activation of PKB in vivo. PtdIns(3,4,5)P3 was determined to have a dual role: Its binding to the pleckstrin homology domain of PKB was required to allow phosphorylation by the upstream kinase and it directly activated the upstream kinase.
Stokoe
D
D
Onyx Pharmaceuticals, 3031 Research Drive, Richmond, CA 94806, USA. stokoe@cc.ucsf.edu
Stephens
L R
LR
Copeland
T
T
Gaffney
P R
PR
Reese
C B
CB
Painter
G F
GF
Holmes
A B
AB
McCormick
F
F
Hawkins
P T
PT
D064413:3-Phosphoinositide-Dependent Protein Kinases; D000255:Adenosine Triphosphate / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001798:Blood Proteins / Q000737:chemistry; D001921:Brain / Q000201:enzymology; D019556:COS Cells; D003600:Cytosol / Q000201:enzymology; D004789:Enzyme Activation; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D010750:Phosphoproteins; D010766:Phosphorylation; D010769:Phosphothreonine / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013237:Stereoisomerism
D001798:Blood Proteins; C000715470:MAS1 protein, human; D018129:Phosphatidylinositol Phosphates; D010750:Phosphoproteins; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; C060974:phosphatidylinositol 3,4,5-triphosphate; C039077:platelet protein P47; D010769:Phosphothreonine; D000255:Adenosine Triphosphate; D064413:3-Phosphoinositide-Dependent Protein Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt