Calmodulin activates phosphatidylinositol 3-kinase.
Calmodulin and phosphatidylinositol 3-kinase are vital components of a number of common intracellular events. Calmodulin, a ubiquitous Ca2+-dependent effector protein, regulates multiple processes in eukaryotic cells, including cytoskeletal organization, vesicular trafficking, and mitogenesis. Phosphatidylinositol 3-kinase participates in events downstream of the receptors for insulin and other growth factors. Here we demonstrate by coimmunoprecipitation and affinity chromatography that Ca2+/calmodulin associates with Src homology 2 domains in the 85-kDa regulatory subunit of phosphatidylinositol 3-kinase, thereby significantly enhancing phosphatidylinositol 3-kinase activity in vitro and in intact cells. Furthermore, CGS9343B, a calmodulin antagonist, inhibited basal and Ca2+-stimulated phosphorylation of phosphatidylinositol in intact cells. These data demonstrate a novel mechanism for modulating phosphatidylinositol 3-kinase and provide a direct link between components of two fundamental signaling pathways.
Joyal
J L
JL
Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Burks
D J
DJ
Pons
S
S
Matter
W F
WF
Vlahos
C J
CJ
White
M F
MF
Sacks
D B
DB
D000818:Animals; D000930:Antidiarrheals / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology; D002147:Calmodulin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D002867:Chromones / Q000494:pharmacology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D015398:Signal Transduction; D018411:Spodoptera; D020764:cdc42 GTP-Binding Protein; D020703:ras GTPase-Activating Proteins
D000930:Antidiarrheals; D001562:Benzimidazoles; D002147:Calmodulin; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D002867:Chromones; D004791:Enzyme Inhibitors; C101203:IQ motif containing GTPase activating protein 1; D009025:Morpholines; D020703:ras GTPase-Activating Proteins; C052087:CGS 9343B; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D019869:Phosphatidylinositol 3-Kinases; D019204:GTP-Binding Proteins; D020764:cdc42 GTP-Binding Protein