Dissecting the role of the 3-phosphoinositide-dependent protein kinase-1 (PDK1) signalling pathways.
The 3-phosphoinositide-dependent protein kinase-1 (PDK1) mediates the cellular effect of insulin and growth factors by activating a group of kinases including PKB/Akt, S6K, RSK, SGK and PKC isoforms. PDK1 possesses two regulatory domains namely a Pleckstrin Homology (PH) domain that binds to the phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P(3)] second messenger, and a substrate binding site termed the PIF-pocket. Employing a combination of biochemical, structural and mouse knock-in approaches we have been able to define the roles that the regulatory domains on PDK1 play. We have established that binding of PDK1 to PtdIns(3,4,5)P(3) is essential for efficient activation of PKB isoforms as well as for maintaining normal cell size and insulin sensitivity. In contrast, the PIF-substrate binding pocket of PDK1 is not required for PKB activation, but is necessary for PDK1 to activate all of its other substrates.
Bayascas
Jose R
JR
Institut de Neurociències & Departament de Bioquiacute;mica i Biologia Molecular, Universitat Autònoma de Barcelona, Barcelona, Spain. joseramon.bayascas@uab.cat
D064413:3-Phosphoinositide-Dependent Protein Kinases; D000818:Animals; D001665:Binding Sites; D007333:Insulin Resistance; D051379:Mice; D010641:Phenotype; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D015398:Signal Transduction
D018129:Phosphatidylinositol Phosphates; D020033:Protein Isoforms; C060974:phosphatidylinositol 3,4,5-triphosphate; D064413:3-Phosphoinositide-Dependent Protein Kinases; C578564:Pdpk1 protein, mouse; D017346:Protein Serine-Threonine Kinases