The PI3K–PDK1 connection: more than just a road to PKB Phosphoinositide 3-kinases (PI3Ks) generate specific inositol lipids that regulate cell growth, proliferation, survival, differentiation, and cytoskeletal changes. One of the best characterized targets of PI3K lipid products is the protein kinase Akt or protein kinase B (PKB). In quiescent cells, PKB resides in the cytosol in a low-activity conformation. Upon cellular stimulation, PKB is activated through recruitment to cellular membranes by PI3K lipid products and phosphorylation by 3'-phosphoinositide-dependent kinase-1 (PDK1). This review discusses the mechanism by which PKB is activated and the evidence that PDK1 may be involved in the activation of protein kinases other than PKB, the mechanisms by which this activity of PDK1 could be regulated, and the possibility that some of the currently postulated PKB substrates might be phosphorylated by PDK1-regulated kinases other than PKB. PI3Ks generate the activating signals for PKB by producing specific inositol phospholipids, such as PtdIns(3,4)P2 and PtdIns(3,4,5)P3, which are recognized by PH domains of PKB. These lipids are crucial for the activation of PKB. Class I PI3Ks, which are heterodimers consisting of a catalytic subunit (p110) and an adaptor/regulatory subunit, are the main PI3Ks that activate PKB in cells. They bind to the monomeric G-protein Ras, but the physiological significance of this interaction is not entirely clear. PH domains are globular protein domains found in over 150 proteins. Some PH domains bind phospholipids with high affinity. Residues in PH domains essential for high-affinity binding to PIs have been identified. These residues lie at the N-terminus, in a KX7-13R/KXR motif. The basic amino acids in this motif direct interactions with the inositol phosphate groups of PIs. PH domains that lack these residues bind PIs with low affinity. PKB is a 57 kDa Ser/Thr kinase with a PH domain that preferentially binds PtdIns(3,4,5)P3 and PtdIns(3,4)P2 over other PIs. Mammals have three closely related PKB genes, encoding the isoforms PKBα, PKBβ, and PKBγ. PKBα, PKBβ, and PKBγ show high amino acid identity with each other. All PKB isoforms show a broad tissue distribution and consist of an N-terminal PH domain, a kinase domain, and a C-terminal regulatory tail.The PI3K–PDK1 connection: more than just a road to PKB Phosphoinositide 3-kinases (PI3Ks) generate specific inositol lipids that regulate cell growth, proliferation, survival, differentiation, and cytoskeletal changes. One of the best characterized targets of PI3K lipid products is the protein kinase Akt or protein kinase B (PKB). In quiescent cells, PKB resides in the cytosol in a low-activity conformation. Upon cellular stimulation, PKB is activated through recruitment to cellular membranes by PI3K lipid products and phosphorylation by 3'-phosphoinositide-dependent kinase-1 (PDK1). This review discusses the mechanism by which PKB is activated and the evidence that PDK1 may be involved in the activation of protein kinases other than PKB, the mechanisms by which this activity of PDK1 could be regulated, and the possibility that some of the currently postulated PKB substrates might be phosphorylated by PDK1-regulated kinases other than PKB. PI3Ks generate the activating signals for PKB by producing specific inositol phospholipids, such as PtdIns(3,4)P2 and PtdIns(3,4,5)P3, which are recognized by PH domains of PKB. These lipids are crucial for the activation of PKB. Class I PI3Ks, which are heterodimers consisting of a catalytic subunit (p110) and an adaptor/regulatory subunit, are the main PI3Ks that activate PKB in cells. They bind to the monomeric G-protein Ras, but the physiological significance of this interaction is not entirely clear. PH domains are globular protein domains found in over 150 proteins. Some PH domains bind phospholipids with high affinity. Residues in PH domains essential for high-affinity binding to PIs have been identified. These residues lie at the N-terminus, in a KX7-13R/KXR motif. The basic amino acids in this motif direct interactions with the inositol phosphate groups of PIs. PH domains that lack these residues bind PIs with low affinity. PKB is a 57 kDa Ser/Thr kinase with a PH domain that preferentially binds PtdIns(3,4,5)P3 and PtdIns(3,4)P2 over other PIs. Mammals have three closely related PKB genes, encoding the isoforms PKBα, PKBβ, and PKBγ. PKBα, PKBβ, and PKBγ show high amino acid identity with each other. All PKB isoforms show a broad tissue distribution and consist of an N-terminal PH domain, a kinase domain, and a C-terminal regulatory tail.