3'-phosphoinositide-dependent kinase-1 (PDK-1) in PI 3-kinase signaling.
The recently discovered 3'-phosphoinositide-dependent kinase-1 (PDK-1) is a serine/threonine protein kinase which phosphorylates several members of the conserved AGC kinase superfamily (comprising the prototypes protein kinases A (PKA), G (PKG) and C (PKC)). Phosphorylation of a threonine or serine residue in the activation loop (also known as the T-loop) of these kinases is a critical step in their activation, and is typically accompanied by additional phosphorylations elsewhere in the molecule. Phosphorylation of the activation loop is a common regulatory mechanism shared by most serine/threonine as well as tyrosine kinases as it facilitates alignment of amino acid residues in the active site which are involved in the phosphotransferase reaction. Therefore the discovery of PDK-1 as the enzyme which mediates this event in many protein kinases introduced a new and important step in signaling pathways which regulate numerous important cellular processes including cellular survival, glucose transport and metabolism, tumor progression as well as protein translation. Moreover, the finding that PDK-1 function is mediated in part by the phosphoinositide 3'-OH-kinase (PI 3-K) pathway also provided an explanation as to how the lipid products of PI 3-K, namely phosphatidylinositol-3,4-bisphosphate (PtdIns-3,4-P2) and phosphatidylinositol-3,4-5-trisphosphate (PtdIns-3,4,5-P3) stimulate the activation of protein kinase-dependent signaling pathways. These initial landmark observations were followed by many important studies which provided additional mechanistic insight into both PDK-1 regulation as well as the role of this kinase in cellular function. This review will focus on the regulation of PDK-1 and the various mechanisms which it uses to contribute to the activation of target kinases.
Storz
Peter
P
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA.
Toker
Alex
A
D064413:3-Phosphoinositide-Dependent Protein Kinases; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D001798:Blood Proteins / Q000737:chemistry; D008954:Models, Biological; D008969:Molecular Sequence Data; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010716:Phosphatidylinositols / Q000378:metabolism; D010750:Phosphoproteins / Q000737:chemistry; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D015398:Signal Transduction
D064413:3-Phosphoinositide-Dependent Protein Kinases; D001798:Blood Proteins; D019869:Phosphatidylinositol 3-Kinases; D010716:Phosphatidylinositols; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; C039077:platelet protein P47