3-Phosphoinositide-Dependent Protein Kinase is a Switchboard from Signaling Lipids to Protein Phosphorylation Cascades

Abstract

While signal perception relies on local assembly of receptor complexes from proteins that have slow diffusion kinetics, signal propagation within cells often depend on more freely diffusible second messenger molecules, such as Ca²⁺, reactive oxygen species, nitric oxide within the cytoplasm, or signaling phospholipids that move only in two dimensions within lipid bilayers. These signaling systems are typically composed of the signal-dependent production of second messenger molecules with spatial and temporal dynamics and the availability of sensors that bind these molecules and decode the information. Lipid binding can activate enzymes or can recruit proteins to membranes via distinct lipid-binding domains, where the local increase in their concentration promotes interactions and downstream signaling. One such characterized downstream signaling component is the 3′-phosphoinositide-dependent kinase-1 (PDK1), that in plants, through its lipid-binding PH domain interacts and is activated by the phospholipids: phosphatidic acid and PI(4,5)P₂. PDK1 is a master kinase that supervises a number of downstream protein kinases belonging to the protein kinase A, cGMP-activated kinase, and protein kinase C family (AGC kinases). These kinases typically possess a C-terminal hydrophobic motif that serves as a docking site for PDK1 to enable the phosphorylation of these kinases by PDK1 at their activation loop. These downstream kinases than can regulate a number of cellular processes, such as the localisation of auxin efflux carriers, the PINs by the pinoid kinase (PID), ROS signaling (OX1), regulation of cell death in pathogen response (ADI3), or regulation of growth and protein translation, the ribosomal S6 kinase (S6K).