single C1domain in aPKC is DAG-insensitive; this group depends on other lipids or protein-protein interactions for functional regulation. Collectively, the pathway regulates cell proliferation, differentiation, polarity and death and plays a role in the cardiac, immune and nervous systems. PKC signaling is initiated downstream of ligand-activated G protein coupled receptors (GPCR) that trigger the signal transduction mediated by the Galphaq family of heterotrimeric G proteins. The Galphaq activates the beta subtype of phospholipase C (PLC; PLC-B). Other PLC subtypes can be activated downstream of receptor tyrosine kinases (RTK) with potential role in PKC activation. PLC catalyzes the hydrolysis of PIP2 to produce DAG and IP3; IP3 promotes calcium release from ER. Newly synthesized PKCs need priming for maturation - a process that involves a series of tightly controlled phosphorylation events. The Hsp90 chaperone and Cdc37co-chaperone are required for the proper processing of cPKC and nPKCs. Pdpk1 phosphorylates the activation loop of PLC, an event that is constitutive for cPKC and nPKCs but agonist dependent for aPKCs. A second phosphorylation at the turn motif, completes the maturation of PKC and is dependent on mTORC2 complex. Whether the role of mTORC2 is direct or indirect, via activation of an upstream kinase, is currently unclear. Mature, fully phosphorylated PKCs are in the cytoplasm and bound to the autoinhibitory  pseudosubstrate. Signals that release calcium facilitate recruitment to the plasma membrane followed by DAG binding or there is direct membrane recruitment via high DAG affinity. At the membrane, PKC is in an open conformation which promotes release of pseudosubstrate and binding of a variety of interactors  - adaptors or scaffolds and other binding partners and substrates, in order to fulfill many cellular tasks. The open conformation can also promotes dephosphorylation by members of PPM phosphatase family. Dephosphorylated PKC is sequestered in insoluble fraction for further dephosphorylation and subsequent degradation. However, it can also be bound by HSP70 which promotes its re-phosphorylation and re-enter into the signaling cycle. Internalization of receptors and conversion of DAG to PA by DGKs terminates signaling (not shown). Deregulation of PKC signaling pathway has been implicated in tumorigenesis and neurodegeneration. To see the Ontology Report, for annotations, GViewer and download, click here
[click to see the ontology report for related GO term - GO:0070528]...(less)