catalytic region that is essential to the viability of the kinase is its phosphorylation. The conventional and novel PKCs have three phosphorylation sites, termed: the activation loop, the turn motif, and the hydrophobic motif. The atypical PKCs are phosphorylated only on the activation loop and the turn motif. Phosphorylation of the hydrophobic motif is rendered unnecessary by the presence of a glutamic acid in place of a serine, which, as a negative charge, acts similar in manner to a phosphorylated residue. These phosphorylation events are essential for the activity of the enzyme, and 3-phosphoinositide-dependent protein kinase-1 (PDPK1) is the upstream kinase responsible for initiating the process by transphosphorylation of the activation loop. The consensus sequence of protein kinase C enzymes is similar to that of protein kinase A, since it contains basic amino acids close to the Ser/Thr to be phosphorylated. Their substrates are, e.g., MARCKS proteins, MAP kinase, transcription factor inhibitor IκB, the vitamin D3 receptor VDR, Raf kinase, calpain, and the epidermal growth factor receptor. Activation Upon activation, protein kinase C enzymes are translocated to the plasma membrane by RACK proteins (membrane-bound receptor for activated protein kinase C proteins). The protein kinase C enzymes are known for their long-term activation: They remain activated after the original activation signal or the Ca2+-wave is gone. It is presumed that this is achieved by the production of diacylglycerol from phosphatidylinositol by a phospholipase; fatty acids may also play a role in long-term activation. A critical part of PKC activation is translocation to the cell membrane. Interestingly, this process is disrupted in microgravity, which causes immunodeficiency of astronauts. Function A multiplicity of functions have been ascribed to PKC. Recurring themes are that PKC is involved in receptor desensitization, in modulating membrane structure events, in regulating transcription, in mediating immune responses, in regulating cell growth, and in learning and memory. These functions are achieved by PKC-mediated phosphorylation of other proteins. PKC plays an important role in the immune system through phosphorylation of CARD-CC family proteins and subsequent NF-κB activation. However, the substrate proteins present for phosphorylation vary, since protein expression is different between different kinds of cells. Thus, effects of PKC are cell-type-specific: Pathology Protein kinase C, activated by tumor promoter phorbol ester, may phosphorylate potent activators of transcription, and thus lead to increased expression of oncogenes, promoting cancer progression, or interfere with other phenomena. Prolonged exposure to phorbol ester, however, promotes the