The article by Alexandra C. Newton provides an in-depth review of protein kinase C (PKC), a family of enzymes that transduce signals promoting lipid hydrolysis. PKC is activated by various signaling pathways, including G protein-coupled receptors, tyrosine kinase receptors, and non-receptor tyrosine kinases, through the production of diacylglycerol. Phorbol esters, potent tumor promoters, can also activate PKC by binding to the C1 domain, leading to prolonged activation. PKC isozymes require phosphatidylserine and, for some, Ca2+ for optimal activity. The structure of PKC is described, highlighting the conserved domains C1-C4, each with specific functions. The C1 domain binds diacylglycerol and phorbol esters, while the C2 domain binds acidic lipids and, in some isozymes, Ca2+. The catalytic core is similar to that of protein kinase A, with a high catalytic efficiency. PKC is regulated by phosphorylation and ligand binding, with the pseudosubstrate being released upon activation. Phosphatidylserine and Ca2+ increase the enzyme's affinity for membranes, and substrates can displace the pseudosubstrate. In vivo, PKC is phosphorylated at multiple sites, regulating its activity and localization. The dual regulation by phosphorylation and ligands allows for fine-tuning of PKC activity in complex signaling pathways.The article by Alexandra C. Newton provides an in-depth review of protein kinase C (PKC), a family of enzymes that transduce signals promoting lipid hydrolysis. PKC is activated by various signaling pathways, including G protein-coupled receptors, tyrosine kinase receptors, and non-receptor tyrosine kinases, through the production of diacylglycerol. Phorbol esters, potent tumor promoters, can also activate PKC by binding to the C1 domain, leading to prolonged activation. PKC isozymes require phosphatidylserine and, for some, Ca2+ for optimal activity. The structure of PKC is described, highlighting the conserved domains C1-C4, each with specific functions. The C1 domain binds diacylglycerol and phorbol esters, while the C2 domain binds acidic lipids and, in some isozymes, Ca2+. The catalytic core is similar to that of protein kinase A, with a high catalytic efficiency. PKC is regulated by phosphorylation and ligand binding, with the pseudosubstrate being released upon activation. Phosphatidylserine and Ca2+ increase the enzyme's affinity for membranes, and substrates can displace the pseudosubstrate. In vivo, PKC is phosphorylated at multiple sites, regulating its activity and localization. The dual regulation by phosphorylation and ligands allows for fine-tuning of PKC activity in complex signaling pathways.