Protein kinase C (PKC) is a family of phospholipid-dependent serine/threonine kinases, which can be further classified into three PKC isozymes subfamilies: conventional or classic, novel or nonclassic, and atypical. PKC isozymes are known to be involved in cell proliferation, survival, invasion, migration, apoptosis, angiogenesis, and drug resistance. Because of their key roles in cell signaling, PKC isozymes also have the potential to be promising therapeutic targets for several diseases, such as cardiovascular diseases, immune and inflammatory diseases, neurological diseases, metabolic disorders, and multiple types of cancer. This review primarily focuses on the activation, mechanism, and function of PKC isozymes during cancer development and progression. 1. Introduction Protein kinase C (PKC) is a family of phospholipid-dependent serine/threonine kinases that function in numerous different cell types. Based on their structural and activation characteristics, this protein family can be further classified into three subfamilies: conventional or classic PKC isozymes (cPKCs; α, βI, βII, and γ), novel or nonclassic PKC isozymes (nPKCs; δ, ε, η, and θ), and atypical PKC isozymes (aPKCs; ζ, ι, and λ). The activation of cPKCs requires diacylglycerol (DAG) as the primary activator along with phosphatidylserine (PS) and calcium (Ca2+) as cofactors of activation. The nPKCs are also regulated by DAG and PS but do not require Ca2+ for activation. In the case of aPKCs, their activity is stimulated only by PS and not by DAG and Ca2+ [1, 2]. PKC isozymes are involved in multiple signal transduction systems that respond to a variety of external stimulators, including hormones, growth factors, and other membrane receptor ligands. For this reason, PKC isozymes can act as therapeutic targets for several diseases, such as cardiovascular diseases (e.g., atherosclerosis, myocardial fibrosis, cardiac hypertrophy, and hypertension) (for reviews, see [3, 4]), immune and inflammatory diseases (e.g., asthma, arthritis, and hepatitis) [5, 6], neurological diseases (e.g., Alzheimer’s disease and bipolar disorder) [7, 8], and metabolic disorders (e.g., obesity, insulin resistance, hyperglycemia, and hypercholesterolemia) [9–11]. Further, significant work has also explored the activation, mechanism, and function of PKC isozymes in the development and progression of multiple types of cancer, which will be the primary focus of this review. 2. PKC Isozymes and Their Target Proteins There are five consensus phosphorylation site motifs recognized by PKC isozymes, each of which has an
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