Two Sides of the Same Coin: Protein Kinase C γ in Cancer and Neurodegeneration

Abstract

Protein kinase C (PKC) isozymes transduce myriad signals within the cell in response to the generation of second messengers from membrane phospholipids. The conventional isozyme PKCγ reversibly binds Ca2+ and diacylglycerol, which leads to an open, active conformation. PKCγ expression is typically restricted to neurons, but evidence for its expression in certain cancers has emerged. PKC isozymes have been labeled as oncogenes since the discovery that they bind tumor-promoting phorbol esters, however, studies of cancer-associated PKC mutations and clinical trial data showing that PKC inhibitors have worsened patient survival have reframed PKC as a tumor suppressor. Aberrant expression of PKCγ in certain cancers suggests a role outside the brain, although whether PKCγ also acts as a tumor suppressor remains to be established. On the other hand, PKCγ variants associated with spinocerebellar ataxia type 14 (SCA14), a neurodegenerative disorder characterized by Purkinje cell degeneration, enhance basal activity while preventing phorbol ester-mediated degradation. Although the basis for SCA14 Purkinje cell degeneration remains unknown, studies have revealed how altered PKCγ activity rewires cerebellar signaling to drive SCA14. Importantly, enhanced basal activity of SCA14-associated mutants inversely correlates with age of onset, supporting that enhanced PKCγ activity drives SCA14. Thus, PKCγ activity should likely be inhibited in SCA14, whereas restoring PKC activity should be the goal in cancer therapies. This review describes how PKCγ activity can be lost or gained in disease and the overarching need for a PKC structure as a powerful tool to predict the effect of PKCγ mutations in disease.

Mutations in protein kinase Cγ promote spinocerebellar ataxia type 14 by impairing kinase autoinhibition

“…First, a network analysis by Verbeek and colleagues ( 72 ) identified alterations in synaptic transmission as one of the main shared mechanisms underlying genetically diverse SCAs, similar to the alterations we observed in the H101Y mouse model. Second, several other genetic causes of SCA directly affect PKCγ regulation, including genes that regulate intracellular Ca 2+ and DAG ( 10 – 13 , 17 , 73 ). Increased DAG is sufficient to produce an ataxic phenotype: Shirai and colleagues ( 74 ) found that mice deficient in DAGKγ, which converts DAG into phosphatidic acid, display an ataxic phenotype.…”

“…Most of these genes encode proteins that regulate Ca 2+ homeostasis, including the inositol 1,4,5-trisphosphate (IP 3 ) receptor IP 3 R1 (SCA15, SCA16, and SCA29); ataxins 2 and 3, which regulate IP 3 R1 function (SCA2 and SCA3, respectively) (10,11); the cation channel TRPC3 (SCA41) (12); and mGluR1, which couples to phospholipase C (SCA44) (13). Spinocerebellar ataxia type 14 (SCA14) is caused by missense variants in PKC (14), a conventional PKC isozyme whose expression is restricted to neurons, particularly Purkinje cells (15)(16)(17). Given that Ca 2+ is an important activator of PKC, one intriguing theory is that enhanced PKC activity is not only central to SCA14 pathology but also at the epicenter of many other types of SCA.…”

Single-residue mutation in protein kinase C toggles between cancer and neurodegeneration

“…Mounting evidence points to cancer-associated variants in PKC generally being loss-of-function and variants present in neurodegenerative disease having gain-of-function alterations (39, 64, 65). In this study, we show that mutation of a conserved residue in the C1A domain of cPKC leads to opposing phenotypes depending on the disease context.…”

“…Gain-of-function mutations that evade downregulation are also associated with another neurodegenerative disease, spinocerebellar ataxia type-14 (SCA14). This autosomal dominant disease is caused by missense variants in PRKCG , the gene encoding PKCγ (37), and leads to cerebellar atrophy and loss of motor coordination and function (38, 39). Recent work has demonstrated that these mutants disrupt autoinhibition, leading to increased basal signaling output, yet are resistant to activator-induced degradation (9).…”

The first family case of spinocerebellar ataxia type 14 in Russia

“…В 2022 г. были описаны 2 новых фенотипа СЦА14: с клинической картиной эпизодической атаксии у пациентки с новой мутацией p.Val138Glu и комбинацией атаксии с нижним спастическим парапарезом у пациентки с мутацией в киназном домене p.Ala461Thr [8]. Предполагается, что мутации в регуляторном домене увеличивают проникновение кальция в нейроны, нарушая дефосфорилирование ПКСГ, что приводит к снижению ее аутоингибирования и деградации и, в конечном счете, к повышенной активности данного фермента [15,16]. В другом исследовании было показано, что мутации в С1-и С2-доменах способствуют формированию амилоидных фибрилл ПКСГ [17].…”