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.

Keywords: autoinhibition; cancer; neurodegeneration; protein kinase C; spinocerebellar ataxia.

FIGURE 1

Domain composition and structural model of PKCγ. (A) Primary structure of PKCγ, including the pseudosubstrate (PS, red), C1A and C1B (orange), C2 (yellow), kinase (cyan), and C-tail (black line). Circles indicate the priming phosphorylation sites: activation loop (pink), turn motif (orange) and hydrophobic motif (green). This structure is conserved amongst conventional PKC isozymes with a noteworthy difference is a short Pro-rich extension of the C-tail for PKCγ. (B) Domain architecture of conventional PKCs with domains labeled. Arrows indicate linker direction. (C) Hypothetical model of PKCγ structure based on the previously published model for general architecture of PKC isozymes (Jones et al., 2020; Pilo et al., 2022), showing kinase domain as cyan surface, and the C1 domains and C2 domains in ribbon representation. SCA14 mutations, represented as red spheres, are concentrated in C1B domain or interfaces with the kinase domain.

FIGURE 2

PKCγ mutations in disease lead to differing effects on kinase activity.Top: In the absence of second messengers, wild-type PKCγ adopts an autoinhibited conformation, in which no signaling occurs (water faucet is “off”). In the presence of Ca²⁺ and DG, wild-type PKCγ adopts an open conformation and is activated (water faucet is “on).Middle: Mutations in SCA14 lead to impaired autoinhibition of PKCγ resulting in “leaky activity”; mutations in the C1 domains protect PKC from down regulation, evading quality control degradation of the impaired PKC. This species can be further activated by second messenger binding for some, but not all, SCA14 mutations (not shown). Bottom: Mutations in cancer lead to loss of PKC function by diverse mechanisms. One common mechanism is by impairing autoinhibition, resulting in the dephosphorylation and degradation of PKC. Mutant PKCγ can also act in a dominant negative manner to suppress signaling by other PKC isozymes.