Equivocal, explicit and emergent actions of PKC isoforms in cancer

Abstract

The maturing mutational landscape of cancer genomes, the development and application of clinical interventions, and evolving insights into tumour-associated functions, reveal unexpected features of the protein kinase C (PKC) family of serine/threonine protein kinases. These advances include recent work showing gain or loss-of-function mutations relating to driver or bystander roles, how conformational constraints and plasticity impact this class of proteins and how emergent cancerassociated properties may offer opportunities for intervention. The profound impact of the tumour microenvironment, reflected in the efficacy of immune checkpoint interventions, further prompts to incorporate PKC family actions and interventions in this eco-system, informed by insights into the control of stromal and immune cell functions. Drugging PKC isoforms has offered much promise, but the when and how is not obvious. [H1] IntroductionThe protein kinase C (PKC) family of serine/threonine protein kinases, comprising the 'classical' PKC (cPKC), 'novel' PKC (nPKC), 'atypical' PKC (aPKC) and PKN

A genetically-encoded crosslinker screen identifies SERBP1 as a PKCε substrate influencing translation and cell division

“…rotective measures are engaged extensively during cell cycle progression to ensure the integrity of genome duplication and the fidelity of the ensuing daughter cells genetic inheritance. A significant role has emerged recently for PKCε in controlling protection from chromosome nondisjunction and successful cell division 1,2 , specifically in a subset of transformed cells that fail to arrest in G2 phase in response to the Topoisomerase 2 (Topo2) inhibitor ICRF-193 3 . Studies to date indicate that PKCε exerts this role in genome protection by directly phosphorylating and switching the specificity of Aurora B 4,5 .…”

Regulation of the Phosphoinositide Code by Phosphorylation of Membrane Readers

“…PAK1 is localized to the cell periphery, where it contributes to gastric cancer progression [ 122 ] and mediates oncogenic signaling [ 123 ]. PKA is targeted to membrane compartments by A-kinase anchoring proteins [ 124 ] and is involved in tumor progression [ 125 ], while PKCs are critical enzymes for cancer intervention [ 126 ]. Targeting these kinases alters membrane recognition, with drug treatment perturbing the PIP-stops of several PX domains, as shown with Abl, BRAF-V600E and MKK1/2 kinase inhibitors [ 127 , 128 ].…”

Developments in the Discovery and Design of Protein Kinase D Inhibitors

“…[2] Insights in the role of protein kinases in cellular signal transduction mechanisms took a giant leap forward with the recognition that second messenger lipid diacylglycerol (DAG) binds and activates protein kinase C (PKC) enzymes. [3][4] Interestingly, with the discovery of the protein kinase D (PKD) family more than a decade later, it became clear that PKD's are targets for DAG as well. [1,[5][6][7][8] This led to a revision of the classical "textbook view" of signaling mechanisms, with a prominent role for the PKD's.…”

“…These studies have ultimately led to the identification of PKD as an attractive drug target [2] . Insights in the role of protein kinases in cellular signal transduction mechanisms took a giant leap forward with the recognition that second messenger lipid diacylglycerol (DAG) binds and activates protein kinase C (PKC) enzymes [3–4] . Interestingly, with the discovery of the protein kinase D (PKD) family more than a decade later, it became clear that PKD's are targets for DAG as well [1,5–8] .…”