Issue 4, 2021

Targeted disruption of PKC from AKAP signaling complexes

Abstract

Protein Kinase C (PKC) is a member of the AGC subfamily of kinases and regulates a wide array of signaling pathways and physiological processes. Protein–protein interactions involving PKC and its scaffolding partners dictate the spatiotemporal dynamics of PKC activity, including its access to activating second messenger molecules and potential substrates. While the A Kinase Anchoring Protein (AKAP) family of scaffold proteins universally bind PKA, several were also found to scaffold PKC, thereby serving to tune its catalytic output. Targeting these scaffolding interactions can further shed light on the effect of subcellular compartmentalization on PKC signaling. Here we report the development of two hydrocarbon stapled peptides, CSTAD5 and CSTAD6, that are cell permeable and bind PKC to disrupt PKCgravin complex formation in cells. Both constrained peptides downregulate PMA-induced cytoskeletal remodeling that is mediated by the PKCgravin complex as measured by cell rounding. Further, these peptides downregulate PKC substrate phosphorylation and cell motility. To the best of our knowledge, no PKC-selective AKAP disruptors have previously been reported and thus CSTAD5 and CSTAD6 are novel disruptors of PKC scaffolding by AKAPs and may serve as powerful tools for dissecting AKAP-localized PKC signaling.

Graphical abstract: Targeted disruption of PKC from AKAP signaling complexes

Supplementary files

Article information

Article type
Communication
Submitted
12 May 2021
Accepted
16 Jul 2021
First published
19 Jul 2021
This article is Open Access
Creative Commons BY-NC license

RSC Chem. Biol., 2021,2, 1227-1231

Targeted disruption of PKC from AKAP signaling complexes

A. J. Limaye, G. N. Bendzunas and E. J. Kennedy, RSC Chem. Biol., 2021, 2, 1227 DOI: 10.1039/D1CB00106J

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