Regulation of Protein Kinase C Substrates in Cell Signaling

Protein Kinase C (PKC) orchestrates a wide range of cellular processes by phosphorylating specific substrates that regulate signal transduction, membrane dynamics and cytoskeletal organisation. Substrates such as the myristoylated alanine-rich C-kinase substrate (MARCKS), growth-associated protein 43 (GAP43) and brain acid-soluble protein 1 (BASP1) undergo tightly regulated cycles of phosphorylation and dephosphorylation that control their subcellular localisation, lipid interactions and downstream effector functions. Upon activation by diacylglycerol or Ca2+, PKC isoforms translocate to membrane compartments where they catalyse the addition of phosphate groups to serine or threonine residues within basic effector domains of their substrates. This modification modulates interactions with phosphatidylinositol-4,5-bisphosphate (PIP2) and actin, thereby influencing processes such as immune cell activation, neuronal growth and vascular homeostasis. Dephosphorylation by phosphatases and regulation by calcium-calmodulin binding restore substrate affinity for membranes and enable dynamic oscillations that underpin signal amplification, compartmentalisation and termination. Dysregulation of PKC-substrate interactions has been implicated in inflammatory diseases, cancer progression and neurodegeneration, highlighting their global significance and potential as therapeutic targets. Recent advances in single-molecule imaging and proteomic profiling have begun to unravel the temporal and spatial complexity of these phosphorylation cycles, offering novel insights into the mechanistic diversity of PKC-dependent signalling networks.

Research from Nature Portfolio

Recent studies have demonstrated that MARCKS acts as a crucial mediator of innate immune signalling by modulating toll-like receptor 4 pathways in macrophages. Phosphorylation of MARCKS by PKC induces its relocalisation from the plasma membrane to endosomal compartments, where it regulates cytokine production and inflammatory gene expression. Loss of MARCKS function attenuates lipopolysaccharide-stimulated release of tumour necrosis factor and interleukin-6, underscoring its role as a PKC substrate that integrates membrane trafficking with immune receptor activation. Comprehensive proteomic and metabolic analyses reveal that PKC-dependent phospho-MARCKS orchestrates specific effector responses, including reactive oxygen species production and ATP-gated ion channel activity, identifying new nodes for therapeutic intervention in inflammatory disorders.

Regulation of Protein Kinase C Substrates in Cell Signaling publication trend

The graph below shows the total number of articles in regulation of protein kinase c substrates in cell signaling across all publications each year (not limited to Nature Index journals).

Technical terms

Protein Kinase C (PKC): A family of serine/threonine kinases activated by diacylglycerol and calcium that phosphorylate target proteins to regulate cell signalling pathways.

Phosphorylation: The enzymatic addition of a phosphate group to amino acid residues, modulating protein activity, interactions and localisation.

Myristoylated Alanine-Rich C-Kinase Substrate (MARCKS): A membrane-associated PKC substrate that binds phospholipids and actin, undergoing cycles of phosphorylation-dependent translocation.

Phosphatidylinositol-4,5-Bisphosphate (PIP2): A membrane phospholipid that serves as both a signalling molecule and a docking site for proteins with basic effector domains.

Effector domain: A basic, unstructured region of a protein that mediates interactions with lipids or other proteins, often the target of PKC phosphorylation.

Calmodulin: A calcium-binding messenger protein that regulates diverse signalling proteins through calcium-dependent binding.

References

1. Marcks and Marcks-like 1 proteins promote spinal cord development and regeneration in Xenopus. eLife (2024).
2. Myristoylated, alanine-rich C-kinase substrate (MARCKS) regulates toll-like receptor 4 signaling in macrophages. Scientific Reports (2023).
3. MARCKS Inhibition Alters Bovine Neutrophil Responses to Salmonella Typhimurium. Biomedicines (2024).
4. Role for the PIP2‐binding protein myristoylated alanine‐rich C‐kinase substrate in vascular tissue: A novel therapeutic target for cardiovascular disease. Journal of Cell Communication and Signaling (2024).