A Reaction-Diffusion Model Explains Amplification of the PLC/PKC Pathway in Fibroblast Chemotaxis

Biophys J. 2017 Jul 11;113(1):185-194. doi: 10.1016/j.bpj.2017.05.035.


During the proliferative phase of cutaneous wound healing, dermal fibroblasts are recruited into the clotted wound by a concentration gradient of platelet-derived growth factor (PDGF), together with other spatial cues. Despite the importance of this chemotactic process, the mechanisms controlling the directed migration of slow-moving mesenchymal cells such as fibroblasts are not well understood. Here, we develop and analyze a reaction-diffusion model of phospholipase C/protein kinase C (PKC) signaling, which was recently identified as a requisite PDGF-gradient-sensing pathway, with the goal of identifying mechanisms that can amplify its sensitivity in the shallow external gradients typical of chemotaxis experiments. We show that phosphorylation of myristoylated alanine-rich C kinase substrate by membrane-localized PKC constitutes a positive feedback that is sufficient for local pathway amplification. The release of phosphorylated myristoylated alanine-rich C kinase substrate and its subsequent diffusion and dephosphorylation in the cytosol also serves to suppress the pathway in down-gradient regions of the cell. By itself, this mechanism only weakly amplifies signaling in a shallow PDGF gradient, but it synergizes with other feedback mechanisms to enhance amplification. This model offers a framework for a mechanistic understanding of phospholipase C/PKC signaling in chemotactic gradient sensing and can guide the design of experiments to assess the roles of putative feedback loops.

MeSH terms

  • Animals
  • Cell Membrane / metabolism
  • Chemotaxis / physiology*
  • Diffusion
  • Feedback, Physiological / physiology
  • Fibroblasts / enzymology*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Membrane Proteins / metabolism
  • Models, Biological*
  • Myristoylated Alanine-Rich C Kinase Substrate
  • Phosphorylation
  • Platelet-Derived Growth Factor / metabolism
  • Protein Kinase C / metabolism*
  • Signal Transduction / physiology
  • Type C Phospholipases / metabolism*


  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Platelet-Derived Growth Factor
  • Myristoylated Alanine-Rich C Kinase Substrate
  • Protein Kinase C
  • Type C Phospholipases