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

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

Author information

1
Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, North Carolina.
2
Biomathematics Graduate Program, North Carolina State University, Raleigh, North Carolina.
3
Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
4
Department of Cell Biology and Physiology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
5
Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, North Carolina. Electronic address: jason_haugh@ncsu.edu.

Abstract

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.

PMID:
28700916
PMCID:
PMC5510763
DOI:
10.1016/j.bpj.2017.05.035
[Indexed for MEDLINE]
Free PMC Article

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