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Epidermal Growth Factor Induces Fibroblast Contractility and Motility via a Protein Kinase C δ-dependent Pathway
Journal article   Open access   Peer reviewed

Epidermal Growth Factor Induces Fibroblast Contractility and Motility via a Protein Kinase C δ-dependent Pathway

Akihiro Iwabu, Kirsty Smith, Fred D. Allen, Douglas A. Lauffenburger, Alan Wells and Keisha A Smith
The Journal of biological chemistry, v 279(15), pp 14551-14560
09 Apr 2004
DOI: https://doi.org/10.1074/jbc.M311981200
PMID: 14747473
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://doi.org/10.1074/jbc.m311981200View
Published, Version of Record (VoR)CC BY V4.0,  Open
url
https://doi.org/10.1074/jbc.M311981200View
Published, Version of Record (VoR) Open

Abstract

Myosin-based cell contractile force is considered to be a critical process in cell motility. However, for epidermal growth factor (EGF)-induced fibroblast migration, molecular links between EGF receptor (EGFR) activation and force generation have not been clarified. Herein, we demonstrate that EGF stimulation increases myosin light chain (MLC) phosphorylation, a marker for contractile force, concomitant with protein kinase C (PKC) activity in mouse fibroblasts expressing human EGFR constructs. Interestingly, PKCδ is the most strongly phosphorylated isoform, and the preferential PKCδ inhibitor rottlerin largely prevented EGF-induced phosphorylation of PKC substrates and MARCKS. The pathway through which EGFR activates PKCδ is suggested by the fact that the MEK-1 inhibitor U0126 and the phosphatidylinositol 3-kinase inhibitor LY294002 had no effect on PKCδ activation, whereas lack of PLCγ signaling resulted in delayed PKCδ activation. EGF-enhanced MLC phosphorylation was prevented by a specific MLC kinase inhibitor ML-7 and the PKC inhibitors chelerythrine chloride and rottlerin. Further indicating that PKCδ is required, a dominant-negative PKCδ construct or RNAi-mediated PKCδ depletion also prevented MLC phosphorylation. In the absence of PLC signaling, MLC phosphorylation and cell force generation were delayed similarly to PKCδ activation. All of the interventions that blocked PKCδ activation or MLC phosphorylation abrogated EGF-induced cell contractile force generation and motility. Our results suggest that PKCδ activation is responsible for a major part of EGF-induced fibroblast contractile force generation. Hence, we identify here a new pathway helping to govern cell motility, with PLC signaling playing a role in activation of PKCδ to promote the acute phase of EGF-induced MLC activation.

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124 citations in Web of Science
120 citations in Scopus

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Collaboration types
Domestic collaboration
Web of Science research areas
Biochemistry & Molecular Biology
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