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1. J Biol Chem. 2018 Oct 15. pii: jbc.RA118.004020. doi: 10.1074/jbc.RA118.004020.

[Epub ahead of print]

Assembly of fibronectin fibrils selectively attenuates platelet-derived growth


factor-induced intracellular calcium release in fibroblasts.

Farrar CS(1), Hocking DC(2).

Author information:
(1)University of Rochester, United States.
(2)Pharmacology and Physiology, University of Rochester, United States.

Cellular responses to platelet-derived growth factor (PDGF) are altered in a


variety of pathological conditions, including cancers, fibroses, and vascular
diseases, making PDGF-induced signaling pathways important therapeutic targets.
The limited success of therapies designed to impact PDGF pathways may be overcome
with a clearer understanding of how cells integrate signals from PDGF and the
extracellular matrix (ECM). Here, we assessed the effects of fibronectin matrix
assembly on the responsiveness of mesenchymal cells to PDGF. Our results indicate
that fibroblast-mediated assembly of fibronectin fibrils attenuates intracellular
calcium release in response to PDGF. The dose-dependent inhibition of
PDGF-induced intracellular calcium release was specific to the ECM form of
fibronectin. Further, a recombinant protein engineered to mimic ECM fibronectin
similarly attenuated intracellular calcium release in response to PDGF. Of note,
fibronectin attenuated the PDGF-calcium signaling axis at the level of
phosphoinositide 3-kinase (PI3K) activation. Interestingly, ECM fibronectin did
not alter other intracellular signals activated by PDGF, including activation of
PDGF receptor β, AKT Ser/Thr kinase, phospholipase Cγ1, and extracellular
signal-regulated kinase 1/2 (ERK1/2). Rather, fibronectin inhibited activation of
the p55 regulatory subunit of PI3K in response to a variety of stimuli,
indicating that ECM fibronectin selectively attenuates the intracellular calcium
release cascade while leaving intact other PDGF signaling pathways. Selective
regulation of calcium signaling by ECM fibronectin via the p55 regulatory subunit
of PI3K represents a mechanism by which cells tune their response to PDGF and may
therefore serve as a target to selectively regulate one branch of PDGF signaling.

Published under license by The American Society for Biochemistry and Molecular
Biology, Inc.

DOI: 10.1074/jbc.RA118.004020
PMID: 30323067