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A Negative Regulatory Mechanism Involving 14-3-3zeta Limits Signaling Downstream of ROCK to Regulate Tissue Stiffness in Epidermal Homeostasis.

Abstract

ROCK signaling causes epidermal hyper-proliferation by increasing ECM production, elevating dermal stiffness, and enhancing Fak-mediated mechano-transduction signaling. Elevated dermal stiffness in turn causes ROCK activation, establishing mechano-reciprocity, a positive feedback loop that can promote tumors. We have identified a negative feedback mechanism that limits excessive ROCK signaling during wound healing and is lost in squamous cell carcinomas (SCCs). Signal flux through ROCK was selectively tuned down by increased levels of 14-3-3zeta, which interacted with Mypt1, a ROCK signaling antagonist. In 14-3-3zeta(-/-) mice, unrestrained ROCK signaling at wound margins elevated ECM production and reduced ECM remodeling, increasing dermal stiffness and causing rapid wound healing. Conversely, 14-3-3zeta deficiency enhanced cutaneous SCC size. Significantly, inhibiting 14-3-3zeta with a novel pharmacological agent accelerated wound healing 2-fold. Patient samples of chronic non-healing wounds overexpressed 14-3-3zeta, while cutaneous SCCs had reduced 14-3-3zeta. These results reveal a novel 14-3-3zeta-dependent mechanism that negatively regulates mechano-reciprocity, suggesting new therapeutic opportunities.

Type Journal
Authors Kular, J.; Scheer, K. G.; Pyne, N. T.; Allam, A. H.; Pollard, A. N.; Magenau, A.; Wright, R. L.; Kolesnikoff, N.; Moretti, P. A.; Wullkopf, L.; Stomski, F. C.; Cowin, A. J.; Woodcock, J. M.; Grimbaldeston, M. A.; Pitson, S. M.; Timpson, P.; Ramshaw, H. S.; Lopez, A. F.; Samuel, M. S.;
Publisher Name DEVELOPMENTAL CELL
Published Date 2015-12-21
Published Volume 35
Published Issue 6
Published Pages 759-74
Status Published in-print
URL link to publisher's version http://www.ncbi.nlm.nih.gov/pubmed/26702834
OpenAccess link to author's accepted manuscript version https://publications.gimr.garvan.org.au/open-access/13105