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

Jasreen Kular; Kaitlin G Scheer; Natasha T Pyne; Amr H Allam; Anthony N Pollard; Astrid Magenau; Rebecca L Wright; Natasha Kolesnikoff; Paul A Moretti; Lena Wullkopf; Frank C Stomski; Allison J Cowin; Joanna M Woodcock; Michele A Grimbaldeston; Stuart M Pitson; Paul Timpson; Hayley S Ramshaw; Angel F Lopez; Michael S Samuel

doi:10.1016/j.devcel.2015.11.026

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

Dev Cell. 2015 Dec 21;35(6):759-74. doi: 10.1016/j.devcel.2015.11.026.

Authors

Jasreen Kular¹, Kaitlin G Scheer¹, Natasha T Pyne¹, Amr H Allam², Anthony N Pollard¹, Astrid Magenau², Rebecca L Wright¹, Natasha Kolesnikoff¹, Paul A Moretti¹, Lena Wullkopf², Frank C Stomski¹, Allison J Cowin³, Joanna M Woodcock¹, Michele A Grimbaldeston⁴, Stuart M Pitson⁴, Paul Timpson², Hayley S Ramshaw⁴, Angel F Lopez⁴, Michael S Samuel⁵

Affiliations

¹ Centre for Cancer Biology, SA Pathology and the University of South Australia, Frome Road, Adelaide 5000, Australia.
² The Kinghorn Cancer Centre & Garvan Institute of Medical Research and St. Vincent's Clinical School, Victoria Street, Darlinghurst, NSW 2010, Australia.
³ Future Industries Institute, University of South Australia, Mawson Lakes 5095, Australia.
⁴ Centre for Cancer Biology, SA Pathology and the University of South Australia, Frome Road, Adelaide 5000, Australia; Faculty of Health Sciences, School of Medicine, University of Adelaide, Adelaide 5000, Australia.
⁵ Centre for Cancer Biology, SA Pathology and the University of South Australia, Frome Road, Adelaide 5000, Australia; Faculty of Health Sciences, School of Medicine, University of Adelaide, Adelaide 5000, Australia. Electronic address: michael.samuel@unisa.edu.au.

PMID: 26702834
DOI: 10.1016/j.devcel.2015.11.026

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 14-3-3ζ, which interacted with Mypt1, a ROCK signaling antagonist. In 14-3-3ζ(-/-) mice, unrestrained ROCK signaling at wound margins elevated ECM production and reduced ECM remodeling, increasing dermal stiffness and causing rapid wound healing. Conversely, 14-3-3ζ deficiency enhanced cutaneous SCC size. Significantly, inhibiting 14-3-3ζ with a novel pharmacological agent accelerated wound healing 2-fold. Patient samples of chronic non-healing wounds overexpressed 14-3-3ζ, while cutaneous SCCs had reduced 14-3-3ζ. These results reveal a novel 14-3-3ζ-dependent mechanism that negatively regulates mechano-reciprocity, suggesting new therapeutic opportunities.

Keywords: 14-3-3ζ; MYPT; ROCK; RhoA; RhoC; mechano-reciprocity; mechano-transduction; re-epithelialization; wound healing.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

14-3-3 Proteins / metabolism*
Animals
Cell Proliferation / physiology*
Epidermis / metabolism
Homeostasis / physiology*
Mice
Signal Transduction / physiology*
Wound Healing / physiology*
rho-Associated Kinases / metabolism*

Substances

14-3-3 Proteins
rho-Associated Kinases