title: A Negative Regulatory Mechanism Involving 14-3-3ζ 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 14-3-3ζ, 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.
authors.affiliation: Centre for Cancer Biology, SA Pathology and the University of South Australia, Frome Road, Adelaide 5000, Australia.
authors.forename: Jasreen
authors.initials: J
authors.lastname: Kular
authors.affiliation: Centre for Cancer Biology, SA Pathology and the University of South Australia, Frome Road, Adelaide 5000, Australia.
authors.forename: Kaitlin G
authors.initials: KG
authors.lastname: Scheer
authors.affiliation: Centre for Cancer Biology, SA Pathology and the University of South Australia, Frome Road, Adelaide 5000, Australia.
authors.forename: Natasha T
authors.initials: NT
authors.lastname: Pyne
authors.affiliation: The Kinghorn Cancer Centre & Garvan Institute of Medical Research and St. Vincent's Clinical School, Victoria Street, Darlinghurst, NSW 2010, Australia.
authors.forename: Amr H
authors.initials: AH
authors.lastname: Allam
authors.affiliation: Centre for Cancer Biology, SA Pathology and the University of South Australia, Frome Road, Adelaide 5000, Australia.
authors.forename: Anthony N
authors.initials: AN
authors.lastname: Pollard
authors.affiliation: The Kinghorn Cancer Centre & Garvan Institute of Medical Research and St. Vincent's Clinical School, Victoria Street, Darlinghurst, NSW 2010, Australia.
authors.forename: Astrid
authors.initials: A
authors.lastname: Magenau
authors.affiliation: Centre for Cancer Biology, SA Pathology and the University of South Australia, Frome Road, Adelaide 5000, Australia.
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Wright
authors.affiliation: Centre for Cancer Biology, SA Pathology and the University of South Australia, Frome Road, Adelaide 5000, Australia.
authors.forename: Natasha
authors.initials: N
authors.lastname: Kolesnikoff
authors.affiliation: Centre for Cancer Biology, SA Pathology and the University of South Australia, Frome Road, Adelaide 5000, Australia.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Moretti
authors.affiliation: The Kinghorn Cancer Centre & Garvan Institute of Medical Research and St. Vincent's Clinical School, Victoria Street, Darlinghurst, NSW 2010, Australia.
authors.forename: Lena
authors.initials: L
authors.lastname: Wullkopf
authors.affiliation: Centre for Cancer Biology, SA Pathology and the University of South Australia, Frome Road, Adelaide 5000, Australia.
authors.forename: Frank C
authors.initials: FC
authors.lastname: Stomski
authors.affiliation: Future Industries Institute, University of South Australia, Mawson Lakes 5095, Australia.
authors.forename: Allison J
authors.initials: AJ
authors.lastname: Cowin
authors.affiliation: Centre for Cancer Biology, SA Pathology and the University of South Australia, Frome Road, Adelaide 5000, Australia.
authors.forename: Joanna M
authors.initials: JM
authors.lastname: Woodcock
authors.affiliation: 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.
authors.forename: Michele A
authors.initials: MA
authors.lastname: Grimbaldeston
authors.affiliation: 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.
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Pitson
authors.affiliation: The Kinghorn Cancer Centre & Garvan Institute of Medical Research and St. Vincent's Clinical School, Victoria Street, Darlinghurst, NSW 2010, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Timpson
authors.affiliation: 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.
authors.forename: Hayley S
authors.initials: HS
authors.lastname: Ramshaw
authors.affiliation: 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.
authors.forename: Angel F
authors.initials: AF
authors.lastname: Lopez
authors.affiliation: 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.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Samuel
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism*; D000818:Animals; D049109:Cell Proliferation / Q000502:physiology*; D004817:Epidermis / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology*; D051379:Mice; D015398:Signal Transduction / Q000502:physiology*; D014945:Wound Healing / Q000502:physiology*; D054460:rho-Associated Kinases / Q000378:metabolism*
chemical_list: D048948:14-3-3 Proteins; D054460:rho-Associated Kinases
keywords: 14-3-3ζ; MYPT; ROCK; RhoA; RhoC; mechano-reciprocity; mechano-transduction; re-epithelialization; wound healing