1. A Negative Regulatory Mechanism Involving 14-3-3ζ Limits Signaling Downstream of ROCK to Regulate Tissue Stiffness in Epidermal Homeostasis
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Paul Timpson, Kaitlin G. Scheer, Lena Wullkopf, Stuart M. Pitson, Natasha Kolesnikoff, Frank C. Stomski, Michael S. Samuel, Jasreen Kular, Amr H. Allam, Joanna M. Woodcock, Anthony N. Pollard, Rebecca L. Wright, Paul A.B. Moretti, Angel F. Lopez, Hayley S. Ramshaw, Allison J. Cowin, Natasha T. Pyne, Michele A. Grimbaldeston, Astrid Magenau, Kular, Jasreen, Scheer, Kaitlin G, Pyne, Natasha T, Allam, Amr H, Pollard, Anthony N., Magenau, Astrid, Wright, Rebecca L, Kolesnikoff, Natasha, Moretti, Paul A, Wullkopf, Lena, Stomski, Frank C, Cowin, Allison J, Woodcock, Joanna M, Grimbaldeston, Michele A, Pitson, Stuart M, Timpson, Paul, Ramshaw, Hayley S, Lopez, Angel F, and Samuel, Michael S
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RHOA ,Cell ,RhoC ,wound healing ,General Biochemistry, Genetics and Molecular Biology ,mechano-transduction ,14-3-3ζ ,MYPT ,Mice ,ROCK ,medicine ,Animals ,Homeostasis ,re-epithelialization ,Molecular Biology ,Cell Proliferation ,rho-Associated Kinases ,biology ,Epidermis (botany) ,integumentary system ,Cell growth ,RhoA ,Anatomy ,Cell Biology ,Cell biology ,medicine.anatomical_structure ,14-3-3 Proteins ,biology.protein ,mechano-reciprocity ,Signal transduction ,Epidermis ,Wound healing ,Signal Transduction ,Developmental Biology - Abstract
ROCK signaling causes epidermal hyper-proliferation by increasing ECM production, elevating dermal stiffness, and enhancing Fak-mediated mechanotransduction 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 14-3-3 zeta, which interacted with Mypt1, a ROCK signaling antagonist. In 14-3-3 zeta(-/-) mice, unrestrained ROCK signaling at wound margins elevated ECM production and reduced ECM remodeling, increasing dermal stiffness and causing rapid wound healing. Conversely, 14-3-3 zeta deficiency enhanced cutaneous SCC size. Significantly, inhibiting 14-33 zeta with a novel pharmacological agent accelerated wound healing 2-fold. Patient samples of chronic non-healing wounds overexpressed 14-3-3 zeta, while cutaneous SCCs had reduced 14-3-3 zeta. These results reveal a novel 14-3-3 zeta-dependent mechanism that negatively regulates mechano-reciprocity, suggesting new therapeutic opportunities. Refereed/Peer-reviewed
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