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

作者：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; Samuel Michael S^*

来源：Developmental Cell, 2015, 35(6): 759-774.

DOI：10.1016/j.devcel.2015.11.026

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.

• 出版日期2015-12-21
• 单位河北医科大学