Epidermal YAP drives ROCK-dependent mechanosignalling and β-catenin activation to induce keratinocyte proliferation in the mouse epidermis in vivo

B Akladios1, V Mendoza-Reinoso1, E Hardeman1, K Khosrotehrani2, B Key3, MS Samuel4 and A Beverdam1,3

  1. School of Medical Sciences - UNSW Australia
  2. UQCCR and UQDI
  3. School of Biomedical Sciences, University of Queensland
  4. CCB, SA Pathology and the University of South Australia

One in three cancers diagnosed globally is a skin cancer. Yes-associated protein (YAP) is a pivotal regulator of stem cell proliferation that is active in cancer. Mechanical force is a crucial player in the regulation of tissue homeostasis, with YAP rapidly taking the center stage as key mechanoprotein. We have generated a viable, fertile transgenic mouse model that expresses constitutively active YAP2-5SA-ΔC in basal keratinocytes. YAP2-5SA-ΔC mice display a dramatic expansion of epidermal stem cell populations. Wnt/β-catenin signalling also controls epidermal regeneration. Here we describe increased nuclear β-catenin in the hyperplastic YAP2-5SA-ΔC epidermis, and increased β-catenin transcriptional activity in the skin of live YAP2-5SA-ΔC/TOPFLASH mice. Loss of β-catenin in basal keratinocytes of YAP2-5SA-ΔC/K14-creERT/CtnnB1lox/lox mice resulted in reduced epidermal proliferation and rescue of the hyperplastic abnormalities. These data show that YAP requires β-catenin activity to drive keratinocyte proliferation. In addition, YAP2-5SA-ΔC keratinocytes displayed prominent cortical actin and increased ROCK activity. This was accompanied by increased collagen, increased expression of ECM molecules, and increased vimentin, demonstrating ECM remodelling in the YAP2-5SA-ΔC dermis. Moreover, we noticed increased phosphorylation of FAK, AKT and GSK3β in the YAP2-5SA-ΔC epidermis, showing that β-catenin is activated in response to integrin signalling due to ECM remodelling. Altogether, this work shows that YAP activates ROCK-dependent mechanosignalling in mouse skin in vivo, eventually resulting in β-catenin activation and keratinocyte proliferation. Our studies have far-reaching implications for our understanding of human cancer displaying increased YAP, β-catenin and ROCK activity.