Delayed Re-epithelialization in Ppm1a Gene-deficient Mice Is Mediated by Enhanced Activation of Smad2

• DOI: 10.1074/jbc.m111.292284
• Publication Date: 2011-10-12T00:28:56Z
• Authors: Xue Yang; Yan Teng; Ning Hou; Xiongwei Fan; Xuan Cheng; Jun Li; Lijuan Wang; Youliang Wang; Xiushan Wu; Xiao Yang
• Keywords: Keratinocytes; Mice, Knockout; Integrins; Wound Healing; 0303 health sciences; Genotype; Models, Genetic; Mice, Transgenic; Smad2 Protein; Protein Phosphatase 2C; Mice; 03 medical and health sciences; Cell Movement; Mutation; Phosphoprotein Phosphatases; Animals; Gene Deletion; Signal Transduction

Protein phosphatase magnesium-dependent 1A (PPM1A), a protein serine/threonine phosphatase, controls several signal pathways through cleavage of phosphate from its substrates. However, the in vivo function of Ppm1a in mammals remains unknown. Here we reported that mice lacking Ppm1a developed normally but were impaired in re-epithelialization process during cutaneous wound healing. Specifically, complete or keratinocyte-specific deletion of Ppm1a led to delayed re-epithelialization with reduced keratinocyte migration upon wounding. We showed that this effect was the result of an increase in Smad2/3 phosphorylation in keratinocytes. Keratinocyte-specific Smad2 deficient mice displayed accelerated re-epithelialization with enhanced keratinocyte migration. Importantly, Smad2 and Ppm1a double mutant mice also exhibited accelerated re-epithelialization, demonstrating that the effect of Ppm1a on promoting re-epithelialization is mediated by Smad2 signaling. Furthermore, the decreased expression of specific integrins and matrix metalloproteinases (MMPs) may contribute to the retarded re-epithelialization in Ppm1a mutant mice. These data indicate that Ppm1a, through suppressing Smad2 signaling, plays a critical role in re-epithelialization during wound healing.