Physiological Role of Shoc2 in Skin Homeostasis

Sibel Sari1* (ORCID: https://orcid.org/0000-0002-2505-5804), Ayse Akarca2 (https://orcid.org/0000-0003-0629-3927), Teresa Marafioti3 (https://orcid.org/0000-0003-1223-6275) and Pablo Rodriguez-Viciana4 (ORCID: https://orcid.org/0000-0002-8846-543X)

*1Abdullah Gul University, Faculty of Life and Natural Sciences, Molecular Biology and Genetics, Kayseri, Turkey. 2,3,4University College London (UCL) Cancer Institute, London, UK

*Corresponding author e-mail: sibel.sari@agu.edu.tr

Abstract

The mammalian skin is the largest organ of the body and serves a main protective barrier between the body and the external environment against mechanical pressure, physical damage, pathogen infection, water loss, and it has immunological functions that help the maintenance of body homeostasis. The EGFR/RAS/RAF/ERK pathway has a well- described role in the skin and hair follicle development. Its function in the skin and its appendages, including hair follicles, is necessary for proper development and tissue homeostasis, and its deregulation rapidly results in defects in cellular proliferation and differentiation.

Dephosphorylation of a conserved inhibitory site on RAF (S259-RAF1, S365-BRAF) by a phosphatase complex comprised of SHOC2, MRAS and PP1 (SHOC2 complex) is one of the key steps in the process of RAF activation.
In order to study the role of SHOC2 in vivo/in tissue homeostasis we have generated 2 mouse models of conditional SHOC2 inactivation. A knockout model (KO) was generated by flanking exon 4 with loxP sites. A Knock-in (KI) model was generated using a minigene strategy, where wild-type SHOC2 is expressed in a cDNA configuration under its endogenous promoter and replaced after Cre-mediated recombination by a mutant SHOC2 D175N allele that is defective for interaction with MRAS and PP1.

The results show that systemic inactivation of SHOC2 in adult mice by using KO and KI models, results in skin dermatitis as well as a range of histopathological alterations that include epidermal hyperproliferation with hyperkeratosis, an increased number of hair follicles that fail to enter catagen and remain in aberrant anagen. The KO and KI mice skin also developed an extensive dermal and epidermal inflammatory infiltrate containing a variety of immune cells. With all of these alterations, Shoc2 KO/KI mice are sharing pathological features associated with human chronic inflammatory skin syndromes such as Atopic Dermatitis and Psoriasis.

Keywords: Shoc2, Skin Homeostasis, Mouse Models