In mammals, the skin is by its size one of the largest organs, covering the entire body and protecting inner tissues against a wide range of environmental threats ranging from UV irradiation to microorganisms and viruses. This function is achieved via a multilayered organization of the skin among which the outermost layer, the epidermis, provides its waterproofing and barrier functions to the skin. Upon excessive physical stress, skin can be damaged and has to be repaired in order to restore its protective function. To this end, keratinocytes from the epidermis migrate from the edges of the wound over the injured tissue. Such migration requires profound morphological changes driven by the cell cytoskeleton and the small G proteins of the Rho family. Besides, we have just observed that the transmembrane protein CD98hc is indeed required for proper epidermal wound healing in vivo. CD98hc is an intriguing protein that functions as both the large subunit of an amino acid transporter (SLC3A2) and a co-receptor for integrins. Additionally, in some instances, CD98hc can regulate Rho proteins activity. Therefore, in my first aim, I would like to address the molecular pathways responsible for Rho proteins regulation during epidermal wound healing and particularly those downstream of CD98hc. During my postdoctoral training in Keith Burridge’s lab, I have learned the techniques required to identify the GEFs and GAPs involved in this regulation. Independently, I also seek to explore the regulation of Rho GTPases by atypical regulators such as RhoGDIs. To this end, I propose, in a second aim, to assess the function of RhoGDI during epidermal wound healing. Along the same line, I seek to identify the GDF proteins responsible for the displacement of Rho from RhoGDI by setting up and screening a yeast 2-hybrid screen. I anticipate that completion these aims will give us a comprehensive understanding of the regulation of Rho proteins during wound healing.
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