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Role and regulation of CD98hc and Rho proteins during skin wound-healing

Final Report Summary - CD98 RHO SKIN (Role and regulation of CD98hc and Rho proteins during skin wound-healing)

In mammals, skin is by its size one of the largest organs, covering the entire body and protecting inner tissues against surrounding environmental hazards such as UV irradiation or microorganisms and viruses. Indeed, skin functions as the first barrier to protect the organism against external threats and as such its integrity must be maintained at all time. Indeed, skin has a very effective multi-step wound repair mechanism that insures fast injury recovery. In a simplified view, the re-epithelialization stage is characterized by the collective migration of keratinocytes from the edges of the wound in order to cover the injured tissue. At the cellular level, the transition of keratinocytes from static to migratory state requires profound morphological and cytoskeletal changes which are generally orchestrated by the small G proteins of the Rho family. Additionally, migration of keratinocytes over the wound bed also requires turnover of cell adhesion sites and proper regulation of integrin receptors. In the funded grant proposal, we planned to investigate original molecular aspects of these two pathways regulating skin physiology.

In the first aim, regarding integrin receptors, we originally proposed to investigate how the integrin β1 transmembrane co-receptor CD98hc regulates Rho proteins activity in the epidermis specifically during wound healing. CD98hc is the regulatory heavy chain of an amino acid transporter which can also regulates integrin function. The rationale, here, is that both integrins and Rho proteins are important in the process of epithelial wound healing and, previously, the PI of the host lab had shown that CD98hc might control Rho GTPases activity in various tissue culture systems. This aim was completed during the previous reporting period. We have found that CD98hc is required for proper skin homeostasis and wound healing, and that it controls RhoA activity jointly via the RhoGEF LARG and via the control of the intracellular concentration of ROS, which alters RhoA activation (Boulter et al., 2013, J. Exp. Med.).
Additionally, we unexpectedly stumbled upon a new function of CD98hc: we found that CD98hc regulates integrin-dependent mechanosensing and mechanotransduction. These deviations from Aim 1 have become one of the main focus of the research of the fellow and his host lab. The fellow has now characterized and dissected this regulation and we are in the process of submitting a manuscript reporting these findings. The host lab has investigated this novel function in the pathological context of skin tumor progression and determined that CD98hc is required for stiffness-dependent tumor progression (Estrach et al, 2014, Cancer Research) Additionally, the results generated by this project have been presented at several scientific conferences which resulted in an invitation for a review article in the European Journal of Cell Biology (Tissot et al, in revision).

In the second aim, we proposed to investigate the regulation of Rho proteins by RhoGDI during epidermal wound healing. We have started investigating this aim and characterized the temporal activation of RhoA during wound-healing both in vivo and in vitro. However, in light of the considerable interest and biological consequences generated by the deviations from Aim 1, we haven’t made much more progress on Aim 2. Indeed, we have invested most of our resources on the deviations from Aim 1 that have now reached the stage of publication.
In conclusion, the work plan has not been completed as originally envisioned but the deviations introduced during the investigation of aim 1 do not weaken the overall significance and reach of the project. Indeed, the deviations from aim 1 constitute a major step forward in the understanding of the function of CD98hc in the skin. More, they constitute the first example of such a regulation of mechanosignaling. We expect the impact of these findings to be . Overall, the completion of this project highlight the pivotal role of CD98hc in the regulation of skin homeostasis at all levels including an unexpected one, mechanical homeostasis.

During the funding period of this grant, the career development and reintegration of the fellow in charge of this project have bolstered since he has secured a tenured Research Associate position in the host lab in 2013 (CR1 at INSERM, a French Medical Research institution). The fellow is now a tenured senior Research Associate at the IRCAN institute. He is gradually becoming more independent by mentoring a graduate student enrolled in the LABEX SIGNALIFE PhD program and by hiring an engineer to receive technical help over the second reporting period.