TGF-Stimulated Secretion of HSP90: Using LRP-1/CD91 Receptor To Promote Human Skin Cell Migration Against TGF-Rich Environment In Wound Healing

Department of Dermatology and the Norris Comprehensive Cancer Center, Department of Surgery, the University of Southern California Keck School of Medicine, Los Angeles, California, 90033, USA

^* To whom correspondence should be addressed. Email: dwoodley{at}usc.edu. wli{at}usc.edu.

	Abstract

Jump-starting and subsequently maintaining epidermal and dermal cell migration are essential for skin wound healing. These events are often disrupted in non-healing wounds, causing patient morbidity and even fatality. Currently-available treatments are unsatisfactory. To identify novel wound-healing targets, we investigated secreted molecules from TGF-stimulated human keratinoytes, which contained a strong motogenic, but not mitogenic, activity. Protein purification allowed us to identify the heat shock protein-90alpha (hsp90) as the factor fully responsible for the motogenic activity in keratinocyte secretion. TGF causes a rapid membrane translocation and subsequent secretion of hsp90 via the unconventional exosome pathway in the cells. The secreted hsp90 promotes both epidermal and dermal cell migration through their surface receptor LRP-1/CD91. The pro-motility activity resides in the middle domain plus the charged sequence of hsp90, but independently of the ATPase activity. Neutralizing the extracellular function of hsp90 blocks TGF-induced keratinicyte migration. Most intriguingly, unlike canonical growth factors, the hsp90 signaling overrides the inhibition of TGF, an abundant inhibitor of dermal cell migration in skin wounds. This finding provides a long-sought answer for how dermal cells migrate into the wound environment to build new connective tissues and blood vessels. Thus, secreted hsp90 is potentially a new agent for wound healing.