Transforming growth factor α (TGFα)-stimulated secretion of HSP90α:: Using the receptor LRF-1/CD91 to promote human skin cell migration against a TGFβ-rich environment during wound healing

Jump-starting and subsequently maintaining epidermal and dermal cell migration are essential processes for skin wound healing. These events are often disrupted in nonhealing wounds, causing patient morbidity and even fatality. Currently available treatments are unsatisfactory. To identify novel wound-healing targets, we investigated secreted molecules from transforming growth factor a (TGF alpha)-stimulated human keratinoytes, which contained strong motogenic, but not mitogenic, activity. Protein purification allowed us to identify the heat shock protein 90 alpha (hsp90 alpha) as the factor fully responsible for the motogenic activity in keratinocyte secretion. TGFa causes rapid membrane translocation and subsequent secretion of hsp90 alpha via the unconventional exosome pathway in the cells. Secreted hsp90a promotes both epidermal and dermal cell migration through the surface receptor LRP-1 (LDL receptor-related protein 1)/CD91. The promotility activity resides in the middle domain plus the charged sequence of hsp90 alpha but is independent of the ATPase activity. Neutralizing the extracellular function of hsp90 alpha blocks TGF alpha-induced keratinicyte migration. Most intriguingly, unlike the effects of canonical growth factors, the hsp90 alpha signaling overrides the inhibition of TGF beta, an abundant inhibitor of dermal cell migration in skin wounds. This finding provides a long-sought answer to the question of how dermal cells migrate into the wound environment to build new connective tissues and blood vessels. Thus, secreted hsp90 alpha is potentially a new agent for wound healing.