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Normal cells secrete heat shock protein 90 alpha (Hsp90α) in response to tissue injury. Tumor cells have managed to constitutively secrete Hsp90α during invasion and metastasis. The sole function of extracellular Hsp90α (eHsp90α) is to promote cell motility, a critical event for both wound healing and tumor progression. The mechanism of promotility action by eHsp90α, however, has remained elusive. A key issue is whether eHsp90α still acts as a chaperone outside the cells or is a new and bona fide signaling molecule. Here, we have provided evidence that eHsp90α utilizes a unique transmembrane signaling mechanism to promote cell motility and wound healing. First, subdomain II in the extracellular part of low-density lipoprotein receptor-related protein 1 (LRP-1) receives the eHsp90α signal. Then, the NPVY but not the NPTY motif in the cytoplasmic tail of LRP-1 connects eHsp90α signaling to serine 473 but not threonine 308 phosphorylation in Akt kinases. Individual knockdown of Aktl, Akt2, or Akt3 revealed the importance of Aktl and Akt2 in eHsp90α-induced cell motility. Akt gene rescue experiments suggest that Aktl and Akt2 work in concert, rather than independently, to mediate eHsp90α promotility signaling. Finally, Aktl and Akt2 knockout mice showed impaired wound healing that cannot be corrected by topical application with the eHsp90α protein. [ABSTRACT FROM AUTHOR]