Secreted heat shock protein-90 (Hsp90) in wound healing and cancer

Abstract

Summary Extracellular Hsp90 proteins, including “membrane-bound”, “released” and “secreted”, were first reported more than two decades ago. Only studies of the past seven years have begun to reveal a picture for when, how and why Hsp90 get exported by both normal and tumor cells. Normal cells secrete Hsp90 in response to tissue injury. Tumor cells have managed to constitutively secrete Hsp90 for tissue invasion. In either case, sufficient supply of the extracellular Hsp90 can be guaranteed by its unusually abundant storage inside the cells. A well-characterized function of secreted Hsp90α is to promote cell motility, a crucial event for both wound healing and cancer. The reported targets for extracellular Hsp90α include MMP2, LRP-1, tyrosine kinase receptors and possibly more. The pro-motility activity of secreted Hsp90α resides within a fragment at the boundary between linker region and middle domain. Inhibition of its secretion, neutralization of its extracellular action or interruption of its signaling through LRP-1 block wound healing and tumor invasion in vitro and in vivo. In normal tissue, topical application of F-5 promotes acute and diabetic wound healing far more effectively than US FDA-approved conventional growth factor therapy in mice. In cancer, drugs that selectively target the F-5 region of secreted Hsp90 by cancer cells may be more effective and less toxic than those that target the ATPase of the intracellular Hsp90.

Extracellular Heat Shock Protein 90 Signals through Subdomain II and the NPVY Motif of LRP-1 Receptor to Akt1 and Akt2: a Circuit Essential for Promoting Skin Cell Migration In Vitro and Wound Healing In Vivo

“…Inside the cell, Hsp90 proteins act as an ATPase-dependent chaperone that binds and protects hundreds of client proteins from misfolding, structural damage, or protease degradation triggered by environmental insults or pathological stress (1)(2)(3)(4). For the past 10 years, in particular, studies have convincingly made it clear that the same stress signals can also trigger the cells to secrete cytosolic Hsp90 proteins into the extracellular environment (5)(6)(7)(8). Outside the cell, the sole function of extracellular Hsp90␣ (eHsp90␣) is to promote cell motility.…”

“…Outside the cell, the sole function of extracellular Hsp90␣ (eHsp90␣) is to promote cell motility. At least one physiological role for eHsp90␣ is promotion of tissue repair, such as skin wound healing (6,9,10). Certain tumor cells, such as those that maintain a steady-state level of hypoxia-inducible factor 1 alpha (HIF-1␣), acquired the ability to constitutively secrete Hsp90␣ for invasion and metastasis (5,6,8,(11)(12)(13)(14).…”

PRAS40 Connects Microenvironmental Stress Signaling to Exosome-Mediated Secretion

“…It is known that TGF-␣ levels are low or undetectable in intact skin and rise when skin is wounded. In contrast, the EGF levels remain unchanged before or after skin wounding (35). Mechanistically, while both TGF-␣ and EGF induce Ser-473 phosphorylation of Akt in keratinocytes, only TGF-␣ induces Thr-308 phosphorylation (the main activation of phosphorylation) of Akt.…”

“…Rather, they secrete exosomes only under environmental stress cues. In contrast to normal cells, many tumor cells constitutively secrete exosomes driven by their intrinsic oncogenic signals (7,35). It would be of a great interest to test whether PRAS40 has any relationship with TSAP6 or Rab27.…”

“…It has been shown that Thr-308-phosphorylated Akt is responsible for phosphorylating PRAS40 at Thr-246 (39), supporting our findings in this study. We have proposed that keratinocytes are the main source of secreted Hsp90a in wounded skin for promoting wound closure (35).…”