Transforming growth factor alpha (TGFalpha)-stimulated secretion of HSP90alpha: using the receptor LRP-1/CD91 to promote human skin cell migration against a TGFbeta-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 alpha (TGFalpha)-stimulated human keratinoytes, which contained strong motogenic, but not mitogenic, activity. Protein purification allowed us to identify the heat shock protein 90alpha (hsp90alpha) as the factor fully responsible for the motogenic activity in keratinocyte secretion. TGFalpha causes rapid membrane translocation and subsequent secretion of hsp90alpha via the unconventional exosome pathway in the cells. Secreted hsp90alpha 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 hsp90alpha but is independent of the ATPase activity. Neutralizing the extracellular function of hsp90alpha blocks TGFalpha-induced keratinicyte migration. Most intriguingly, unlike the effects of canonical growth factors, the hsp90alpha signaling overrides the inhibition of TGFbeta, 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 hsp90alpha is potentially a new agent for wound healing.
Cheng
Chieh-Fang
CF
Department of Dermatology, University of Southern California Keck School of Medicine, 1441 Eastlake Ave., Room 6320, Los Angeles, CA 90033, USA.
Fan
Jianhua
J
Fedesco
Mark
M
Guan
Shengxi
S
Li
Yong
Y
Bandyopadhyay
Balaji
B
Bright
Alexandra M
AM
Yerushalmi
Dalia
D
Liang
Mengmeng
M
Chen
Mei
M
Han
Yuan-Ping
YP
Woodley
David T
DT
Li
Wei
W
D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D017931:DNA Primers / Q000235:genetics; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000502:physiology; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D034741:RNA, Small Interfering / Q000235:genetics; D012867:Skin / Q000187:drug effects / Q000293:injuries; D016211:Transforming Growth Factor alpha / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects* / Q000502:physiology*
D015703:Antigens, CD; D017931:DNA Primers; D018841:HSP90 Heat-Shock Proteins; C475476:LRP1 protein, human; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D034741:RNA, Small Interfering; D016211:Transforming Growth Factor alpha; D016212:Transforming Growth Factor beta