Participation of the lipoprotein receptor LRP1 in hypoxia-HSP90alpha autocrine signaling to promote keratinocyte migration.
Hypoxia is a microenvironmental stress in many pathological conditions, including wound healing and tumor invasion. Under hypoxia, the cells are forced to adapt alternative and self-supporting mechanisms. Understanding these mechanisms may lead to new insights into human disorders. We report here a novel autocrine signaling mechanism by which hypoxia promotes human keratinocyte (HK) migration. First, hypoxia triggers HKs to secrete heat shock protein 90-alpha (HSP90alpha) via a HIF1-dependent pathway. The secreted HSP90alpha in turn promotes migration, but not proliferation, of the cells. Disruption of the secretion or extracellular function of HSP90alpha blocked hypoxia-stimulated HK migration. The ubiquitously expressed surface receptor, LRP1 (LDL-receptor-related protein 1), mediates the HSP90alpha signaling. Inhibition of LRP1 binding to extracellular HSP90alpha by neutralizing antibodies or genetic silencing of the LRP1 receptor by RNAi completely nullified hypoxia-driven HK migration. Finally, re-introducing a RNAi-resistant LRP1 cDNA into LRP1-downregulated HKs rescued the motogenic response of the cells to hypoxia. We propose that the hypoxia-HSP90alpha-LRP1 autocrine loop provides previously unrecognized therapeutic targets for human disorders such as chronic wounds and cancer invasion.
Woodley
David T
DT
Department of Dermatology and the USC-Norris Comprehensive Cancer Center, the University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA.
Fan
Jianhua
J
Cheng
Chieh-Fang
CF
Li
Yong
Y
Chen
Mei
M
Bu
Guojun
G
Li
Wei
W
D000906:Antibodies; D019898:Autocrine Communication; D015687:Cell Hypoxia; D002465:Cell Movement; D002478:Cells, Cultured; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism*; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D009154:Mutation; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection
D000906:Antibodies; C497442:HIF1A protein, human; D018841:HSP90 Heat-Shock Proteins; C533585:HSP90AA2P protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D034741:RNA, Small Interfering