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First published online 21 April 2009
doi: 10.1242/jcs.047894

Journal of Cell Science 122, 1495-1498 (2009)
Published by The Company of Biologists 2009
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Short Report

Participation of the lipoprotein receptor LRP1 in hypoxia-HSP90{alpha} autocrine signaling to promote keratinocyte migration

David T. Woodley1, Jianhua Fan1, Chieh-Fang Cheng1, Yong Li1,*, Mei Chen1, Guojun Bu2 and Wei Li1,{ddagger}

1 Department of Dermatology and the USC-Norris Comprehensive Cancer Center, the University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA
2 The Department of Pediatrics, Washington University School of Medicine, St Louis, MO 63130, USA

{ddagger} Author for correspondence (e-mail: wli{at}usc.edu)

Accepted 23 January 2009

Summary

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 (HSP90{alpha}) via a HIF1-dependent pathway. The secreted HSP90{alpha} in turn promotes migration, but not proliferation, of the cells. Disruption of the secretion or extracellular function of HSP90{alpha} blocked hypoxia-stimulated HK migration. The ubiquitously expressed surface receptor, LRP1 (LDL-receptor-related protein 1), mediates the HSP90{alpha} signaling. Inhibition of LRP1 binding to extracellular HSP90{alpha} 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-HSP90{alpha}-LRP1 autocrine loop provides previously unrecognized therapeutic targets for human disorders such as chronic wounds and cancer invasion.

Key words: Keratinocytes, Hypoxia, HSP90{alpha}, LRP1, Cell motility


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