Participation of the lipoprotein receptor LRP1 in hypoxia-HSP90α autocrine signaling to promote keratinocyte migration

David T. Woodley, Jianhua Fan, Chieh Fang Cheng, Yong Li, Mei Chen, Guojun D Bu, Wei Li

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

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 (HSP90α) via a HIF1-dependent pathway. The secreted HSP90α in turn promotes migration, but not proliferation, of the cells. Disruption of the secretion or extracellular function of HSP90α blocked hypoxia-stimulated HK migration. The ubiquitously expressed surface receptor, LRP1 (LDL-receptor-related protein 1), mediates the HSP90α signaling. Inhibition of LRP1 binding to extracellular HSP90α 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-HSP90α-LRP1 autocrine loop provides previously unrecognized therapeutic targets for human disorders such as chronic wounds and cancer invasion.

Original languageEnglish (US)
Pages (from-to)1495-1498
Number of pages4
JournalJournal of Cell Science
Volume122
Issue number10
DOIs
StatePublished - May 15 2009
Externally publishedYes

Fingerprint

Autocrine Communication
Low Density Lipoprotein Receptor-Related Protein-1
Lipoprotein Receptors
HSP90 Heat-Shock Proteins
Keratinocytes
RNA Interference
Cell Hypoxia
Hypoxia
Neutralizing Antibodies
Protein Binding
Wound Healing
Neoplasms
Down-Regulation
Complementary DNA
Cell Proliferation
Wounds and Injuries

Keywords

  • Cell motility
  • HSP90α
  • Hypoxia
  • Keratinocytes
  • LRP1

ASJC Scopus subject areas

  • Cell Biology

Cite this

Participation of the lipoprotein receptor LRP1 in hypoxia-HSP90α autocrine signaling to promote keratinocyte migration. / Woodley, David T.; Fan, Jianhua; Cheng, Chieh Fang; Li, Yong; Chen, Mei; Bu, Guojun D; Li, Wei.

In: Journal of Cell Science, Vol. 122, No. 10, 15.05.2009, p. 1495-1498.

Research output: Contribution to journalArticle

Woodley, David T. ; Fan, Jianhua ; Cheng, Chieh Fang ; Li, Yong ; Chen, Mei ; Bu, Guojun D ; Li, Wei. / Participation of the lipoprotein receptor LRP1 in hypoxia-HSP90α autocrine signaling to promote keratinocyte migration. In: Journal of Cell Science. 2009 ; Vol. 122, No. 10. pp. 1495-1498.
@article{0c424196bfae4423b8aadcbcb8177df0,
title = "Participation of the lipoprotein receptor LRP1 in hypoxia-HSP90α autocrine signaling to promote keratinocyte migration",
abstract = "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 (HSP90α) via a HIF1-dependent pathway. The secreted HSP90α in turn promotes migration, but not proliferation, of the cells. Disruption of the secretion or extracellular function of HSP90α blocked hypoxia-stimulated HK migration. The ubiquitously expressed surface receptor, LRP1 (LDL-receptor-related protein 1), mediates the HSP90α signaling. Inhibition of LRP1 binding to extracellular HSP90α 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-HSP90α-LRP1 autocrine loop provides previously unrecognized therapeutic targets for human disorders such as chronic wounds and cancer invasion.",
keywords = "Cell motility, HSP90α, Hypoxia, Keratinocytes, LRP1",
author = "Woodley, {David T.} and Jianhua Fan and Cheng, {Chieh Fang} and Yong Li and Mei Chen and Bu, {Guojun D} and Wei Li",
year = "2009",
month = "5",
day = "15",
doi = "10.1242/jcs.047894",
language = "English (US)",
volume = "122",
pages = "1495--1498",
journal = "Journal of Cell Science",
issn = "0021-9533",
publisher = "Company of Biologists Ltd",
number = "10",

}

TY - JOUR

T1 - Participation of the lipoprotein receptor LRP1 in hypoxia-HSP90α autocrine signaling to promote keratinocyte migration

AU - Woodley, David T.

AU - Fan, Jianhua

AU - Cheng, Chieh Fang

AU - Li, Yong

AU - Chen, Mei

AU - Bu, Guojun D

AU - Li, Wei

PY - 2009/5/15

Y1 - 2009/5/15

N2 - 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 (HSP90α) via a HIF1-dependent pathway. The secreted HSP90α in turn promotes migration, but not proliferation, of the cells. Disruption of the secretion or extracellular function of HSP90α blocked hypoxia-stimulated HK migration. The ubiquitously expressed surface receptor, LRP1 (LDL-receptor-related protein 1), mediates the HSP90α signaling. Inhibition of LRP1 binding to extracellular HSP90α 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-HSP90α-LRP1 autocrine loop provides previously unrecognized therapeutic targets for human disorders such as chronic wounds and cancer invasion.

AB - 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 (HSP90α) via a HIF1-dependent pathway. The secreted HSP90α in turn promotes migration, but not proliferation, of the cells. Disruption of the secretion or extracellular function of HSP90α blocked hypoxia-stimulated HK migration. The ubiquitously expressed surface receptor, LRP1 (LDL-receptor-related protein 1), mediates the HSP90α signaling. Inhibition of LRP1 binding to extracellular HSP90α 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-HSP90α-LRP1 autocrine loop provides previously unrecognized therapeutic targets for human disorders such as chronic wounds and cancer invasion.

KW - Cell motility

KW - HSP90α

KW - Hypoxia

KW - Keratinocytes

KW - LRP1

UR - http://www.scopus.com/inward/record.url?scp=67649950623&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=67649950623&partnerID=8YFLogxK

U2 - 10.1242/jcs.047894

DO - 10.1242/jcs.047894

M3 - Article

VL - 122

SP - 1495

EP - 1498

JO - Journal of Cell Science

JF - Journal of Cell Science

SN - 0021-9533

IS - 10

ER -