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.

Hsp90α and Hsp90β Co-Operate a Stress-Response Mechanism to Cope With Hypoxia and Nutrient Paucity during Wound Healing

“…We focused on the stability of LRP-1, the cell surface receptor that mediates hypoxia-induced cell migration (Cheng et al, 2008;Woodley et al, 2009). We first examined which Hsp90 isoform, Hsp90a or Hsp90b, binds to the short (100 amino acids) cytoplasmic tail of LRP-1 as a chaperone.…”

The Roles of Growth Factors in Keratinocyte Migration

“…It has been shown that in vitro hypoxic conditions activate hypoxia-inducible factor 1, which induces KCs to express heat shock protein 90 (HSP90), which then acts in an autocrine fashion on KCs via the LDL receptor-related protein 1 (LRP-1) to activate KC migration but not proliferation. 86 It has also been shown that TGF-a upregulates HSP90 expression, thereby inducing KC migration. 87 Activation of LRP-1 by HSP90 leads to the activation of Akt1 and 2, which induces faster wound healing in vivo.…”

A fragment of secreted Hsp90α carries properties that enable it to accelerate effectively both acute and diabetic wound healing in mice

“…It is known that all forms of diabetes are characterized by chronic hyperglycemia in circulation, which is blamed for delayed healing of diabetic wounds (44). Reportedly, hyperglycemia was able to destabilize HIF-1α protein (45), the key regulator of Hsp90α secretion in HKs and HDFs (29,46). We specifically tested whether hyperglycemia blocks hypoxia-induced HDF motility and whether F-5 is able to bypass the blockage of hyperglycemia and rescue HDF migration.…”