Research ArticleStress responses

The receptor tyrosine kinase HIR-1 coordinates HIF-independent responses to hypoxia and extracellular matrix injury

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Sci. Signal.  02 Oct 2018:
Vol. 11, Issue 550, eaat0138
DOI: 10.1126/scisignal.aat0138

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Help during hypoxia from HIR-1

Metazoans require a constant supply of oxygen, and inappropriate hypoxic adaptation is pathological—an example of which occurs in solid tumors. Using the model organism Caenorhabditis elegans, Vozdek et al. searched for pathways involved in coping with hypoxic environments and identified a receptor tyrosine kinase that they called HIR-1. Worms exposed to hypoxia had compromised cuticles, and this damage was recapitulated by loss of HIR-1. Moreover, worms lacking HIR-1 showed changes in the expression of genes involved in cuticle integrity and impaired recovery after severe hypoxia. If a human ortholog of HIR-1 is found, the authors speculate that it could be targeted to treat solid tumors.

Abstract

Inadequate tissue oxygen, or hypoxia, is a central concept in the pathophysiology of ischemic disorders and cancer. Hypoxia promotes extracellular matrix (ECM) remodeling, cellular metabolic adaptation, and cancer cell metastasis. To discover new pathways through which cells respond to hypoxia, we performed a large-scale forward genetic screen in Caenorhabditis elegans and identified a previously uncharacterized receptor tyrosine kinase named HIR-1. Loss of function in hir-1 phenocopied the impaired ECM integrity associated with hypoxia or deficiency in the oxygen-dependent dual oxidase, heme peroxidases, or cuticular collagens involved in ECM homeostasis. Genetic suppressor screens identified NHR-49 and MDT-15 as transcriptional regulators downstream of HIR-1. Furthermore, hir-1 mutants showed defects in adapting to and recovering from prolonged severe hypoxia. We propose that C. elegans HIR-1 coordinates hypoxia-inducible factor–independent responses to hypoxia and hypoxia-associated ECM remodeling through mechanisms that are likely conserved in other organisms.

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