PT  - JOURNAL ARTICLE
AU  - Roman Vozdek
AU  - Yong Long
AU  - Dengke K. Ma
TI  - HIR-1 Mediates Response to Hypoxia-Induced Extracellular Matrix Remodeling
AID  - 10.1101/302638
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 302638
4099  - http://biorxiv.org/content/early/2018/04/16/302638.short
4100  - http://biorxiv.org/content/early/2018/04/16/302638.full
AB  - Inadequate tissue oxygen, or hypoxia, is a central concept in pathophysiology of ischemic disorders and cancer. Hypoxia promotes extracellular matrix (ECM) remodeling, cellular metabolic adaptation and metastasis. To determine how cells respond to hypoxia-induced ECM remodeling, we performed a large-scale forward genetic screen in C. elegans. We identified a previously uncharacterized receptor tyrosine kinase (RTK) named HIR-1 as a key mediator in a pathway that orchestrates transcriptional responses to hypoxia-induced ECM remodeling. Impaired ECM integrity caused by hypoxia or deficiency of the oxygen-dependent procollagen hydroxylases, heme peroxidases or cuticular collagens activates gene expression through inhibition of HIR-1. Genetic suppressor screens identified NHR-49 and MDT-15 as transcriptional regulators downstream of HIR-1. Cellular responses through HIR-1 maintain ECM homeostasis and promote animal adaptation to severe hypoxia. We propose that C. elegans HIR-1 defines an unprecedented type of RTK that mediates responses to hypoxia-induced ECM remodeling by mechanisms that are likely conserved in other organisms.ONE-SENTENCE SUMMARY A regulatory pathway for ECM homeostasis underlies adaptation to hypoxia and re-oxygenation