FIH-1 disrupts an LRRK1/EGFR complex to positively regulate keratinocyte migration

Han Peng, Nihal Kaplan, Wending Yang, Spiro Getsios, Robert M. Lavker*

*Corresponding author for this work

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

Factor inhibiting hypoxia-inducible factor 1 (FIH-1; official symbol HIF1AN) is a hydroxylase that negatively regulates hypoxia-inducible factor 1α but also targets other ankyrin repeat domain-containing proteins such as Notch receptor to limit epithelial differentiation. We show that FIH-1 null mutant mice exhibit delayed wound healing. Importantly, in vitro scratch wound assays demonstrate that the positive role of FIH-1 in migration is independent of Notch signaling, suggesting that this hydroxylase targets another ankyrin repeat domain-containing protein to positively regulate motogenic signaling pathways. Accordingly, FIH-1 increases epidermal growth factor receptor (EGFR) signaling, which in turn enhances keratinocyte migration via mitogen-activated protein kinase pathway, leading to extracellular signal-regulated kinase 1/2 activation. Our studies identify leucine-rich repeat kinase 1 (LRRK1), a key regulator of the EGFR endosomal trafficking and signaling, as an FIH-1 binding partner. Such an interaction prevents the formation of an EGFR/LRRK1 complex, necessary for proper EGFR turnover. The identification of LRRK1 as a novel target for FIH-1 provides new insight into how FIH-1 functions as a positive regulator of epithelial migration.

Original languageEnglish (US)
Pages (from-to)3262-3271
Number of pages10
JournalAmerican Journal of Pathology
Volume184
Issue number12
DOIs
StatePublished - Dec 1 2014

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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