Year: 2014
Type: article
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.
Source: American Journal Of Pathology
Institution: Northwestern University
Language: English
Topic: Wound Healing and Treatments
Subfield: Rehabilitation
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $2,800
Awards: G245216419, MicroRNAs and Corneal Epithelial Stem Cells, G2814385370, Epha/Ephrin - A Signaling in Epidermal Differentiation and Disease, G5431120201, Northwestern University Skin Disease Research Core Center, G6603037202, Corneal Epithelial Stem Cells, DEVELOPING VISUAL PATHWAYS DEFINED BY AN EPH/RTK LIGAND, The Role of MicroRNAs in Corneal Epithelial Homeostasis, G8758594162, G9000353441
OpenAlex ID: W2034287590