title: FIH-1 disrupts an LRRK1/EGFR complex to positively regulate keratinocyte migration.
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.
authors.affiliation: Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Han
authors.initials: H
authors.lastname: Peng
authors.affiliation: Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Nihal
authors.initials: N
authors.lastname: Kaplan
authors.affiliation: Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Wending
authors.initials: W
authors.lastname: Yang
authors.affiliation: Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Spiro
authors.initials: S
authors.lastname: Getsios
authors.affiliation: Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois. Electronic address: r-lavker@northwestern.edu.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Lavker
mesh_terms: D000818:Animals; D002465:Cell Movement; D002478:Cells, Cultured; D004848:Epithelium / Q000196:embryology; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D015603:Keratinocytes / Q000166:cytology* / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D014945:Wound Healing
chemical_list: D006899:Mixed Function Oxygenases; C551240:factor inhibiting hypoxia-inducible factor 1, mouse; D066246:ErbB Receptors; C585046:Lrrk1 protein, mouse; D017346:Protein Serine-Threonine Kinases