| First Author | Peng H | Year | 2014 |
| Journal | Am J Pathol | Volume | 184 |
| Issue | 12 | Pages | 3262-71 |
| PubMed ID | 25455687 | Mgi Jnum | J:217812 |
| Mgi Id | MGI:5615853 | Doi | 10.1016/j.ajpath.2014.08.014 |
| Citation | Peng H, et al. (2014) FIH-1 disrupts an LRRK1/EGFR complex to positively regulate keratinocyte migration. Am J Pathol 184(12):3262-71 |
| abstractText | Factor inhibiting hypoxia-inducible factor 1 (FIH-1; official symbol HIF1AN) is a hydroxylase that negatively regulates hypoxia-inducible factor 1alpha 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. |
