Abstract
The Plasminogen-Apple-Nematode (PAN) domain, with a core of four to six cysteine residues, is found in > 28,000 proteins across 959 genera. Still, its role in protein function is not fully understood. The PAN domain was initially characterized in numerous proteins, including HGF. Dysregulation of HGF-mediated signaling results in multiple deadly cancers. The binding of HGF to its cell surface receptor, c-MET, triggers all biological impacts. Here, we show that mutating four core cysteine residues in the HGF PAN domain reduces c-MET interaction, subsequent c-MET autophosphorylation, and phosphorylation of its downstream targets, perinuclear localization, cellular internalization of HGF, and its receptor, c-MET, and c-MET ubiquitination. Furthermore, transcriptional activation of HGF/c-MET signaling-related genes involved in cancer progression, invasion, metastasis, and cell survival were impaired. Thus, targeting the PAN domain of HGF may represent a mechanism for selectively regulating the binding and activation of the c-MET pathway.
| Original language | English |
|---|---|
| Article number | 646 |
| Journal | Communications Biology |
| Volume | 5 |
| Issue number | 1 |
| DOIs | |
| State | Published - Dec 2022 |
Funding
This manuscript has been authored by UT-Battelle, LLC under Contract No. DE-AC05-00OR22725 with the U.S. Department of Energy. The United States Government retains and the publisher, by accepting the article for publication, acknowledges that the United States Government retains a non-exclusive, paid-up, irrevocable, world-wide license to publish or reproduce the published form of this manuscript, or allow others to do so, for United States Government purposes. The Department of Energy will provide public access to these results of federally sponsored research in accordance with the DOE Public Access Plan ( http://energy.gov/downloads/doe-public-access-plan ). All data are available in the main text or the and the Supplementary Data –. Uncropped gel scans for all presented western blots are included in the Supplementary Figs. –. The raw RNA-seq reads have been deposited at NCBI under BioProject ID PRJNA718097 and the link to access the data is. Bioinformatics analyses of PAN domain distribution and functional inference was supported by the United States Department of Energy, Office of Science, Early Career Research Program under the Biological and Environmental Research office. Biochemical, immunofluorescence, and transcriptome analyses in human cell lines, and protein modeling and simulation were supported by the Lab Directed Research Development program at Oak Ridge National Laboratory (ORNL). Part of this research used resources at the Oak Ridge Leadership Computing Facility (OLCF) and the Compute and Data Environment for Science (CADES) at ORNL, which is managed by UT-Battelle, LLC for the U.S. Department of Energy under Contract Number DE-AC05-00OR22725.
