Abstract

Neuropilin-1 (NRP1) is an essential transmembrane receptor with a variety of cellular functions. Here, we identify two human NRP1 splice variants resulting from the skipping of exon 4 and 5, respectively, in colorectal cancer (CRC). Both NRP1 variants exhibit increased endocytosis/recycling activity and decreased levels of degradation, leading to accumulation on endosomes. This increased endocytic trafficking of the two NRP1 variants, upon HGF stimulation, is due to loss of N-glycosylation at the Asn150 or Asn261 site, respectively. Moreover, these NRP1 variants enhance interactions with the Met and β1-integrin receptors, resulting in Met/β1-integrin co-internalization and co-accumulation on endosomes. This provides persistent signals to activate the FAK/p130Cas pathway, thereby promoting CRC cell migration, invasion and metastasis. Blocking endocytosis or endosomal Met/β1-integrin/FAK signaling profoundly inhibits the oncogenic effects of both NRP1 variants. These findings reveal an important role for these NRP1 splice variants in the regulation of endocytic trafficking for cancer cell dissemination.

Details

Title
N-glycosylation-defective splice variants of neuropilin-1 promote metastasis by activating endosomal signals
Author
Huang, Xiuping 1 ; Ye, Qing 2 ; Chen, Min 3 ; Li, Aimin 4 ; Mi, Wenting 4 ; Fang, Yuxin 4 ; Zaytseva, Yekaterina Y 3 ; Kathleen L O’Connor 5 ; Vander Kooi, Craig W 5 ; Liu, Side 4 ; Qing-Bai She 2   VIAFID ORCID Logo 

1  Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY, USA 
2  Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY, USA; Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, USA 
3  Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY, USA; Department of Toxicology and Cancer Biology, University of Kentucky College of Medicine, Lexington, KY, USA 
4  Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China 
5  Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY, USA; Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, KY, USA 
Pages
1-16
Publication year
2019
Publication date
Aug 2019
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-019-11580-4
ProQuest document ID
2274347797
Copyright
© 2019. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.