N-glycosylation-defective splice variants of neuropilin-1 promote metastasis by activating endosomal signals

Xiuping Huang, Qing Ye, Min Chen, Aimin Li, Wenting Mi, Yuxin Fang, Yekaterina Y. Zaytseva, Kathleen L. O’Connor, Craig W. Vander Kooi, Side Liu, Qing Bai She

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

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.

Original languageEnglish
Article number3708
JournalNature Communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

Bibliographical note

Funding Information:
We thank the Markey Cancer Center’s Research Communications Office for assistance with manuscript preparation, Emilia Galperin for helpful discussions, and Qun Yan, Yanying Nong and Yuqian Zhou for helpful collection of colorectal cancer specimens. The authors also acknowledge the assistance of the Biospecimen Procurement and Translational Pathology Shared Resource Facility of the Markey Cancer Center (P30CA177558). This work was supported by NCI grant R01CA203257, start-up funds, and pilot grants from CCSG P30CA177558 (UK Markey Cancer Center) and CCTS UL1TR001998 (University of Kentucky). This work was also supported in part by funding from Guangdong Gastrointestinal Disease Research Center (No. 2017B02029003 to S.L.).

Publisher Copyright:
© 2019, The Author(s).

ASJC Scopus subject areas

  • Chemistry (all)
  • Biochemistry, Genetics and Molecular Biology (all)
  • Physics and Astronomy (all)

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