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. Kooi, Side Liu () and Qing-Bai She ()
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Xiuping Huang: Southern Medical University
Qing Ye: University of Kentucky College of Medicine
Min Chen: University of Kentucky College of Medicine
Aimin Li: Southern Medical University
Wenting Mi: Southern Medical University
Yuxin Fang: Southern Medical University
Yekaterina Y. Zaytseva: University of Kentucky College of Medicine
Kathleen L. O’Connor: University of Kentucky College of Medicine
Craig W. Kooi: University of Kentucky College of Medicine
Side Liu: Southern Medical University
Qing-Bai She: University of Kentucky College of Medicine

Nature Communications, 2019, vol. 10, issue 1, 1-16

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-11580-4

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