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

Author

Listed:
  • Xiuping Huang

    (Southern Medical University
    University of Kentucky College of Medicine)

  • Qing Ye

    (University of Kentucky College of Medicine
    University of Kentucky College of Medicine)

  • Min Chen

    (University of Kentucky College of Medicine
    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
    University of Kentucky College of Medicine)

  • Kathleen L. O’Connor

    (University of Kentucky College of Medicine
    University of Kentucky College of Medicine)

  • Craig W. Kooi

    (University of Kentucky College of Medicine
    University of Kentucky College of Medicine)

  • Side Liu

    (Southern Medical University)

  • Qing-Bai She

    (University of Kentucky College of Medicine
    University of Kentucky College of Medicine)

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.

Suggested Citation

  • Xiuping Huang & Qing Ye & Min Chen & Aimin Li & Wenting Mi & Yuxin Fang & Yekaterina Y. Zaytseva & Kathleen L. O’Connor & Craig W. Kooi & Side Liu & Qing-Bai She, 2019. "N-glycosylation-defective splice variants of neuropilin-1 promote metastasis by activating endosomal signals," Nature Communications, Nature, vol. 10(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-11580-4
    DOI: 10.1038/s41467-019-11580-4
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