2. Academic Validation
  3. N-glycosylation-defective splice variants of neuropilin-1 promote metastasis by activating endosomal signals

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

  • Nat Commun. 2019 Aug 16;10(1):3708. doi: 10.1038/s41467-019-11580-4.
Xiuping Huang 1 2,  Qing Ye 2 3,  Min Chen 2 4,  Aimin Li 1,  Wenting Mi 1,  Yuxin Fang 1,  Yekaterina Y Zaytseva 2 4,  Kathleen L O'Connor 2 5,  Craig W Vander Kooi 2 5,  Side Liu 6,  Qing-Bai She 7 8
Affiliations

Affiliations

  • 1 Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
  • 2 Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY, 40506, USA.
  • 3 Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, 40506, USA.
  • 4 Department of Toxicology and Cancer Biology, University of Kentucky College of Medicine, Lexington, KY, 40506, USA.
  • 5 Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, KY, 40506, USA.
  • 6 Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China. [email protected].
  • 7 Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY, 40506, USA. [email protected].
  • 8 Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, 40506, USA. [email protected].
PMID: 31420553 DOI: 10.1038/s41467-019-11580-4
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.

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Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-12289
    99.87%, FAK Inhibitor
    FAK