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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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.).
All data supporting the findings of this study are available within the article and its supplementary information files and from the corresponding author upon reasonable request. A reporting summary for this article is available as a supplementary information file. The source data underlying figures and supplementary figures are provided as a Source Data file.
Huang, Xiuping; Ye, Qing; Chen, Min; Li, Aimin; Mi, Wenting; Fang, Yuxin; Zaytseva, Yekaterina Y.; O'Connor, Kathleen L.; Vander Kooi, Craig W.; Liu, Side; and She, Qing-Bai, "N-Glycosylation-Defective Splice Variants of Neuropilin-1 Promote Metastasis by Activating Endosomal Signals" (2019). Markey Cancer Center Faculty Publications. 163.