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


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 ?1-integrin receptors, resulting in Met/?1-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/?1-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.

SUBMITTER: Huang X 

PROVIDER: S-EPMC6697747 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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

Huang Xiuping X   Ye Qing Q   Chen Min M   Li Aimin A   Mi Wenting W   Fang Yuxin Y   Zaytseva Yekaterina Y YY   O'Connor Kathleen L KL   Vander Kooi Craig W CW   Liu Side S   She Qing-Bai QB  

Nature communications 20190816 1


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 th  ...[more]

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2024-07-16 | GSE269782 | GEO