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. Vander Kooi; Side Liu; Qing Bai She

doi:10.1038/s41467-019-11580-4

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. Vander Kooi, Side Liu, Qing Bai She

Research output: Contribution to journal › Article › peer-review

36 Scopus citations

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.

Original language	English
Article number	3708
Journal	Nature Communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-11580-4
State	Published - Dec 1 2019

Bibliographical note

Publisher Copyright:
© 2019, The Author(s).

Funding

We thank the Markey Cancer Center’s Research Communications Office for assistance with manuscript preparation, Emilia Galperin for helpful discussions, and Qun Yan, Yanying Nong and Yuqian Zhou for helpful collection of colorectal cancer specimens. The authors also acknowledge the assistance of the Biospecimen Procurement and Translational Pathology Shared Resource Facility of the Markey Cancer Center (P30CA177558). 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.).

Funders	Funder number
CCSG
Guangdong Gastrointestinal Disease Research Center	2017B02029003
Markey Cancer Center	CCTS UL1TR001998
National Childhood Cancer Registry – National Cancer Institute	P30CA177558, R01CA203257
National Center for Advancing Translational Sciences (NCATS)	UL1TR001998
University of Kentucky

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-019-11580-4

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title = "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 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.",

author = "Xiuping Huang and Qing Ye and Min Chen and Aimin Li and Wenting Mi and Yuxin Fang and Zaytseva, {Yekaterina Y.} and O{\textquoteright}Connor, {Kathleen L.} and {Vander Kooi}, {Craig W.} and Side Liu and She, {Qing Bai}",

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AU - Chen, Min

AU - Li, Aimin

AU - Mi, Wenting

AU - Fang, Yuxin

AU - Zaytseva, Yekaterina Y.

AU - O’Connor, Kathleen L.

AU - Vander Kooi, Craig W.

AU - Liu, Side

AU - She, Qing Bai

PY - 2019/12/1

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N2 - 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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N-glycosylation-defective splice variants of neuropilin-1 promote metastasis by activating endosomal signals

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

UN SDGs

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