title: Neuropilin-2 Regulates Endosome Maturation and EGFR Trafficking to Support Cancer Cell Pathobiology.
abstract: Neuropilin-2 (NRP2) is a non-tyrosine kinase receptor frequently overexpressed in various malignancies, where it has been implicated in promoting many protumorigenic behaviors, such as imparting therapeutic resistance to metastatic cancer cells. Here, we report a novel function of NRP2 as a regulator of endocytosis, which is enhanced in cancer cells and is often associated with increased metastatic potential and drug resistance. We found that NRP2 depletion in human prostate and pancreatic cancer cells resulted in the accumulation of EEA1/Rab5-positive early endosomes concomitant with a decrease in Rab7-positive late endosomes, suggesting a delay in early-to-late endosome maturation. NRP2 depletion also impaired the endocytic transport of cell surface EGFR, arresting functionally active EGFR in endocytic vesicles that consequently led to aberrant ERK activation and cell death. Mechanistic investigations revealed that WD-repeat- and FYVE-domain-containing protein 1 (WDFY1) functioned downstream of NRP2 to promote endosome maturation, thereby influencing the endosomal trafficking of EGFR and the formation of autolysosomes responsible for the degradation of internalized cargo. Overall, our results indicate that the NRP2/WDFY1 axis is required for maintaining endocytic activity in cancer cells, which supports their oncogenic activities and confers drug resistance. Therefore, therapeutically targeting endocytosis may represent an attractive strategy to selectively target cancer cells in multiple malignancies.
authors.affiliation: Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Samikshan
authors.initials: S
authors.lastname: Dutta
authors.affiliation: Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Sohini
authors.initials: S
authors.lastname: Roy
authors.affiliation: Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Navatha S
authors.initials: NS
authors.lastname: Polavaram
authors.affiliation: Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Marissa J
authors.initials: MJ
authors.lastname: Stanton
authors.affiliation: Department of Urologic Research, Biochemistry, Mayo Clinic College of Medicine, Rochester, Minnesota.
authors.forename: Heyu
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Tanvi
authors.initials: T
authors.lastname: Bhola
authors.affiliation: Institute of Pathology, University Hospital Carl Gustav Carus, TU, Dresden, Germany.
authors.forename: Pia
authors.initials: P
authors.lastname: Hönscheid
authors.affiliation: Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska. Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska. Omaha VA Medical Center, Omaha, Nebraska.
authors.forename: Terrence M
authors.initials: TM
authors.lastname: Donohue
authors.affiliation: Buffett Cancer Center, Eppley Cancer Institute, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Hamid
authors.initials: H
authors.lastname: Band
authors.affiliation: Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska. Buffett Cancer Center, Eppley Cancer Institute, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Surinder K
authors.initials: SK
authors.lastname: Batra
authors.affiliation: Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska. Institute of Pathology, University Hospital Carl Gustav Carus, TU, Dresden, Germany.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Muders
authors.affiliation: Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska. Buffett Cancer Center, Eppley Cancer Institute, University of Nebraska Medical Center, Omaha, Nebraska. kaustubh.datta@unmc.edu.
authors.forename: Kaustubh
authors.initials: K
authors.lastname: Datta
mesh_terms: D045744:Cell Line, Tumor; D011992:Endosomes / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D039943:Neuropilin-2 / Q000235:genetics* / Q000378:metabolism*
chemical_list: D039943:Neuropilin-2; D066246:ErbB Receptors