Neuropilin-2 regulates endosome maturation and EGFR trafficking to support cancer cell pathobiology

Samikshan Dutta, Sohini Roy, Navatha S. Polavaram, Marissa J. Stanton, Heyu Zhang, Tanvi Bhola, Pia Hönscheid, Terrence Donohue, Hamid Band, Surinder Kumar Batra, Michael H. Muders, Kaustubh Datta

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Neuropilin-2 (NRP2) is a non-tyrosine kinase receptor frequently overexpressed in various malignancies, where it has been implicated in promotingmany 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-tolate 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.

Original languageEnglish (US)
Pages (from-to)418-428
Number of pages11
JournalCancer Research
Volume76
Issue number2
DOIs
StatePublished - Jan 15 2016

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Neuropilin-2
Endosomes
Neoplasms
Endocytosis
Drug Resistance
Transport Vesicles
Pancreatic Neoplasms
Prostatic Neoplasms
Cell Death
Phosphotransferases

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Neuropilin-2 regulates endosome maturation and EGFR trafficking to support cancer cell pathobiology. / Dutta, Samikshan; Roy, Sohini; Polavaram, Navatha S.; Stanton, Marissa J.; Zhang, Heyu; Bhola, Tanvi; Hönscheid, Pia; Donohue, Terrence; Band, Hamid; Batra, Surinder Kumar; Muders, Michael H.; Datta, Kaustubh.

In: Cancer Research, Vol. 76, No. 2, 15.01.2016, p. 418-428.

Research output: Contribution to journalArticle

Dutta, Samikshan ; Roy, Sohini ; Polavaram, Navatha S. ; Stanton, Marissa J. ; Zhang, Heyu ; Bhola, Tanvi ; Hönscheid, Pia ; Donohue, Terrence ; Band, Hamid ; Batra, Surinder Kumar ; Muders, Michael H. ; Datta, Kaustubh. / Neuropilin-2 regulates endosome maturation and EGFR trafficking to support cancer cell pathobiology. In: Cancer Research. 2016 ; Vol. 76, No. 2. pp. 418-428.
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