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Nat Commun. 2014 Oct 3;5:4904. doi: 10.1038/ncomms5904.

An endocytosis pathway initiated through neuropilin-1 and regulated by nutrient availability.

Author information

1
Cancer Research Center, Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA.
2
1] Cancer Research Center, Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA [2] Center for Nanomedicine, Department of Cell, Molecular and Developmental Biology, University of California Santa Barbara, Santa Barbara, California 93106-9610, USA.
3
1] Cancer Research Center, Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA [2] Department of Surgery, Columbia University, College of Physicians and Surgeons, New York, New York 10032, USA.
4
1] Cancer Research Center, Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA [2] Laboratory of Cancer Biology, Institute of Biomedicine and Translational Medicine, Centre of Excellence for Translational Medicine, University of Tartu, 50411 Tartu, Estonia.

Abstract

Neuropilins (NRPs) are trans-membrane receptors involved in axon guidance and vascular development. Many growth factors and other signalling molecules bind to NRPs through a carboxy (C)-terminal, basic sequence motif (C-end Rule or CendR motif). Peptides with this motif (CendR peptides) are taken up into cells by endocytosis. Tumour-homing CendR peptides penetrate through tumour tissue and have shown utility in enhancing drug delivery into tumours. Here we show, using RNAi screening and subsequent validation studies, that NRP1-mediated endocytosis of CendR peptides is distinct from known endocytic pathways. Ultrastructurally, CendR endocytosis resembles macropinocytosis, but is mechanistically different. We also show that nutrient-sensing networks such as mTOR signalling regulate CendR endocytosis and subsequent intercellular transport of CendR cargo, both of which are stimulated by nutrient depletion. As CendR is a bulk transport pathway, our results suggest a role for it in nutrient transport; CendR-enhanced drug delivery then makes use of this natural pathway.

PMID:
25277522
PMCID:
PMC4185402
DOI:
10.1038/ncomms5904
[Indexed for MEDLINE]
Free PMC Article

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