title: An endocytosis pathway initiated through neuropilin-1 and regulated by nutrient availability.
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.
authors.affiliation: Cancer Research Center, Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA.
authors.forename: Hong-Bo
authors.initials: HB
authors.lastname: Pang
authors.affiliation: 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.
authors.forename: Gary B
authors.initials: GB
authors.lastname: Braun
authors.affiliation: 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.
authors.forename: Tomas
authors.initials: T
authors.lastname: Friman
authors.affiliation: Cancer Research Center, Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA.
authors.forename: Pedro
authors.initials: P
authors.lastname: Aza-Blanc
authors.affiliation: Cancer Research Center, Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA.
authors.forename: Manuel E
authors.initials: ME
authors.lastname: Ruidiaz
authors.affiliation: 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.
authors.forename: Kazuki N
authors.initials: KN
authors.lastname: Sugahara
authors.affiliation: 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.
authors.forename: Tambet
authors.initials: T
authors.lastname: Teesalu
authors.affiliation: 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.
authors.forename: Erkki
authors.initials: E
authors.lastname: Ruoslahti
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D016503:Drug Delivery Systems; D004705:Endocytosis; D005502:Food; D006046:Gold / Q000737:chemistry; D006367:HeLa Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008024:Ligands; D008297:Male; D053768:Metal Nanoparticles / Q000737:chemistry; D051379:Mice; D008856:Microscopy, Fluorescence; D009368:Neoplasm Transplantation; D039942:Neuropilin-1 / Q000502:physiology*; D010455:Peptides / Q000737:chemistry; D010873:Pinocytosis; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D012834:Silver / Q000737:chemistry
chemical_list: D008024:Ligands; D010455:Peptides; D039942:Neuropilin-1; D012834:Silver; D006046:Gold