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

Hong Bo Pang; Gary B. Braun; Tomas Friman; Pedro Aza-Blanc; Manuel E. Ruidiaz; Kazuki N. Sugahara; Tambet Teesalu; Erkki Ruoslahti

doi:10.1038/ncomms5904

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

Hong Bo Pang, Gary B. Braun, Tomas Friman, Pedro Aza-Blanc, Manuel E. Ruidiaz, Kazuki N. Sugahara, Tambet Teesalu, Erkki Ruoslahti

Pharmaceutics

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

137 Scopus citations

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.

Original language	English (US)
Article number	4904
Journal	Nature communications
Volume	5
DOIs	https://doi.org/10.1038/ncomms5904
State	Published - Oct 3 2014

Bibliographical note

Funding Information:
We thank Drs Marilyn G. Farquhar and Sumit Chanda for comments on the manuscript, Dr Kun-Liang Guan for advice on nutrient regulation and Craig W. Vander Kooi for NRP1 b1b2 cDNA. This work was supported by grant CA152327 and Cancer Center Support grant CA30199 from the NCI. T.T. is supported by Susan Komen for Cure Foundation career development award KG110704. G.B.B. was supported by NIH T32 fellowship (CA121949). T.T. is supported by the European Research Council under the European Union’s Seventh Framework Programme (FP/2007–2013)/ERC Starting Grant Agreement No. 291910. The views and opinions of authors expressed on OER websites do not necessarily state or reflect those of the U.S. Government, and they may not be used for advertising or product endorsement purposes.

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© 2014 Macmillan Publishers Limited. All rights reserved.

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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.",

author = "Pang, {Hong Bo} and Braun, {Gary B.} and Tomas Friman and Pedro Aza-Blanc and Ruidiaz, {Manuel E.} and Sugahara, {Kazuki N.} and Tambet Teesalu and Erkki Ruoslahti",

note = "Funding Information: We thank Drs Marilyn G. Farquhar and Sumit Chanda for comments on the manuscript, Dr Kun-Liang Guan for advice on nutrient regulation and Craig W. Vander Kooi for NRP1 b1b2 cDNA. This work was supported by grant CA152327 and Cancer Center Support grant CA30199 from the NCI. T.T. is supported by Susan Komen for Cure Foundation career development award KG110704. G.B.B. was supported by NIH T32 fellowship (CA121949). T.T. is supported by the European Research Council under the European Union{\textquoteright}s Seventh Framework Programme (FP/2007–2013)/ERC Starting Grant Agreement No. 291910. The views and opinions of authors expressed on OER websites do not necessarily state or reflect those of the U.S. Government, and they may not be used for advertising or product endorsement purposes. Publisher Copyright: {\textcopyright} 2014 Macmillan Publishers Limited. All rights reserved.",

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AU - Sugahara, Kazuki N.

AU - Teesalu, Tambet

AU - Ruoslahti, Erkki

N1 - Funding Information: We thank Drs Marilyn G. Farquhar and Sumit Chanda for comments on the manuscript, Dr Kun-Liang Guan for advice on nutrient regulation and Craig W. Vander Kooi for NRP1 b1b2 cDNA. This work was supported by grant CA152327 and Cancer Center Support grant CA30199 from the NCI. T.T. is supported by Susan Komen for Cure Foundation career development award KG110704. G.B.B. was supported by NIH T32 fellowship (CA121949). T.T. is supported by the European Research Council under the European Union’s Seventh Framework Programme (FP/2007–2013)/ERC Starting Grant Agreement No. 291910. The views and opinions of authors expressed on OER websites do not necessarily state or reflect those of the U.S. Government, and they may not be used for advertising or product endorsement purposes. Publisher Copyright: © 2014 Macmillan Publishers Limited. All rights reserved.

PY - 2014/10/3

Y1 - 2014/10/3

N2 - 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.

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

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