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.
Bibliographical noteFunding 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.