title: Neuropilin-1-dependent regulation of EGF-receptor signaling.
abstract: Neuropilin-1 (NRP1) is a coreceptor for multiple extracellular ligands. NRP1 is widely expressed in cancer cells and in advanced human tumors; however, its functional relevance and signaling mechanisms are unclear. Here, we show that NRP1 expression controls viability and proliferation of different cancer cells, independent of its short intracellular tail. We found that the extracellular domain of NRP1 interacts with the EGF receptor (EGFR) and promotes its signaling cascade elicited upon EGF or TGF-α stimulation. Upon NRP1 silencing, the ability of ligand-bound EGFR to cluster on the cell surface, internalize, and activate the downstream AKT pathway is severely impaired. EGFR is frequently activated in human tumors due to overexpression, mutation, or sustained autocrine/paracrine stimulation. Here we show that NRP1-blocking antibodies and NRP1 silencing can counteract ligand-induced EGFR activation in cancer cells. Thus our findings unveil a novel molecular mechanism by which NRP1 can control EGFR signaling and tumor growth.
authors.affiliation: Institute for Cancer Research at Candiolo, IRC@C, and University of Torino Medical School, Candiolo, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Rizzolio
authors.forename: Noa
authors.initials: N
authors.lastname: Rabinowicz
authors.forename: Elena
authors.initials: E
authors.lastname: Rainero
authors.forename: Letizia
authors.initials: L
authors.lastname: Lanzetti
authors.forename: Guido
authors.initials: G
authors.lastname: Serini
authors.forename: Jim
authors.initials: J
authors.lastname: Norman
authors.forename: Gera
authors.initials: G
authors.lastname: Neufeld
authors.forename: Luca
authors.initials: L
authors.lastname: Tamagnone
mesh_terms: D000818:Animals; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D004705:Endocytosis; D066246:ErbB Receptors / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D039942:Neuropilin-1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D015398:Signal Transduction; D014162:Transfection; D014183:Transplantation, Heterologous
chemical_list: D034741:RNA, Small Interfering; D039942:Neuropilin-1; D066246:ErbB Receptors