title: Neuropilin-1 exerts co-receptor function for TGF-beta-1 on the membrane of cancer cells and enhances responses to both latent and active TGF-beta.
abstract: Neuropilin (Nrp)-1 and Nrp-2 are multifunctional proteins frequently expressed by cancer cells and contribute to tumor progression by mechanisms that are not well understood. They are co-receptors for vascular endothelial growth factor and class 3 semaphorins, but recently we found that Nrp1 also binds latent and active transforming growth factor (TGF)-β1, and activates the latent form latency-associated peptide (LAP)-TGF-β1. Here, we report that Nrp1 has affinity for TGF-β receptors TβRI and TβRII, the signaling TGF-β receptors, as well as TβRIII (betaglycan), as determined in binding assays, pull down assays and confocal microscopy. Nrp1 had a higher affinity for TβRI than TβRII and could form a complex with these receptors. In breast cancer cells, Nrp1 and TβRI cointernalized in the presence of TGF-β1. Nrp1 acted as a TGF-β co-receptor by augmenting canonical Smad2/3 signaling. Importantly, Nrp-positive cancer cells, unlike negative cells, were able to activate latent TGF-β1 and respond. We examined two other membrane proteins that bind LAP-TGF-β, i.e. an RGD-binding integrin (αvβ3) and Glycoprotein A repetitions predominant (CLRRC32). RGD-binding integrins are frequently expressed by cancer cells, and glycoprotein A repetitions predominant is expressed by activated regulatory T cells that appear linked to poor tumor immunity. In vitro, these receptors did not activate LAP-TGF-β1, but subsequent addition of Nrp1 activated the cytokine. Thus, Nrp1 might collaborate with other latent TGF-β receptors in TGF-β capture and activation. We also show that Nrp2 has activities similar to Nrp1. We conclude that Nrp1 is a co-receptor for TGF-β1 and augments responses to latent and active TGF-β. Since TGF-β promotes metastasis this is highly relevant to cancer biology.
authors.affiliation: Department of Laboratory Medicine and Keenan Research Center in the Li Ka Shing Knowledge Institute, St Michael's Hospital, Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada M5B 1W8.
authors.forename: Yelena
authors.initials: Y
authors.lastname: Glinka
authors.forename: Snejana
authors.initials: S
authors.lastname: Stoilova
authors.forename: Nada
authors.initials: N
authors.lastname: Mohammed
authors.forename: Gérald J
authors.initials: GJ
authors.lastname: Prud'homme
mesh_terms: D045744:Cell Line, Tumor; D006801:Humans; D009369:Neoplasms / Q000378:metabolism*; D039942:Neuropilin-1 / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011509:Proteoglycans / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D015398:Signal Transduction; D051785:Smad Proteins / Q000502:physiology; D053773:Transforming Growth Factor beta1 / Q000502:physiology*
chemical_list: D011509:Proteoglycans; D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; D053773:Transforming Growth Factor beta1; D039942:Neuropilin-1; C071736:betaglycan; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II