Abstract
The neuropilins (Nrps) interact with a number of growth factors (GFs) and/or their receptors. This includes vascular endothelial growth factor (VEGF), transforming growth factor β1 (TGF-β1), hepatocyte growth factor (HGF), platelet-derived growth factor (PDGF), and epidermal growth factor receptor (EGFR). These interactions can involve one or both homologues, Nrp1 and Nrp2, and generally enhance the response to these GFs. Here, we will review non-VEGF interactions, with emphasis on TGF-β. We found that both Nrp1 and Nrp2 bind active TGF-β1 and its latent form denoted latency associated peptide (LAP)-TGF-β1. The Nrps also bind to the signaling TGF-β receptors (TβRI and TβRII) and the co-receptor betaglycan (TβRIII). Studies by us and others established that Nrp1 and Nrp2 augment TGF-β canonical (Smad2/3-dependent) or noncanonical signaling. This was observed in fibroblasts, hepatic stellate cells, lymphocytes, endothelial cells, cardiomyocytes, and several types of cancer cells. TGF-β1-mediated effects that were reduced by Nrp1 or Nrp2 knockdown and/or enhanced by their overexpression include collagen production, epithelial-to-mesenchymal transition (EMT), endothelial-to-mesenchymal transition (EndMT), cancer cell activities (e.g., migration and invasion), and regulatory T-cell-mediated suppression. TGF-β markedly upregulated the expression of Nrp2 on cancer cells, which promoted EMT. Conventional CD4+ T lymphocytes induced to express Nrp1 acquired immunosuppressive activity. These effects appear cell type and context dependent, and in some cases Nrps did not enhance or reduced canonical signaling. In conclusion, the Nrps impact on the stimulatory capacity of TGF-β and other GFs, and this is relevant to angiogenesis, wound healing, cancer biology, immunity, and other processes. As such, the Nrps are important targets for drug development.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Prud’homme GJ, Glinka Y (2012) Neuropilins are multifunctional coreceptors involved in tumor initiation, growth, metastasis and immunity. Oncotarget 3(9):921–939
Goel HL, Mercurio AM (2013) VEGF targets the tumour cell. Nat Rev Cancer 13(12):871–882
Wild JR, Staton CA, Chapple K, Corfe BM (2012) Neuropilins: expression and roles in the epithelium. Int J Exp Pathol 93(2):81–103
Jubb AM, Strickland LA, Liu SD, Mak J, Schmidt M, Koeppen H (2012) Neuropilin-1 expression in cancer and development. J Pathol 226(1):50–60
Jubb AM, Sa SM, Ratti N, Strickland LA, Schmidt M, Callahan CA, Koeppen H (2012) Neuropilin-2 expression in cancer. Histopathology 61(3):340–349
Bielenberg DR, Pettaway CA, Takashima S, Klagsbrun M (2006) Neuropilins in neoplasms: expression, regulation, and function. Exp Cell Res 312(5):584–593
Ellis LM (2006) The role of neuropilins in cancer. Mol Cancer Ther 5(5):1099–1107
Bagri A, Tessier-Lavigne M, Watts RJ (2009) Neuropilins in tumor biology. Clin Cancer Res (An Official Journal of the American Association for Cancer Research) 15(6):1860–1864
Guttmann-Raviv N, Kessler O, Shraga-Heled N, Lange T, Herzog Y, Neufeld G (2006) The neuropilins and their role in tumorigenesis and tumor progression. Cancer Lett 231(1):1–11
Glinka Y, Prud’homme GJ (2008) Neuropilin-1 is a receptor for transforming growth factor beta-1, activates its latent form, and promotes regulatory T cell activity. J Leukoc Biol 84(1):302–310
Glinka Y, Stoilova S, Mohammed N, Prud’homme GJ (2011) 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. Carcinogenesis 32(4):613–621
Cao Y, Szabolcs A, Dutta SK, Yaqoob U, Jagavelu K, Wang L, Leof EB, Urrutia RA, Shah VH, Mukhopadhyay D (2010) Neuropilin-1 mediates divergent R-Smad signaling and the myofibroblast phenotype. J Biol Chem 285(41):31840–31848
Grandclement C, Pallandre JR, Valmary Degano S, Viel E, Bouard A, Balland J, Remy-Martin JP, Simon B, Rouleau A, Boireau W et al (2011) Neuropilin-2 expression promotes TGF-beta1-mediated epithelial to mesenchymal transition in colorectal cancer cells. PLoS One 6(7):e20444
West DC, Rees CG, Duchesne L, Patey SJ, Terry CJ, Turnbull JE, Delehedde M, Heegaard CW, Allain F, Vanpouille C et al (2005) Interactions of multiple heparin binding growth factors with neuropilin-1 and potentiation of the activity of fibroblast growth factor-2. J Biol Chem 280(14):13457–13464
Matsushita A, Gotze T, Korc M (2007) Hepatocyte growth factor-mediated cell invasion in pancreatic cancer cells is dependent on neuropilin-1. Cancer Res 67(21):10309–10316
Evans IM, Yamaji M, Britton G, Pellet-Many C, Lockie C, Zachary IC, Frankel P (2011) Neuropilin-1 signaling through p130Cas tyrosine phosphorylation is essential for growth factor-dependent migration of glioma and endothelial cells. Mol Cell Biol 31(6):1174–1185
Cao S, Yaqoob U, Das A, Shergill U, Jagavelu K, Huebert RC, Routray C, Abdelmoneim S, Vasdev M, Leof E et al (2010) Neuropilin-1 promotes cirrhosis of the rodent and human liver by enhancing PDGF/TGF-beta signaling in hepatic stellate cells. J Clin Invest 120(7):2379–2394
Pellet-Many C, Frankel P, Evans IM, Herzog B, Junemann-Ramirez M, Zachary IC (2011) Neuropilin-1 mediates PDGF stimulation of vascular smooth muscle cell migration and signalling via p130Cas. Biochem J 435(3):609–618
Rizzolio S, Rabinowicz N, Rainero E, Lanzetti L, Serini G, Norman J, Neufeld G, Tamagnone L (2012) Neuropilin-1-dependent regulation of EGF-receptor signaling. Cancer Res 72(22):5801–5811
Castellani V, Chedotal A, Schachner M, Faivre-Sarrailh C, Rougon G (2000) Analysis of the L1-deficient mouse phenotype reveals cross-talk between Sema3A and L1 signaling pathways in axonal guidance. Neuron 27(2):237–249
Castellani V, Falk J, Rougon G (2004) Semaphorin3A-induced receptor endocytosis during axon guidance responses is mediated by L1 CAM. Mol Cell Neurosci 26(1):89–100
Hsieh SH, Ying NW, Wu MH, Chiang WF, Hsu CL, Wong TY, Jin YT, Hong TM, Chen YL (2008) Galectin-1, a novel ligand of neuropilin-1, activates VEGFR-2 signaling and modulates the migration of vascular endothelial cells. Oncogene 27(26):3746–3753
Ghez D, Lepelletier Y, Lambert S, Fourneau JM, Blot V, Janvier S, Arnulf B, van Endert PM, Heveker N, Pique C et al (2006) Neuropilin-1 is involved in human T-cell lymphotropic virus type 1 entry. J Virol 80(14):6844–6854
Yaqoob U, Cao S, Shergill U, Jagavelu K, Geng Z, Yin M, de Assuncao TM, Cao Y, Szabolcs A, Thorgeirsson S et al (2012) Neuropilin-1 stimulates tumor growth by increasing fibronectin fibril assembly in the tumor microenvironment. Cancer Res 72(16):4047–4059
Valdembri D, Caswell PT, Anderson KI, Schwarz JP, Konig I, Astanina E, Caccavari F, Norman JC, Humphries MJ, Bussolino F et al (2009) Neuropilin-1/GIPC1 signaling regulates alpha5beta1 integrin traffic and function in endothelial cells. PLoS Biol 7(1):e25
Fukasawa M, Matsushita A, Korc M (2007) Neuropilin-1 interacts with integrin beta1 and modulates pancreatic cancer cell growth, survival and invasion. Cancer Biol Ther 6(8):1173–1180
Robinson SD, Reynolds LE, Kostourou V, Reynolds AR, da Silva RG, Tavora B, Baker M, Marshall JF, Hodivala-Dilke KM (2009) Alphav beta3 integrin limits the contribution of neuropilin-1 to vascular endothelial growth factor-induced angiogenesis. J Biol Chem 284(49):33966–33981
Teesalu T, Sugahara KN, Kotamraju VR, Ruoslahti E (2009) C-end rule peptides mediate neuropilin-1-dependent cell, vascular, and tissue penetration. Proc Natl Acad Sci U S A 106(38):16157–16162
Sugahara KN, Teesalu T, Karmali PP, Kotamraju VR, Agemy L, Greenwald DR, Ruoslahti E (2010) Coadministration of a tumor-penetrating peptide enhances the efficacy of cancer drugs. Science 328(5981):1031–1035
Sugahara KN, Teesalu T, Karmali PP, Kotamraju VR, Agemy L, Girard OM, Hanahan D, Mattrey RF, Ruoslahti E (2009) Tissue-penetrating delivery of compounds and nanoparticles into tumors. Cancer Cell 16(6):510–520
Haspel N, Zanuy D, Nussinov R, Teesalu T, Ruoslahti E, Aleman C (2011) Binding of a C-end rule peptide to the neuropilin-1 receptor: a molecular modeling approach. Biochemistry 50(10):1755–1762
Roth L, Agemy L, Kotamraju VR, Braun G, Teesalu T, Sugahara KN, Hamzah J, Ruoslahti E (2012) Transtumoral targeting enabled by a novel neuropilin-binding peptide. Oncogene 31(33):3754–3763
Hong TM, Chen YL, Wu YY, Yuan A, Chao YC, Chung YC, Wu MH, Yang SC, Pan SH, Shih JY et al (2007) Targeting neuropilin 1 as an antitumor strategy in lung cancer. Clin Cancer Res (An Official Journal of the American Association for Cancer Research) 13(16):4759–4768
Barr MP, Byrne AM, Duffy AM, Condron CM, Devocelle M, Harriott P, Bouchier-Hayes DJ, Harmey JH (2005) A peptide corresponding to the neuropilin-1-binding site on VEGF(165) induces apoptosis of neuropilin-1-expressing breast tumour cells. Br J Cancer 92(2):328–333
Starzec A, Vassy R, Martin A, Lecouvey M, Di Benedetto M, Crepin M, Perret GY (2006) Antiangiogenic and antitumor activities of peptide inhibiting the vascular endothelial growth factor binding to neuropilin-1. Life Sci 79(25):2370–2381
Jia H, Cheng L, Tickner M, Bagherzadeh A, Selwood D, Zachary I (2010) Neuropilin-1 antagonism in human carcinoma cells inhibits migration and enhances chemosensitivity. Br J Cancer 102(3):541–552
Karjalainen K, Jaalouk DE, Bueso-Ramos CE, Zurita AJ, Kuniyasu A, Eckhardt BL, Marini FC, Lichtiger B, O’Brien S, Kantarjian HM et al (2011) Targeting neuropilin-1 in human leukemia and lymphoma. Blood 117(3):920–927
Pang HB, Braun GB, Ruoslahti E (2015) Neuropilin-1 and heparan sulfate proteoglycans cooperate in cellular uptake of nanoparticles functionalized by cationic cell-penetrating peptides. Sci Adv 1(10):e1500821
Sugahara KN, Braun GB, de Mendoza TH, Kotamraju VR, French RP, Lowy AM, Teesalu T, Ruoslahti E (2015) Tumor-penetrating iRGD peptide inhibits metastasis. Mol Cancer Ther 14(1):120–128
Pang HB, Braun GB, Friman T, Aza-Blanc P, Ruidiaz ME, Sugahara KN, Teesalu T, Ruoslahti E (2014) An endocytosis pathway initiated through neuropilin-1 and regulated by nutrient availability. Nat Commun 5:4904
Teesalu T, Sugahara KN, Ruoslahti E (2013) Tumor-penetrating peptides. Front Oncol 3:216
Prud’homme GJ (2007) Pathobiology of transforming growth factor beta in cancer, fibrosis and immunologic disease, and therapeutic considerations. Lab Investig (A Journal of Technical Methods and Pathology) 87(11):1077–1091
Groppe J, Hinck CS, Samavarchi-Tehrani P, Zubieta C, Schuermann JP, Taylor AB, Schwarz PM, Wrana JL, Hinck AP (2008) Cooperative assembly of TGF-beta superfamily signaling complexes is mediated by two disparate mechanisms and distinct modes of receptor binding. Mol Cell 29(2):157–168
Huang T, David L, Mendoza V, Yang Y, Villarreal M, De K, Sun L, Fang X, Lopez-Casillas F, Wrana JL et al (2011) TGF-beta signalling is mediated by two autonomously functioning TbetaRI:TbetaRII pairs. EMBO J 30(7):1263–1276
Moustakas A, Heldin CH (2013) Coordination of TGF-beta signaling by ubiquitylation. Mol Cell 51(5):555–556
Meyer AE, Mythreye K, Blobe GC (2013) Emerging roles of TGF-β co-receptors in human disease. In: Moustakas A, Miyazawa K (eds) TGF-β in human disease. Springer, Tokyo, pp 59–89
Tazat K, Hector-Greene M, Blobe GC, Henis YI (2015) TbetaRIII independently binds type I and type II TGF-beta receptors to inhibit TGF-beta signaling. Mol Biol Cell 26(19):3535–3545
Gonzalez-Nunez M, Munoz-Felix JM, Lopez-Novoa JM (2013) The ALK-1/Smad1 pathway in cardiovascular physiopathology. A new target for therapy? Biochim Biophys Acta 1832(10):1492–1510
Goumans MJ, Carvalho R, Mummery C, ten Dijke P (2008) The TGF-β family in endothelial cell differentiation and cardiovascular development and function. In: Derynck R, Miyazono K (eds) The TGF-β family. Cold Spring Harbor Laboratory Press, New York, pp 761–788
Pomeraniec L, Hector-Greene M, Ehrlich M, Blobe GC, Henis YI (2015) Regulation of TGF-beta receptor hetero-oligomerization and signaling by endoglin. Mol Biol Cell 26(17):3117–3127
Zhang YE (2009) Non-Smad pathways in TGF-beta signaling. Cell Res 19(1):128–139
Landstrom M (2010) The TAK1-TRAF6 signalling pathway. Int J Biochem Cell Biol 42(5):585–589
Heldin CH (2013) Transforming growth factor-β signaling. In: Moustakas A, Miyazawa K (eds) TGF-β in human disease. Springer, Tokyo, pp 3–32
Bruder D, Probst-Kepper M, Westendorf AM, Geffers R, Beissert S, Loser K, von Boehmer H, Buer J, Hansen W (2004) Neuropilin-1: a surface marker of regulatory T cells. Eur J Immunol 34(3):623–630
Hirota S, Clements TP, Tang LK, Morales JE, Lee HS, Oh SP, Rivera GM, Wagner DS, McCarty JH (2015) Neuropilin 1 balances beta8 integrin-activated TGFbeta signaling to control sprouting angiogenesis in the brain. Development 142(24):4363–4373
Wang R, Zhu J, Dong X, Shi M, Lu C, Springer TA (2012) GARP regulates the bioavailability and activation of TGFbeta. Mol Biol Cell 23(6):1129–1139
Robertson IB, Horiguchi M, Zilberberg L, Dabovic B, Hadjiolova K, Rifkin DB (2015) Latent TGF-beta-binding proteins. Matrix Biol (Journal of the International Society for Matrix Biology) 47:44–53
Probst-Kepper M, Geffers R, Kroger A, Viegas N, Erck C, Hecht HJ, Lunsdorf H, Roubin R, Moharregh-Khiabani D, Wagner K et al (2009) GARP: a key receptor controlling FOXP3 in human regulatory T cells. J Cell Mol Med 13(9B):3343–3357
Tran DQ, Andersson J, Wang R, Ramsey H, Unutmaz D, Shevach EM (2009) GARP (LRRC32) is essential for the surface expression of latent TGF-beta on platelets and activated FOXP3+ regulatory T cells. Proc Natl Acad Sci U S A 106(32):13445–13450
Wang R, Kozhaya L, Mercer F, Khaitan A, Fujii H, Unutmaz D (2009) Expression of GARP selectively identifies activated human FOXP3+ regulatory T cells. Proc Natl Acad Sci U S A 106(32):13439–13444
Stockis J, Colau D, Coulie PG, Lucas S (2009) Membrane protein GARP is a receptor for latent TGF-beta on the surface of activated human Treg. Eur J Immunol 39(12):3315–3322
Sheppard D (2005) Integrin-mediated activation of latent transforming growth factor beta. Cancer Metastasis Rev 24(3):395–402
Young GD, Murphy-Ullrich JE (2004) Molecular interactions that confer latency to transforming growth factor-beta. J Biol Chem 279(36):38032–38039
Shi M, Zhu J, Wang R, Chen X, Mi L, Walz T, Springer TA (2011) Latent TGF-beta structure and activation. Nature 474(7351):343–349
Wipff PJ, Hinz B (2008) Integrins and the activation of latent transforming growth factor beta1 – an intimate relationship. Eur J Cell Biol 87(8–9):601–615
Travis MA, Sheppard D (2014) TGF-beta activation and function in immunity. Annu Rev Immunol 32:51–82
Matkar PN, Singh KK, Rudenko D, Kim YJ, Kuliszewski MA, Prud’homme GJ, Hedley DW, Leong-Poi H (2016) Novel regulatory role of neuropilin-1 in endothelial-to-mesenchymal transition and fibrosis in pancreatic ductal adenocarcinoma. Oncotarget 7(43):69489–69506
Wang Y, Cao Y, Yamada S, Thirunavukkarasu M, Nin V, Joshi M, Rishi MT, Bhattacharya S, Camacho-Pereira J, Sharma AK et al (2015) Cardiomyopathy and worsened ischemic heart failure in SM22-alpha cre-mediated Neuropilin-1 null mice: dysregulation of PGC1alpha and mitochondrial homeostasis. Arterioscler Thromb Vasc Biol 35(6):1401–1412
Nasarre P, Gemmill RM, Potiron VA, Roche J, Lu X, Baron AE, Korch C, Garrett-Mayer E, Lagana A, Howe PH et al (2013) Neuropilin-2 Is upregulated in lung cancer cells during TGF-beta1-induced epithelial-mesenchymal transition. Cancer Res 73(23):7111–7121
Aspalter IM, Gordon E, Dubrac A, Ragab A, Narloch J, Vizan P, Geudens I, Collins RT, Franco CA, Abrahams CL et al (2015) Alk1 and Alk5 inhibition by Nrp1 controls vascular sprouting downstream of Notch. Nat Commun 6:7264
Thijssen VL, Heusschen R, Caers J, Griffioen AW (2015) Galectin expression in cancer diagnosis and prognosis: a systematic review. Biochim Biophys Acta 1855(2):235–247
Hokama A, Mizoguchi E, Mizoguchi A (2008) Roles of galectins in inflammatory bowel disease. World J Gastroenterol 14(33):5133–5137
Rabinovich GA, Baum LG, Tinari N, Paganelli R, Natoli C, Liu FT, Iacobelli S (2002) Galectins and their ligands: amplifiers, silencers or tuners of the inflammatory response? Trends Immunol 23(6):313–320
Smetana K Jr, Szabo P, Gal P, Andre S, Gabius HJ, Kodet O, Dvorankova B (2015) Emerging role of tissue lectins as microenvironmental effectors in tumors and wounds. Histol Histopathol 30(3):293–309
Lin YT, Chen JS, Wu MH, Hsieh IS, Liang CH, Hsu CL, Hong TM, Chen YL (2015) Galectin-1 accelerates wound healing by regulating the neuropilin-1/Smad3/NOX4 pathway and ROS production in myofibroblasts. J Invest Dermatol 135(1):258–268
Miyauchi JT, Chen D, Choi M, Nissen JC, Shroyer KR, Djordevic S, Zachary IC, Selwood D, Tsirka SE (2016) Ablation of neuropilin 1 from glioma-associated microglia and macrophages slows tumor progression. Oncotarget 7(9):9801–9814
Thiery JP, Acloque H, Huang RY, Nieto MA (2009) Epithelial-mesenchymal transitions in development and disease. Cell 139(5):871–890
Kalluri R, Neilson EG (2003) Epithelial-mesenchymal transition and its implications for fibrosis. J Clin Invest 112(12):1776–1784
Lin RL, Zhao LJ (2015) Mechanistic basis and clinical relevance of the role of transforming growth factor-beta in cancer. Cancer Biol Med 12(4):385–393
Papageorgis P (2015) TGFbeta signaling in tumor initiation, epithelial-to-mesenchymal transition, and metastasis. J Oncol 2015:587193
Fuxe J, Vincent T, Garcia de Herreros A (2010) Transcriptional crosstalk between TGF-beta and stem cell pathways in tumor cell invasion: role of EMT promoting Smad complexes. Cell Cycle 9(12):2363–2374
Bianchi A, Gervasi ME, Bakin A (2010) Role of beta5-integrin in epithelial-mesenchymal transition in response to TGF-beta. Cell Cycle 9(8):1647–1659
Adham SA, Al Harrasi I, Al Haddabi I, Al Rashdi A, Al Sinawi S, Al Maniri A, Ba-Omar T, Coomber BL (2014) Immunohistological insight into the correlation between neuropilin-1 and epithelial-mesenchymal transition markers in epithelial ovarian cancer. J Histochem Cytochem (Official Journal of the Histochemistry Society) 62(9):619–631
Chu W, Song X, Yang X, Ma L, Zhu J, He M, Wang Z, Wu Y (2014) Neuropilin-1 promotes epithelial-to-mesenchymal transition by stimulating nuclear factor-kappa B and is associated with poor prognosis in human oral squamous cell carcinoma. PLoS One 9(7):e101931
Wittmann P, Grubinger M, Groger C, Huber H, Sieghart W, Peck-Radosavljevic M, Mikulits W (2015) Neuropilin-2 induced by transforming growth factor-beta augments migration of hepatocellular carcinoma cells. BMC Cancer 15(1):909
Fischer KR, Durrans A, Lee S, Sheng J, Li F, Wong ST, Choi H, El Rayes T, Ryu S, Troeger J et al (2015) Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance. Nature 527(7579):472–476
Zheng X, Carstens JL, Kim J, Scheible M, Kaye J, Sugimoto H, Wu CC, LeBleu VS, Kalluri R (2015) Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature 527(7579):525–530
Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, Brooks M, Reinhard F, Zhang CC, Shipitsin M et al (2008) The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133(4):704–715
Ma JL, Zeng S, Zhang Y, Deng GL, Shen H (2015) Epithelial-mesenchymal transition plays a critical role in drug resistance of hepatocellular carcinoma cells to oxaliplatin. Tumour Biol (The Journal of the International Society for Oncodevelopmental Biology and Medicine) 37(5):6177–6184
Potenta S, Zeisberg E, Kalluri R (2008) The role of endothelial-to-mesenchymal transition in cancer progression. Br J Cancer 99(9):1375–1379
Thiery JP, Sleeman JP (2006) Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol 7(2):131–142
Piera-Velazquez S, Li Z, Jimenez SA (2011) Role of endothelial-mesenchymal transition (EndoMT) in the pathogenesis of fibrotic disorders. Am J Pathol 179(3):1074–1080
Zeisberg EM, Potenta S, Xie L, Zeisberg M, Kalluri R (2007) Discovery of endothelial to mesenchymal transition as a source for carcinoma-associated fibroblasts. Cancer Res 67(21):10123–10128
Fukahi K, Fukasawa M, Neufeld G, Itakura J, Korc M (2004) Aberrant expression of neuropilin-1 and -2 in human pancreatic cancer cells. Clin Cancer Res (An Official Journal of the American Association for Cancer Research) 10(2):581–590
Hansel DE, Wilentz RE, Yeo CJ, Schulick RD, Montgomery E, Maitra A (2004) Expression of neuropilin-1 in high-grade dysplasia, invasive cancer, and metastases of the human gastrointestinal tract. Am J Surg Pathol 28(3):347–356
Ballmer-Hofer K, Andersson AE, Ratcliffe LE, Berger P (2011) Neuropilin-1 promotes VEGFR-2 trafficking through Rab11 vesicles thereby specifying signal output. Blood 118(3):816–826
Siemion IZ, Kluczyk A (1999) Tuftsin: on the 30-year anniversary of Victor Najjar’s discovery. Peptides 20(5):645–674
von Wronski MA, Raju N, Pillai R, Bogdan NJ, Marinelli ER, Nanjappan P, Ramalingam K, Arunachalam T, Eaton S, Linder KE et al (2006) Tuftsin binds neuropilin-1 through a sequence similar to that encoded by exon 8 of vascular endothelial growth factor. J Biol Chem 281(9):5702–5710
Kamarulzaman EE, Vanderesse R, Gazzali AM, Barberi-Heyob M, Boura C, Frochot C, Shawkataly O, Aubry A, Wahab HA (2016) Molecular modelling, synthesis and biological evaluation of peptide inhibitors as anti-angiogenic agent targeting Neuropilin-1 for anticancer application. J Biomol Struct Dyn 23:1–49
Vander Kooi CW, Jusino MA, Perman B, Neau DB, Bellamy HD, Leahy DJ (2007) Structural basis for ligand and heparin binding to neuropilin B domains. Proc Natl Acad Sci U S A 104(15):6152–6157
Parker MW, Xu P, Li X, Vander Kooi CW (2012) Structural basis for selective vascular endothelial growth factor-A (VEGF-A) binding to neuropilin-1. J Biol Chem 287(14):11082–11089
Nissen JC, Selwood DL, Tsirka SE (2013) Tuftsin signals through its receptor neuropilin-1 via the transforming growth factor beta pathway. J Neurochem 127(3):394–402
Romeo PH, Lemarchandel V, Tordjman R (2002) Neuropilin-1 in the immune system. Adv Exp Med Biol 515:49–54
Corbel C, Lemarchandel V, Thomas-Vaslin V, Pelus AS, Agboton C, Romeo PH (2007) Neuropilin 1 and CD25 co-regulation during early murine thymic differentiation. Dev Comp Immunol 31(11):1082–1094
Lepelletier Y, Smaniotto S, Hadj-Slimane R, Villa-Verde DM, Nogueira AC, Dardenne M, Hermine O, Savino W (2007) Control of human thymocyte migration by Neuropilin-1/Semaphorin-3A-mediated interactions. Proc Natl Acad Sci U S A 104(13):5545–5550
Mendes-da-Cruz DA, Lepelletier Y, Brignier AC, Smaniotto S, Renand A, Milpied P, Dardenne M, Hermine O, Savino W (2009) Neuropilins, semaphorins, and their role in thymocyte development. Ann N Y Acad Sci 1153:20–28
Mendes-da-Cruz DA, Linhares-Lacerda L, Smaniotto S, Dardenne M, Savino W (2012) Semaphorins and neuropilins: new players in the neuroendocrine control of the intrathymic T-cell migration in humans. Exp Physiol 97(11):1146–1150
Tordjman R, Lepelletier Y, Lemarchandel V, Cambot M, Gaulard P, Hermine O, Romeo PH (2002) A neuronal receptor, neuropilin-1, is essential for the initiation of the primary immune response. Nat Immunol 3(5):477–482
Dzionek A, Inagaki Y, Okawa K, Nagafune J, Rock J, Sohma Y, Winkels G, Zysk M, Yamaguchi Y, Schmitz J (2002) Plasmacytoid dendritic cells: from specific surface markers to specific cellular functions. Hum Immunol 63(12):1133–1148
Grage-Griebenow E, Loseke S, Kauth M, Gehlhar K, Zawatzky R, Bufe A (2007) Anti-BDCA-4 (neuropilin-1) antibody can suppress virus-induced IFN-alpha production of plasmacytoid dendritic cells. Immunol Cell Biol 85(5):383–390
Battaglia A, Buzzonetti A, Monego G, Peri L, Ferrandina G, Fanfani F, Scambia G, Fattorossi A (2008) Neuropilin-1 expression identifies a subset of regulatory T cells in human lymph nodes that is modulated by preoperative chemoradiation therapy in cervical cancer. Immunology 123(1):129–138
Tran DQ, Shevach EM (2009) Therapeutic potential of FOXP3(+) regulatory T cells and their interactions with dendritic cells. Hum Immunol 70(5):294–299
Yadav M, Louvet C, Davini D, Gardner JM, Martinez-Llordella M, Bailey-Bucktrout S, Anthony BA, Sverdrup FM, Head R, Kuster DJ et al (2012) Neuropilin-1 distinguishes natural and inducible regulatory T cells among regulatory T cell subsets in vivo. J Exp Med 209(10):1713–1722 S1711–1719
Weiss JM, Bilate AM, Gobert M, Ding Y, Curotto de Lafaille MA, Parkhurst CN, Xiong H, Dolpady J, Frey AB, Ruocco MG et al (2012) Neuropilin 1 is expressed on thymus-derived natural regulatory T cells, but not mucosa-generated induced Foxp3+ T reg cells. J Exp Med 209(10):1723–1742 S1721
Milpied P, Renand A, Bruneau J, Mendes-da-Cruz DA, Jacquelin S, Asnafi V, Rubio MT, MacIntyre E, Lepelletier Y, Hermine O (2009) Neuropilin-1 is not a marker of human Foxp3+ Treg. Eur J Immunol 39(6):1466–1471
Solomon BD, Mueller C, Chae WJ, Alabanza LM, Bynoe MS (2011) Neuropilin-1 attenuates autoreactivity in experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A 108(5):2040–2045
Delgoffe GM, Woo SR, Turnis ME, Gravano DM, Guy C, Overacre AE, Bettini ML, Vogel P, Finkelstein D, Bonnevier J et al (2013) Stability and function of regulatory T cells is maintained by a neuropilin-1-semaphorin-4a axis. Nature 501(7466):252–256
Chaudhary B, Elkord E (2015) Novel expression of Neuropilin 1 on human tumor-infiltrating lymphocytes in colorectal cancer liver metastases. Expert Opin Ther Targets 19(2):147–161
Battaglia A, Buzzonetti A, Martinelli E, Fanelli M, Petrillo M, Ferrandina G, Scambia G, Fattorossi A (2010) Selective changes in the immune profile of tumor-draining lymph nodes after different neoadjuvant chemoradiation regimens for locally advanced cervical cancer. Int J Radiat Oncol Biol Phys 76(5):1546–1553
Battaglia A, Buzzonetti A, Baranello C, Ferrandina G, Martinelli E, Fanfani F, Scambia G, Fattorossi A (2009) Metastatic tumour cells favour the generation of a tolerogenic milieu in tumour draining lymph node in patients with early cervical cancer. Cancer Immunol Immunother (CII) 58(9):1363–1373
Rizzolio S, Tamagnone L (2011) Multifaceted role of neuropilins in cancer. Curr Med Chem 18(23):3563–3575
Grandclement C, Borg C (2011) Neuropilins: a new target for cancer therapy. Cancers 3(2):1899–1928
Narimatsu M, Samavarchi-Tehrani P, Varelas X, Wrana JL (2015) Distinct polarity cues direct Taz/Yap and TGFbeta receptor localization to differentially control TGFbeta-induced Smad signaling. Dev Cell 32(5):652–656
Hiemer SE, Szymaniak AD, Varelas X (2014) The transcriptional regulators TAZ and YAP direct transforming growth factor beta-induced tumorigenic phenotypes in breast cancer cells. J Biol Chem 289(19):13461–13474
Zachary IC (2011) How neuropilin-1 regulates receptor tyrosine kinase signalling: the knowns and known unknowns. Biochem Soc Trans 39(6):1583–1591
Cabodi S, del Pilar C-LM, Di Stefano P, Defilippi P (2010) Integrin signalling adaptors: not only figurants in the cancer story. Nat Rev Cancer 10(12):858–870
Kim W, Seok Kang Y, Soo Kim J, Shin NY, Hanks SK, Song WK (2008) The integrin-coupled signaling adaptor p130Cas suppresses Smad3 function in transforming growth factor-beta signaling. Mol Biol Cell 19(5):2135–2146
Wendt MK, Smith JA, Schiemann WP (2009) p130Cas is required for mammary tumor growth and transforming growth factor-beta-mediated metastasis through regulation of Smad2/3 activity. J Biol Chem 284(49):34145–34156
Ge X, Milenkovic L, Suyama K, Hartl T, Purzner T, Winans A, Meyer T, Scott MP (2015) Phosphodiesterase 4D acts downstream of Neuropilin to control Hedgehog signal transduction and the growth of medulloblastoma. Elife 4:e07068
Hillman RT, Feng BY, Ni J, Woo WM, Milenkovic L, Hayden Gephart MG, Teruel MN, Oro AE, Chen JK, Scott MP (2011) Neuropilins are positive regulators of Hedgehog signal transduction. Genes Dev 25(22):2333–2346
Hayden Gephart MG, Su YS, Bandara S, Tsai FC, Hong J, Conley N, Rayburn H, Milenkovic L, Meyer T, Scott MP (2013) Neuropilin-2 contributes to tumorigenicity in a mouse model of Hedgehog pathway medulloblastoma. J Neurooncol 115(2):161–168
Goel HL, Pursell B, Standley C, Fogarty K, Mercurio AM (2012) Neuropilin-2 regulates alpha6beta1 integrin in the formation of focal adhesions and signaling. J Cell Sci 125(Pt 2):497–506
Cao Y, Wang L, Nandy D, Zhang Y, Basu A, Radisky D, Mukhopadhyay D (2008) Neuropilin-1 upholds dedifferentiation and propagation phenotypes of renal cell carcinoma cells by activating Akt and sonic hedgehog axes. Cancer Res 68(21):8667–8672
Beck B, Driessens G, Goossens S, Youssef KK, Kuchnio A, Caauwe A, Sotiropoulou PA, Loges S, Lapouge G, Candi A et al (2011) A vascular niche and a VEGF-Nrp1 loop regulate the initiation and stemness of skin tumours. Nature 478(7369):399–403
Prud’homme GJ (2012) Cancer stem cells and novel targets for antitumor strategies. Curr Pharm Des 18(19):2838–2849
Dragu DL, Necula LG, Bleotu C, Diaconu CC, Chivu-Economescu M (2015) Therapies targeting cancer stem cells: current trends and future challenges. World J Stem Cells 7(9):1185–1201
Khan IN, Al-Karim S, Bora RS, Chaudhary AG, Saini KS (2015) Cancer stem cells: a challenging paradigm for designing targeted drug therapies. Drug Discov Today 20(10):1205–1216
Qiu H, Fang X, Luo Q, Ouyang G (2015) Cancer stem cells: a potential target for cancer therapy. Cell Mol Life Sci (CMLS) 72(18):3411–3424
Glinka Y, Mohammed N, Subramaniam V, Jothy S, Prud’homme GJ (2012) Neuropilin-1 is expressed by breast cancer stem-like cells and is linked to NF-kappaB activation and tumor sphere formation. Biochem Biophys Res Commun 425(4):775–780
Lambert S, Bouttier M, Vassy R, Seigneuret M, Petrow-Sadowski C, Janvier S, Heveker N, Ruscetti FW, Perret G, Jones KS et al (2009) HTLV-1 uses HSPG and neuropilin-1 for entry by molecular mimicry of VEGF165. Blood 113(21):5176–5185
Gurrola GB, Capes EM, Zamudio FZ, Possani LD, Valdivia HH (2010) Imperatoxin A, a Cell-Penetrating Peptide from Scorpion Venom, as a Probe of Ca-Release Channels/Ryanodine Receptors. Pharmaceuticals(Basel) 3(4):1093–1107
Acknowledgments
Our studies were supported by Ontario Institute for Cancer Research (Province of Ontario, Canada), the Canadian Institutes of Health Research, the Canadian Breast Cancer Research Alliance, the Juvenile Diabetes Research Foundation International, the Keenan Centre for Biomedical Science of St. Michael’s Hospital (Toronto, Canada), an equipment grant from the Canadian Foundation for Innovation (Ottawa, Ontario, Canada), and a grant from the Krembil Foundation. PNM is a recipient of the Peterborough K. M. Hunter Charitable Foundation Graduate Award, Faculty of Medicine, University of Toronto. HL-P is supported by the Brazilian Ball Chair in Cardiovascular Research from St. Michael’s Hospital, University of Toronto, and by an Early Researcher Award from the Ministry of Research and Innovation, Ontario, Canada.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2017 Springer International Publishing AG
About this chapter
Cite this chapter
Prud’homme, G.J., Glinka, Y., Matkar, P.N., Leong-Poi, H. (2017). The Role of Neuropilins in TGF-β Signaling and Cancer Biology. In: Neufeld, G., Kessler, O. (eds) The Neuropilins: Role and Function in Health and Disease. Springer, Cham. https://doi.org/10.1007/978-3-319-48824-0_11
Download citation
DOI: https://doi.org/10.1007/978-3-319-48824-0_11
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-48822-6
Online ISBN: 978-3-319-48824-0
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)