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Semaphorin receptors meet receptor tyrosine kinases on the way of tumor progression

Abstract

Semaphorins are extracellular signals known to guide migrating cells during developmental morphogenesis and in adult tissues. Semaphorin receptors, that is plexins and neuropilins, have been found in association with diverse receptor tyrosine kinases (RTKs), such as Met, ErbB2 and VEGFR2. These receptor complexes are formed in a cell-specific manner and can mediate distinctive signalling cascades, sometimes leading to divergent functional outcomes. This is particularly intriguing in cancer, since the same semaphorin has been found to mediate either tumor-promoting or tumor-suppressing functions, depending on the cancer type and cellular context. We will therefore review the current understanding about the role of RTKs in neuropilin and plexin signalling, putatively accounting for the multifaceted role of semaphorins in cancer.

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References

  1. Kolodkin AL, Matthes DJ, Goodman CS . The semaphorin genes encode a family of transmembrane and secreted growth cone guidance molecules. Cell 1993; 75: 1389–1399.

    CAS  PubMed  Google Scholar 

  2. Kruger RP, Aurandt J, Guan KL . Semaphorins command cells to move. Nat Rev Mol Cell Biol 2005; 6: 789–800.

    CAS  PubMed  Google Scholar 

  3. Tamagnone L . Emerging role of semaphorins as major regulatory signals and potential therapeutic targets in cancer. Cancer Cell 2012; 22: 145–152.

    CAS  PubMed  Google Scholar 

  4. Gherardi E, Love CA, Esnouf RM, Jones EY . The sema domain. Curr Opin Struct Biol 2004; 14: 669–678.

    CAS  PubMed  Google Scholar 

  5. Zhou Y, Gunput RA, Pasterkamp RJ . Semaphorin signaling: progress made and promises ahead. Trends Biochem Sci 2008; 33: 161–170.

    CAS  PubMed  Google Scholar 

  6. Tamagnone L, Comoglio PM . Signalling by semaphorin receptors: cell guidance and beyond. Trends Cell Biol 2000; 10: 377–383.

    CAS  PubMed  Google Scholar 

  7. Hota PK, Buck M . Plexin structures are coming: opportunities for multilevel investigations of semaphorin guidance receptors, their cell signaling mechanisms, and functions. Cell Mol Life Sci 2012; 69: 3765–3805.

    CAS  PubMed  Google Scholar 

  8. Capparuccia L, Tamagnone L . Semaphorin signaling in cancer cells and in cells of the tumor microenvironment—two sides of a coin. J Cell Sci 2009; 122 (Pt 11): 1723–1736.

    CAS  PubMed  Google Scholar 

  9. Rehman M, Tamagnone L . Semaphorins in cancer: biological mechanisms and therapeutic approaches. Semin Cell Dev Biol 2013; 24: 179–189.

    CAS  PubMed  Google Scholar 

  10. Gu C, Giraudo E . The role of semaphorins and their receptors in vascular development and cancer. Exp Cell Res 2013; 319: 1306–1316.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Segarra M, Ohnuki H, Maric D, Salvucci O, Hou X, Kumar A et al. Semaphorin 6A regulates angiogenesis by modulating VEGF signaling. Blood 2012; 120: 4104–4115.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Sierra JR, Corso S, Caione L, Cepero V, Conrotto P, Cignetti A et al. Tumor angiogenesis and progression are enhanced by Sema4D produced by tumor-associated macrophages. J Exp Med 2008; 205: 1673–1685.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Guttmann-Raviv N, Shraga-Heled N, Varshavsky A, Guimaraes-Sternberg C, Kessler O, Neufeld G . Semaphorin-3A and semaphorin-3F work together to repel endothelial cells and to inhibit their survival by induction of apoptosis. J Biol Chem 2007; 282: 26294–26305.

    CAS  PubMed  Google Scholar 

  14. Muratori C, Tamagnone L . Semaphorin signals tweaking the tumor microenvironment. Adv Cancer Res 2012; 114: 59–85.

    CAS  PubMed  Google Scholar 

  15. Oinuma I, Ishikawa Y, Katoh H, Negishi M . The Semaphorin 4D receptor Plexin-B1 is a GTPase activating protein for R-Ras. Science 2004; 305: 862–865.

    CAS  PubMed  Google Scholar 

  16. Uesugi K, Oinuma I, Katoh H, Negishi M . Different requirement for Rnd GTPases of R-Ras GAP activity of Plexin-C1 and Plexin-D1. J Biol Chem 2009; 284: 6743–6751.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Rohm B, Rahim B, Kleiber B, Hovatta I, Puschel AW . The semaphorin 3A receptor may directly regulate the activity of small GTPases. FEBS Lett 2000; 486: 68–72.

    CAS  PubMed  Google Scholar 

  18. Barberis D, Artigiani S, Casazza A, Corso S, Giordano S, Love CA et al. Plexin signaling hampers integrin-based adhesion, leading to Rho-kinase independent cell rounding, and inhibiting lamellipodia extension and cell motility. FASEB J 2004; 18: 592–594.

    CAS  PubMed  Google Scholar 

  19. Wang H, Hota PK, Tong Y, Li B, Shen L, Nedyalkova L et al. Structural basis of Rnd1 binding to plexin Rho GTPase binding domains (RBDs). J Biol Chem 2011; 286: 26093–26106.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Yang T, Terman JR . 14-3-3epsilon Couples Protein Kinase A to Semaphorin Signaling and Silences Plexin RasGAP-Mediated Axonal Repulsion. Neuron 2012; 74: 108–121.

    CAS  PubMed  Google Scholar 

  21. Keely PJ, Rusyn EV, Cox AD, Parise LV . R-Ras signals through specific integrin alpha cytoplasmic domains to promote migration and invasion of breast epithelial cells. J Cell Biol 1999; 145: 1077–1088.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Serini G, Valdembri D, Zanivan S, Morterra G, Burkhardt C, Caccavari F et al. Class 3 semaphorins control vascular morphogenesis by inhibiting integrin function. Nature 2003; 424: 391–397.

    CAS  PubMed  Google Scholar 

  23. Swiercz JM, Kuner R, Behrens J, Offermanns S . Plexin-B1 directly interacts with PDZ-RhoGEF/LARG to regulate RhoA and growth cone morphology. Neuron 2002; 35: 51–63.

    CAS  PubMed  Google Scholar 

  24. Aurandt J, Vikis HG, Gutkind JS, Ahn N, Guan KL . The semaphorin receptor plexin-B1 signals through a direct interaction with the Rho-specific nucleotide exchange factor, LARG. Proc Natl Acad Sci USA 2002; 99: 12085–12090.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Perrot V, Vazquez-Prado J, Gutkind JS . Plexin B regulates Rho through the guanine nucleotide exchange factors leukemia-associated Rho GEF (LARG) and PDZ-RhoGEF. J Biol Chem 2002; 277: 43115–43120.

    CAS  PubMed  Google Scholar 

  26. Franco M, Tamagnone L . Tyrosine phosphorylation in semaphorin signalling: shifting into overdrive. EMBO Rep 2008; 9: 865–871.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Giordano S, Corso S, Conrotto P, Artigiani S, Gilestro G, Barberis D et al. The semaphorin 4D receptor controls invasive growth by coupling with Met. Nat Cell Biol 2002; 4: 720–724.

    CAS  PubMed  Google Scholar 

  28. Valente G, Nicotra G, Arrondini M, Castino R, Capparuccia L, Prat M et al. Co-expression of plexin-B1 and Met in human breast and ovary tumours enhances the risk of progression. Cell Oncol 2009; 31: 423–436.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Conrotto P, Corso S, Gamberini S, Comoglio PM, Giordano S . Interplay between scatter factor receptors and B plexins controls invasive growth. Oncogene 2004; 23: 5131–5137.

    CAS  PubMed  Google Scholar 

  30. Basile JR, Castilho RM, Williams VP, Gutkind JS . Semaphorin 4D provides a link between axon guidance processes and tumor-induced angiogenesis. Proc Natl Acad Sci USA 2006; 103: 9017–9022.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Wong OG, Nitkunan T, Oinuma I, Zhou C, Blanc V, Brown RS et al. Plexin-B1 mutations in prostate cancer. Proc Natl Acad Sci USA 2007; 104: 19040–19045.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Zhou C, Wong OG, Masters JR, Williamson M . Effect of cancer-associated mutations in the PlexinB1 gene. Mol Cancer 2012; 11: 11.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Conrotto P, Valdembri D, Corso S, Serini G, Tamagnone L, Comoglio PM et al. Sema4D induces angiogenesis through Met recruitment by Plexin B1. Blood 2005; 105: 4321–4329.

    CAS  PubMed  Google Scholar 

  34. Rody A, Karn T, Ruckhaberle E, Hanker L, Metzler D, Muller V et al. Loss of Plexin B1 is highly prognostic in low proliferating ER positive breast cancers—results of a large scale microarray analysis. Eur J Cancer 2009; 45: 405–413.

    CAS  PubMed  Google Scholar 

  35. Rody A, Holtrich U, Gaetje R, Gehrmann M, Engels K, von MG et al. Poor outcome in estrogen receptor-positive breast cancers predicted by loss of plexin B1. Clin Cancer Res 2007; 13: 1115–1122.

    CAS  PubMed  Google Scholar 

  36. Argast GM, Croy CH, Couts KL, Zhang Z, Litman E, Chan DC et al. Plexin B1 is repressed by oncogenic B-Raf signaling and functions as a tumor suppressor in melanoma cells. Oncogene 2009; 28: 2697–2709.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Stevens L, McClelland L, Fricke A, Williamson M, Kuo I, Scott G . Plexin B1 suppresses c-Met in melanoma: a role for plexin B1 as a tumor-suppressor protein through regulation of c-Met. J Invest Dermatol 2010; 130: 1636–1645.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Otsuka T, Takayama H, Sharp R, Celli G, LaRochelle WJ, Bottaro DP et al. c-Met autocrine activation induces development of malignant melanoma and acquisition of the metastatic phenotype. Cancer Res 1998; 58: 5157–5167.

    CAS  PubMed  Google Scholar 

  39. Soong J, Chen Y, Shustef EM, Scott GA . Sema4D, the ligand for Plexin B1, suppresses c-Met activation and migration and promotes melanocyte survival and growth. J Invest Dermatol 2012; 132: 1230–1238.

    CAS  PubMed  Google Scholar 

  40. Soong J, Scott G . Plexin B1 inhibits MET through direct association and regulates Shp2 expression in melanocytes. J Cell Sci 2013; 126 (Pt 2): 688–695.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Li G, Schaider H, Satyamoorthy K, Hanakawa Y, Hashimoto K, Herlyn M . Downregulation of E-cadherin and Desmoglein 1 by autocrine hepatocyte growth factor during melanoma development. Oncogene 2001; 20: 8125–8135.

    Article  CAS  PubMed  Google Scholar 

  42. Ridley AJ . Rho family proteins: coordinating cell responses. Trends Cell Biol 2001; 11: 471–477.

    CAS  PubMed  Google Scholar 

  43. Narumiya S, Tanji M, Ishizaki T . Rho signaling, ROCK and mDia1, in transformation, metastasis and invasion. Cancer Metastasis Rev 2009; 28: 65–76.

    CAS  PubMed  Google Scholar 

  44. Routhier A, Astuccio M, Lahey D, Monfredo N, Johnson A, Callahan W et al. Pharmacological inhibition of Rho-kinase signaling with Y-27632 blocks melanoma tumor growth. Oncol Rep 2010; 23: 861–867.

    CAS  PubMed  Google Scholar 

  45. McClelland L, Chen Y, Soong J, Kuo I, Scott G . Plexin B1 inhibits integrin-dependent pp125FAK and Rho activity in melanoma. Pigment Cell Melanoma Res 2011; 24: 165–174.

    CAS  PubMed  Google Scholar 

  46. Swiercz JM, Worzfeld T, Offermanns S . ErbB-2 and met reciprocally regulate cellular signaling via plexin-B1. J Biol Chem 2008; 283: 1893–1901.

    CAS  PubMed  Google Scholar 

  47. Sun T, Krishnan R, Swiercz JM . Grb2 mediates semaphorin-4D-dependent RhoA inactivation. J Cell Sci 2012; 125 (Pt 15): 3557–3567.

    CAS  PubMed  Google Scholar 

  48. Barberis D, Casazza A, Sordella R, Corso S, Artigiani S, Settleman J et al. p190 Rho-GTPase activating protein associates with plexins and it is required for semaphorin signalling. J Cell Sci 2005; 118 (Pt 20): 4689–4700.

    CAS  PubMed  Google Scholar 

  49. Giacobini P, Messina A, Morello F, Ferraris N, Corso S, Penachioni J et al. Semaphorin 4D regulates gonadotropin hormone-releasing hormone-1 neuronal migration through PlexinB1-Met complex. J Cell Biol 2008; 183: 555–566.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Swiercz JM, Kuner R, Offermanns S . Plexin-B1/RhoGEF-mediated RhoA activation involves the receptor tyrosine kinase ErbB-2. J Cell Biol 2004; 165: 869–880.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL . Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 1987; 235: 177–182.

    CAS  PubMed  Google Scholar 

  52. Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 1989; 244: 707–712.

    Article  CAS  PubMed  Google Scholar 

  53. Worzfeld T, Swiercz JM, Looso M, Straub BK, Sivaraj KK, Offermanns S . ErbB-2 signals through Plexin-B1 to promote breast cancer metastasis. J Clin Invest 2012; 122: 1296–1305.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Kluger HM, DiVito K, Berger AJ, Halaban R, Ariyan S, Camp RL et al. Her2/neu is not a commonly expressed therapeutic target in melanoma — a large cohort tissue microarray study. Melanoma Res 2004; 14: 207–210.

    CAS  PubMed  Google Scholar 

  55. van der ZB, Hellemons AJ, Leenders WP, Burbach JP, Brunner HG, Padberg GW et al. PLEXIN-D1, a novel plexin family member, is expressed in vascular endothelium and the central nervous system during mouse embryogenesis. Dev Dyn 2002; 225: 336–343.

    Google Scholar 

  56. Gu C, Yoshida Y, Livet J, Reimert DV, Mann F, Merte J et al. Semaphorin 3E and plexin-D1 control vascular pattern independently of neuropilins. Science 2005; 307: 265–268.

    CAS  PubMed  Google Scholar 

  57. Fukushima Y, Okada M, Kataoka H, Hirashima M, Yoshida Y, Mann F et al. Sema3E-PlexinD1 signaling selectively suppresses disoriented angiogenesis in ischemic retinopathy in mice. J Clin Invest 2011; 121: 1974–1985.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Sakurai A, Gavard J, nnas-Linhares Y, Basile JR, Amornphimoltham P, Palmby TR et al. Semaphorin 3E initiates antiangiogenic signaling through plexin D1 by regulating Arf6 and R-Ras. Mol Cell Biol 2010; 30: 3086–3098.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Sakurai A, Jian X, Lee CJ, Manavski Y, Chavakis E, Donaldson J et al. Phosphatidylinositol-4-phosphate 5-kinase and GEP100/Brag2 protein mediate antiangiogenic signaling by semaphorin 3E-plexin-D1 through Arf6 protein. J Biol Chem 2011; 286: 34335–34345.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Roodink I, Raats J, van der ZB, Verrijp K, Kusters B, van BH et al. Plexin D1 expression is induced on tumor vasculature and tumor cells: a novel target for diagnosis and therapy? Cancer Res 2005; 65: 8317–8323.

    CAS  PubMed  Google Scholar 

  61. Casazza A, Finisguerra V, Capparuccia L, Camperi A, Swiercz JM, Rizzolio S et al. Sema3E-Plexin D1 signaling drives human cancer cell invasiveness and metastatic spreading in mice. J Clin Invest 2010; 120: 2684–2698.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Christensen C, Ambartsumian N, Gilestro G, Thomsen B, Comoglio P, Tamagnone L et al. Proteolytic processing converts the repelling signal Sema3E into an inducer of invasive growth and lung metastasis. Cancer Res 2005; 65: 6167–6177.

    CAS  PubMed  Google Scholar 

  63. Casazza A, Kigel B, Maione F, Capparuccia L, Kessler O, Giraudo E et al. Tumour growth inhibition and anti-metastatic activity of a mutated furin-resistant Semaphorin 3E isoform. EMBO Mol Med 2012; 4: 234–250.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Guttmann-Raviv N, Kessler O, Shraga-Heled N, Lange T, Herzog Y, Neufeld G . The neuropilins and their role in tumorigenesis and tumor progression. Cancer Lett 2006; 231: 1–11.

    CAS  PubMed  Google Scholar 

  65. Pellet-Many C, Frankel P, Jia H, Zachary I . Neuropilins: structure, function and role in disease. Biochem J 2008; 411: 211–226.

    CAS  PubMed  Google Scholar 

  66. Rizzolio S, Tamagnone L . Multifaceted role of neuropilins in cancer. Curr Med Chem 2011; 18: 3563–3575.

    CAS  PubMed  Google Scholar 

  67. Bielenberg DR, Pettaway CA, Takashima S, Klagsbrun M . Neuropilins in neoplasms: expression, regulation, and function. Exp Cell Res 2006; 312: 584–593.

    CAS  PubMed  Google Scholar 

  68. Ellis LM . The role of neuropilins in cancer. Mol Cancer Ther 2006; 5: 1099–1107.

    CAS  PubMed  Google Scholar 

  69. Parikh AA, Liu WB, Fan F, Stoeltzing O, Reinmuth N, Bruns CJ et al. Expression and regulation of the novel vascular endothelial growth factor receptor neuropilin-1 by epidermal growth factor in human pancreatic carcinoma. Cancer 2003; 98: 720–729.

    CAS  PubMed  Google Scholar 

  70. Akagi M, Kawaguchi M, Liu W, McCarty MF, Takeda A, Fan F et al. Induction of neuropilin-1 and vascular endothelial growth factor by epidermal growth factor in human gastric cancer cells. Br J Cancer 2003; 88: 796–802.

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Rizzolio S, Rabinowicz N, Rainero E, Lanzetti L, Serini G, Norman J et al. Neuropilin-1-dependent regulation of EGF-receptor signaling. Cancer Res 2012; 72: 5801–5811.

    CAS  PubMed  Google Scholar 

  72. Hofman EG, Bader AN, Voortman J, van den Heuvel DJ, Sigismund S, Verkleij AJ et al. Ligand-induced EGF receptor oligomerization is kinase-dependent and enhances internalization. J Biol Chem 2010; 285: 39481–39489.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Sorkin A . Internalization of the epidermal growth factor receptor: role in signalling. Biochem Soc Trans 2001; 29 (Pt 4): 480–484.

    CAS  PubMed  Google Scholar 

  74. Sigismund S, Argenzio E, Tosoni D, Cavallaro E, Polo S, Di Fiore PP . Clathrin-mediated internalization is essential for sustained EGFR signaling but dispensable for degradation. Dev Cell 2008; 15: 209–219.

    CAS  PubMed  Google Scholar 

  75. Salikhova A, Wang L, Lanahan AA, Liu M, Simons M, Leenders WP et al. Vascular endothelial growth factor and semaphorin induce neuropilin-1 endocytosis via separate pathways. Circ Res 2008; 103: e71–e79.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Toyofuku T, Zhang H, Kumanogoh A, Takegahara N, Suto F, Kamei J et al. Dual roles of Sema6D in cardiac morphogenesis through region-specific association of its receptor, Plexin-A1, with off-track and vascular endothelial growth factor receptor type 2. Genes Dev 2004; 18: 435–447.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Bellon A, Luchino J, Haigh K, Rougon G, Haigh J, Chauvet S et al. VEGFR2 (KDR/Flk1) signaling mediates axon growth in response to semaphorin 3E in the developing brain. Neuron 2010; 66: 205–219.

    CAS  PubMed  Google Scholar 

  78. Kerbel RS . Tumor angiogenesis. N Engl J Med 2008; 358: 2039–2049.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Catalano A, Lazzarini R, Di NS, Orciari S, Procopio A . The plexin-A1 receptor activates vascular endothelial growth factor-receptor 2 and nuclear factor-kappaB to mediate survival and anchorage-independent growth of malignant mesothelioma cells. Cancer Res 2009; 69: 1485–1493.

    CAS  PubMed  Google Scholar 

  80. Strizzi L, Catalano A, Vianale G, Orecchia S, Casalini A, Tassi G et al. Vascular endothelial growth factor is an autocrine growth factor in human malignant mesothelioma. J Pathol 2001; 193: 468–475.

    CAS  PubMed  Google Scholar 

  81. Suto F, Ito K, Uemura M, Shimizu M, Shinkawa Y, Sanbo M et al. Plexin-a4 mediates axon-repulsive activities of both secreted and transmembrane semaphorins and plays roles in nerve fiber guidance. J Neurosci 2005; 25: 3628–3637.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Kigel B, Rabinowicz N, Varshavsky A, Kessler O, Neufeld G . Plexin-A4 promotes tumor progression and tumor angiogenesis by enhancement of VEGF and bFGF signaling. Blood 2011; 118: 4285–4296.

    CAS  PubMed  Google Scholar 

  83. Dhanabal M, Wu F, Alvarez E, McQueeney KD, Jeffers M, MacDougall J et al. Recombinant semaphorin 6A-1 ectodomain inhibits in vivo growth factor and tumor cell line-induced angiogenesis. Cancer Biol Ther 2005; 4: 659–668.

    CAS  PubMed  Google Scholar 

  84. Soker S, Takashima S, Miao HQ, Neufeld G, Klagsbrun M . Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor. Cell 1998; 92: 735–745.

    CAS  PubMed  Google Scholar 

  85. Fuh G, Garcia KC, de Vos AM . The interaction of neuropilin-1 with vascular endothelial growth factor and its receptor flt-1. J Biol Chem 2000; 275: 26690–26695.

    CAS  PubMed  Google Scholar 

  86. Soker S, Miao HQ, Nomi M, Takashima S, Klagsbrun M . VEGF165 mediates formation of complexes containing VEGFR-2 and neuropilin-1 that enhance VEGF165-receptor binding. J Cell Biochem 2002; 85: 357–368.

    CAS  PubMed  Google Scholar 

  87. Gluzman-Poltorak Z, Cohen T, Herzog Y, Neufeld G . Neuropilin-2 is a receptor for the vascular endothelial growth factor (VEGF) forms VEGF-145 and VEGF-165 [corrected]. J Biol Chem 2000; 275: 18040–18045.

    CAS  PubMed  Google Scholar 

  88. Park JE, Keller GA, Ferrara N . The vascular endothelial growth factor (VEGF) isoforms: differential deposition into the subepithelial extracellular matrix and bioactivity of extracellular matrix-bound VEGF. Mol Biol Cell 1993; 4: 1317–1326.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Makinen T, Olofsson B, Karpanen T, Hellman U, Soker S, Klagsbrun M et al. Differential binding of vascular endothelial growth factor B splice and proteolytic isoforms to neuropilin-1. J Biol Chem 1999; 274: 21217–21222.

    CAS  PubMed  Google Scholar 

  90. Migdal M, Huppertz B, Tessler S, Comforti A, Shibuya M, Reich R et al. Neuropilin-1 is a placenta growth factor-2 receptor. J Biol Chem 1998; 273: 22272–22278.

    CAS  PubMed  Google Scholar 

  91. Karpanen T, Heckman CA, Keskitalo S, Jeltsch M, Ollila H, Neufeld G et al. Functional interaction of VEGF-C and VEGF-D with neuropilin receptors. FASEB J 2006; 20: 1462–1472.

    CAS  PubMed  Google Scholar 

  92. Whitaker GB, Limberg BJ, Rosenbaum JS . Vascular endothelial growth factor receptor-2 and neuropilin-1 form a receptor complex that is responsible for the differential signaling potency of VEGF(165) and VEGF(121). J Biol Chem 2001; 276: 25520–25531.

    CAS  PubMed  Google Scholar 

  93. Prahst C, Heroult M, Lanahan AA, Uziel N, Kessler O, Shraga-Heled N et al. Neuropilin-1-VEGFR-2 complexing requires the PDZ-binding domain of neuropilin-1. J Biol Chem 2008; 283: 25110–25114.

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Cai H, Reed RR . Cloning and characterization of neuropilin-1-interacting protein: a PSD-95/Dlg/ZO-1 domain-containing protein that interacts with the cytoplasmic domain of neuropilin-1. J Neurosci 1999; 19: 6519–6527.

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Horowitz A, Seerapu HR . Regulation of VEGF signaling by membrane traffic. Cell Signal 2012; 24: 1810–1820.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Pan Q, Chanthery Y, Liang WC, Stawicki S, Mak J, Rathore N et al. Blocking neuropilin-1 function has an additive effect with anti-VEGF to inhibit tumor growth. Cancer Cell 2007; 11: 53–67.

    CAS  PubMed  Google Scholar 

  97. Bachelder RE, Crago A, Chung J, Wendt MA, Shaw LM, Robinson G et al. Vascular endothelial growth factor is an autocrine survival factor for neuropilin-expressing breast carcinoma cells. Cancer Res 2001; 61: 5736–5740.

    CAS  PubMed  Google Scholar 

  98. Bachelder RE, Lipscomb EA, Lin X, Wendt MA, Chadborn NH, Eickholt BJ et al. Competing autocrine pathways involving alternative neuropilin-1 ligands regulate chemotaxis of carcinoma cells. Cancer Res 2003; 63: 5230–5233.

    CAS  PubMed  Google Scholar 

  99. Beck B, Driessens G, Goossens S, Youssef KK, Kuchnio A, Caauwe A et al. A vascular niche and a VEGF-Nrp1 loop regulate the initiation and stemness of skin tumours. Nature 2011; 478: 399–403.

    CAS  PubMed  Google Scholar 

  100. Carmeliet P, Moons L, Luttun A, Vincenti V, Compernolle V, De MM et al. Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions. Nat Med 2001; 7: 575–583.

    CAS  PubMed  Google Scholar 

  101. Slongo ML, Molena B, Brunati AM, Frasson M, Gardiman M, Carli M et al. Functional VEGF and VEGF receptors are expressed in human medulloblastomas. Neuro Oncol 2007; 9: 384–392.

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Lassen U, Nielsen DL, Sorensen M, Winstedt L, Niskanen T, Stenberg Y et al. A phase I, dose-escalation study of TB-403, a monoclonal antibody directed against PlGF, in patients with advanced solid tumours. Br J Cancer 2012; 106: 678–684.

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Martinsson-Niskanen T, Riisbro R, Larsson L, Winstedt L, Stenberg Y, Pakola S et al. Monoclonal antibody TB-403: a first-in-human, Phase I, double-blind, dose escalation study directed against placental growth factor in healthy male subjects. Clin Ther 2011; 33: 1142–1149.

    CAS  PubMed  Google Scholar 

  104. Snuderl M, Batista A, Kirkpatrick ND, Ruiz de AC, Riedemann L, Walsh EC et al. Targeting placental growth factor/neuropilin 1 pathway inhibits growth and spread of medulloblastoma. Cell 2013; 152: 1065–1076.

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Yao J, Wu X, Zhuang G, Kasman IM, Vogt T, Phan V et al. Expression of a functional VEGFR-1 in tumor cells is a major determinant of anti-PlGF antibodies efficacy. Proc Natl Acad Sci USA 2011; 108: 11590–11595.

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Bais C, Wu X, Yao J, Yang S, Crawford Y, McCutcheon K et al. PlGF blockade does not inhibit angiogenesis during primary tumor growth. Cell 2010; 141: 166–177.

    CAS  PubMed  Google Scholar 

  107. Lichtenberger BM, Tan PK, Niederleithner H, Ferrara N, Petzelbauer P, Sibilia M . Autocrine VEGF signaling synergizes with EGFR in tumor cells to promote epithelial cancer development. Cell 2010; 140: 268–279.

    CAS  PubMed  Google Scholar 

  108. Rossiter H, Barresi C, Pammer J, Rendl M, Haigh J, Wagner EF et al. Loss of vascular endothelial growth factor a activity in murine epidermal keratinocytes delays wound healing and inhibits tumor formation. Cancer Res 2004; 64: 3508–3516.

    CAS  PubMed  Google Scholar 

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Acknowledgements

The authors wish to thank all Tamagnone lab members, in particular Sabrina Rizzolio for advice and suggestions. Thanks to Francesca Natale for revising the English. Research activity in the author’s lab is supported by the Italian Association for Cancer Research (AIRC, IG-11598), the Italian Ministry for Research (PRIN Grant) and the University of Torino-Compagnia di San Paolo (Grant ORTO11RKTW).

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Correspondence to L Tamagnone.

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Cagnoni, G., Tamagnone, L. Semaphorin receptors meet receptor tyrosine kinases on the way of tumor progression. Oncogene 33, 4795–4802 (2014). https://doi.org/10.1038/onc.2013.474

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  • DOI: https://doi.org/10.1038/onc.2013.474

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