title: Plexin-B1 mutations in prostate cancer.
abstract: Semaphorins are a large class of secreted or membrane-associated proteins that act as chemotactic cues for cell movement via their transmembrane receptors, plexins. We hypothesized that the function of the semaphorin signaling pathway in the control of cell migration could be harnessed by cancer cells during invasion and metastasis. We now report 13 somatic missense mutations in the cytoplasmic domain of the Plexin-B1 gene. Mutations were found in 89% (8 of 9) of prostate cancer bone metastases, in 41% (7 of 17) of lymph node metastases, and in 46% (41 of 89) of primary cancers. Forty percent of prostate cancers contained the same mutation. Overexpression of the Plexin-B1 protein was found in the majority of primary tumors. The mutations hinder Rac and R-Ras binding and R-RasGAP activity, resulting in an increase in cell motility, invasion, adhesion, and lamellipodia extension. These results identify a key role for Plexin-B1 and the semaphorin signaling pathway it mediates in prostate cancer.
authors.affiliation: Prostate Cancer Research Centre, Institute of Urology, University College London, 67 Riding House Street, London W1W 7EJ, United Kingdom.
authors.forename: Oscar Gee-Wan
authors.initials: OG
authors.lastname: Wong
authors.forename: Tharani
authors.initials: T
authors.lastname: Nitkunan
authors.forename: Izumi
authors.initials: I
authors.lastname: Oinuma
authors.forename: Chun
authors.initials: C
authors.lastname: Zhou
authors.forename: Veronique
authors.initials: V
authors.lastname: Blanc
authors.forename: Richard S D
authors.initials: RS
authors.lastname: Brown
authors.forename: Simon R J
authors.initials: SR
authors.lastname: Bott
authors.forename: Joseph
authors.initials: J
authors.lastname: Nariculam
authors.forename: Gary
authors.initials: G
authors.lastname: Box
authors.forename: Phillipa
authors.initials: P
authors.lastname: Munson
authors.forename: Jason
authors.initials: J
authors.lastname: Constantinou
authors.forename: Mark R
authors.initials: MR
authors.lastname: Feneley
authors.forename: Helmut
authors.initials: H
authors.lastname: Klocker
authors.forename: Suzanne A
authors.initials: SA
authors.lastname: Eccles
authors.forename: Manabu
authors.initials: M
authors.lastname: Negishi
authors.forename: Alex
authors.initials: A
authors.lastname: Freeman
authors.forename: John R
authors.initials: JR
authors.lastname: Masters
authors.forename: Magali
authors.initials: M
authors.lastname: Williamson
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology / Q000556:secondary; D001859:Bone Neoplasms / Q000235:genetics / Q000556:secondary; D002448:Cell Adhesion / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008207:Lymphatic Metastasis / Q000235:genetics; D008297:Male; D020125:Mutation, Missense; D009361:Neoplasm Invasiveness / Q000235:genetics; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D018807:Polymorphism, Single-Stranded Conformational; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D017434:Protein Structure, Tertiary; D011554:Pseudopodia / Q000648:ultrastructure; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D015398:Signal Transduction; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
chemical_list: D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; C492119:PLXNB1 protein, human; C107953:RAC1 protein, human; D011956:Receptors, Cell Surface; C085929:RRAS protein, human; D020830:rac1 GTP-Binding Protein; D018631:ras Proteins