Plexin-B1 mutations in prostate cancer.
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.
Wong
Oscar Gee-Wan
OG
Prostate Cancer Research Centre, Institute of Urology, University College London, 67 Riding House Street, London W1W 7EJ, United Kingdom.
Nitkunan
Tharani
T
Oinuma
Izumi
I
Zhou
Chun
C
Blanc
Veronique
V
Brown
Richard S D
RS
Bott
Simon R J
SR
Nariculam
Joseph
J
Box
Gary
G
Munson
Phillipa
P
Constantinou
Jason
J
Feneley
Mark R
MR
Klocker
Helmut
H
Eccles
Suzanne A
SA
Negishi
Manabu
M
Freeman
Alex
A
Masters
John R
JR
Williamson
Magali
M
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
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