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Molecular Cancer
Published in: Molecular Cancer 1/2012

Open Access 01-12-2012 | Research

Effect of cancer-associated mutations in the PlexinB1 gene

Authors: Chun Zhou, Oscar Gee-Wan Wong, John R Masters, Magali Williamson

Published in: Molecular Cancer | Issue 1/2012

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Abstract

Background

Semaphorins act as chemotactic cues for cell movement via their transmembrane receptors, plexins. Somatic missense mutations in the plexinB1 gene coupled with overexpression of the protein frequently occur in prostate tumours, indicating a role for plexinB1 in the pathogenesis of prostate cancer.

Results

Two specific mutations found in prostate cancer enhance RhoD binding and one other mutation results in loss of inhibition of Rac-dependent Pak1 phosphorylation and lamellipodia formation and in impairment of trafficking of plexinB1 to the membrane. None of the three characterised mutations affect PDZRhoGEF binding, RhoA activity, the interaction of plexinB1with the oncogenes ErbB2 or c-Met or ErbB2 phosphorylation. The mutations have the net effect of increasing cell motility by blocking plexinB1-mediated inhibition of Rac while enhancing the interaction with RhoD, an anti-migratory factor.

Conclusions

PlexinB1 mutations block plexinB1-mediated signalling pathways that inhibit cell motility.
Appendix
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Literature
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. 10.1016/0092-8674(93)90625-ZCrossRefPubMed
2.
Tamagnone L, Artigiani S, Chen H, He Z, Ming GI, Song H, Chedotal A, Winberg ML, Goodman CS, Poo M, Tessier-Lavigne M, Comoglio PM: Plexins are a large family of receptors for transmembrane, secreted, and GPI-anchored semaphorins in vertebrates. Cell. 1999, 99: 71-80. 10.1016/S0092-8674(00)80063-XCrossRefPubMed
3.
4.
Trusolino L, Comoglio PM: Scatter-factor and semaphorin receptors: cell signalling for invasive growth. Nat Rev Cancer. 2002, 2: 289-300. 10.1038/nrc779CrossRefPubMed
5.
Serini G, Valdembri D, Zanivan S, Morterra G, Burkhardt C, Caccavari F, Zammataro L, Primo L, Tamagnone L, Logan M, Tessier-Lavigne M, Taniguchi M, Puschel AW, Bussolino F: Class 3 semaphorins control vascular morphogenesis by inhibiting integrin function. Nature. 2003, 424: 391-397. 10.1038/nature01784CrossRefPubMed
6.
Luo Y, Raible D, Raper JA: Collapsin: a protein in brain that induces the collapse and paralysis of neuronal growth cones. Cell. 1993, 75: 217-227. 10.1016/0092-8674(93)80064-LCrossRefPubMed
7.
Neufeld G, Kessler O: The semaphorins: versatile regulators of tumour progression and tumour angiogenesis. Nat Rev Cancer. 2008, 8: 632-645. 10.1038/nrc2404CrossRefPubMed
8.
Eickholt BJ, Mackenzie SL, Graham A, Walsh FS, Doherty P: Evidence for collapsin-1 functioning in the control of neural crest migration in both trunk and hindbrain regions. Development. 1999, 126: 2181-2189.PubMed
9.
Tamamaki N, Fujimori K, Nojyo Y, Kaneko T, Takauji R: Evidence that Sema3A and Sema3F regulate the migration of GABAergic neurons in the developing neocortex. J Comp Neurol. 2003, 455: 238-248. 10.1002/cne.10476CrossRefPubMed
10.
Kumanogoh A, Kikutani H: Roles of the semaphorin family in immune regulation. Adv Immunol. 2003, 81: 173-198.CrossRefPubMed
11.
Polleux F, Giger RJ, Ginty DD, Kolodkin AL, Ghosh A: Patterning of cortical efferent projections by semaphorin-neuropilin interactions. Science. 1998, 282: 1904-1906.CrossRefPubMed
12.
Marin O, Yaron A, Bagri A, Tessier-Lavigne M, Rubenstein JL: Sorting of striatal and cortical interneurons regulated by semaphorin-neuropilin interactions. Science. 2001, 293: 872-875. 10.1126/science.1061891CrossRefPubMed
13.
Kagoshima M, Ito T: Diverse gene expression and function of semaphorins in developing lung: positive and negative regulatory roles of semaphorins in lung branching morphogenesis. Genes Cells. 2001, 6: 559-571. 10.1046/j.1365-2443.2001.00441.xCrossRefPubMed
14.
Korostylev A, Worzfeld T, Deng S, Friedel RH, Swiercz JM, Vodrazka P, Maier V, Hirschberg A, Ohoka Y, Inagaki S, Offermanns S, Kuner R: A functional role for semaphorin 4D/plexin B1 interactions in epithelial branching morphogenesis during organogenesis. Development. 2008, 135: 3333-3343. 10.1242/dev.019760CrossRefPubMed
15.
Behar O, Golden JA, Mashimo H, Schoen FJ, Fishman MC: Semaphorin III is needed for normal patterning and growth of nerves, bones and heart. Nature. 1996, 383: 525-528. 10.1038/383525a0CrossRefPubMed
16.
Toyofuku T, Zhang H, Kumanogoh A, Takegahara N, Suto F, Kamei J, Aoki K, Yabuki M, Hori M, Fujisawa H, Kikutani H: 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. 10.1101/gad.1167304PubMedCentralCrossRefPubMed
17.
Chen H, He Z, Tessier-Lavigne M: Axon guidance mechanisms: semaphorins as simultaneous repellents and anti-repellents. Nat Neurosci. 1998, 1: 436-439. 10.1038/2154CrossRefPubMed
18.
Chen H, He Z, Bagri A, Tessier-Lavigne M: Semaphorin-neuropilin interactions underlying sympathetic axon responses to class III semaphorins. Neuron. 1998, 21: 1283-1290. 10.1016/S0896-6273(00)80648-0CrossRefPubMed
19.
Driessens MH, Hu H, Nobes CD, Self A, Jordens I, Goodman CS, Hall A: Plexin-B semaphorin receptors interact directly with active Rac and regulate the actin cytoskeleton by activating Rho. Curr Biol. 2001, 11: 339-344. 10.1016/S0960-9822(01)00092-6CrossRefPubMed
20.
Vikis HG, Li W, He Z, Guan KL: The semaphorin receptor plexin-B1 specifically interacts with active Rac in a ligand-dependent manner. Proc Natl Acad Sci USA. 2000, 97: 12457-12462. 10.1073/pnas.220421797PubMedCentralCrossRefPubMed
21.
Vikis HG, Li W, Guan KL: The plexin-B1/Rac interaction inhibits PAK activation and enhances Sema4D ligand binding. Genes Dev. 2002, 16: 836-845. 10.1101/gad.966402PubMedCentralCrossRefPubMed
22.
Oinuma I, Katoh H, Harada A, Negishi M: Direct interaction of Rnd1 with Plexin-B1 regulates PDZ-RhoGEF-mediated Rho activation by Plexin-B1 and induces cell contraction in COS-7 cells. J Biol Chem. 2003, 278: 25671-25677. 10.1074/jbc.M303047200CrossRefPubMed
23.
Tong Y, Chugha P, Hota PK, Alviani RS, Li M, Tempel W, Shen L, Park HW, Buck M: Binding of Rac1, Rnd1, and RhoD to a novel Rho GTPase interaction motif destabilizes dimerization of the plexin-B1 effector domain. J Biol Chem. 2007, 282: 37215-37224. 10.1074/jbc.M703800200PubMedCentralCrossRefPubMed
24.
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. 10.1126/science.1097545CrossRefPubMed
25.
Oinuma I, Katoh H, Negishi M: Semaphorin 4D/Plexin-B1-mediated R-Ras GAP activity inhibits cell migration by regulating beta(1) integrin activity. J Cell Biol. 2006, 173: 601-613. 10.1083/jcb.200508204PubMedCentralCrossRefPubMed
26.
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. 10.1016/S0896-6273(02)00750-XCrossRefPubMed
27.
Barberis D, Casazza A, Sordella R, Corso S, Artigiani S, Settleman J, Comoglio PM, Tamagnone L: p190 Rho-GTPase activating protein associates with plexins and it is required for semaphorin signalling. J Cell Sci. 2005, 118: 4689-4700. 10.1242/jcs.02590CrossRefPubMed
28.
Giordano S, Corso S, Conrotto P, Artigiani S, Gilestro G, Barberis D, Tamagnone L, Comoglio PM: The semaphorin 4D receptor controls invasive growth by coupling with Met. Nat Cell Biol. 2002, 4: 720-724. 10.1038/ncb843CrossRefPubMed
29.
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. 10.1083/jcb.200312094PubMedCentralCrossRefPubMed
30.
Swiercz JM, Worzfeld T, Offermanns S: Semaphorin 4D signaling requires the recruitment of phospholipase Cgamma into the plexin-B1 receptor complex. Mol Cell Biol. 2009, 29: 6321-6334. 10.1128/MCB.00103-09PubMedCentralCrossRefPubMed
31.
Swiercz JM, Worzfeld T, Offermanns S: ErbB-2 and met reciprocally regulate cellular signaling via plexin-B1. J Biol Chem. 2008, 283: 1893-1901.CrossRefPubMed
32.
Tong Y, Hota PK, Penachioni JY, Hamaneh MB, Kim S, Alviani RS, Shen L, He H, Tempel W, Tamagnone L, Park HW, Buck M: Structure and function of the intracellular region of the plexin-b1 transmembrane receptor. J Biol Chem. 2009, 284: 35962-35972. 10.1074/jbc.M109.056275PubMedCentralCrossRefPubMed
33.
Bell CH, Aricescu AR, Jones EY, Siebold CA: Dual binding mode for RhoGTPases in plexin signalling. PLoS Biol. 2011, 9: e1001134- 10.1371/journal.pbio.1001134PubMedCentralCrossRefPubMed
34.
Wong OG, Nitkunan T, Oinuma I, Zhou C, Blanc V, Brown RS, Bott SR, Nariculam J, Box G, Munson P, Constantinou J, Feneley MR, Klocker H, Eccles SA, Negishi M, Freeman A, Masters JR, Williamson M: Plexin-B1 mutations in prostate cancer. Proc Natl Acad Sci USA. 2007, 104: 19040-19045. 10.1073/pnas.0702544104PubMedCentralCrossRefPubMed
35.
Tong Y, Hota PK, Hamaneh MB, Buck M: Insights into oncogenic mutations of plexin-B1 based on the solution structure of the Rho GTPase binding domain. Structure. 2008, 16: 246-258. 10.1016/j.str.2007.12.012PubMedCentralCrossRefPubMed
36.
Nikolic M, Chou MM, Lu W, Mayer BJ, Tsai LH: The p35/Cdk5 kinase is a neuron-specific Rac effector that inhibits Pak1 activity. Nature. 1998, 395: 194-198. 10.1038/26034CrossRefPubMed
37.
Wang H, Hota PK, Tong Y, Li B, Shen L, Nedyalkova L, Borthakur S, Kim S, Tempel W, Buck M, Park HW: Structural basis of Rnd1 binding to plexin Rho GTPase binding domains (RBDs). J Biol Chem. 2011, 286: 26093-26106. 10.1074/jbc.M110.197053PubMedCentralCrossRefPubMed
38.
Zanata SM, Hovatta I, Rohm B, Puschel AW: Antagonistic effects of Rnd1 and RhoD GTPases regulate receptor activity in Semaphorin 3A-induced cytoskeletal collapse. J Neurosci. 2002, 22: 471-477.PubMed
39.
Tsubakimoto K, Matsumoto K, Abe H, Ishii J, Amano M, Kaibuchi K, Endo T: Small GTPase RhoD suppresses cell migration and cytokinesis. Oncogene. 1999, 18: 2431-2440. 10.1038/sj.onc.1202604CrossRefPubMed
Metadata
Title
Effect of cancer-associated mutations in the PlexinB1 gene
Authors
Chun Zhou
Oscar Gee-Wan Wong
John R Masters
Magali Williamson
Publication date
01-12-2012
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2012
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/1476-4598-11-11

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