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Molecular Cancer

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Open Access 01-12-2008 | Research

Myeloproliferative disorder FOP-FGFR1 fusion kinase recruits phosphoinositide-3 kinase and phospholipase Cγ at the centrosome

Authors: Hélène Lelièvre, Véronique Chevrier, Anne-Marie Tassin, Daniel Birnbaum

Published in: Molecular Cancer | Issue 1/2008

Abstract

Background

The t(6;8) translocation found in rare and agressive myeloproliferative disorders results in a chimeric gene encoding the FOP-FGFR1 fusion protein. This protein comprises the N-terminal region of the centrosomal protein FOP and the tyrosine kinase of the FGFR1 receptor. FOP-FGFR1 is localized at the centrosome where it exerts a constitutive kinase activity.

Results

We show that FOP-FGFR1 interacts with the large centrosomal protein CAP350 and that CAP350 is necessary for FOP-FGFR1 localisation at centrosome. FOP-FGFR1 activates the phosphoinositide-3 kinase (PI3K) pathway. We show that p85 interacts with tyrosine 475 of FOP-FGFR1, which is located in a YXXM consensus binding sequence for an SH2 domain of p85. This interaction is in part responsible for PI3K activation. Ba/F3 cells that express FOP-FGFR1 mutated at tyrosine 475 have reduced proliferative ability. Treatment with PI3K pathway inhibitors induces death of FOP-FGFR1 expressing cells. FOP-FGFR1 also recruits phospholipase Cγ1 (PLCγ1) at the centrosome. We show that this enzyme is recruited by FOP-FGFR1 at the centrosome during interphase.

Conclusion

These results delineate a particular type of oncogenic mechanism by which an ectopic kinase recruits its substrates at the centrosome whence unappropriate signaling induces continuous cell growth and MPD.

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Popovici C, Roubin R, Coulier F, Birnbaum D: An evolutionary history of the FGF superfamily. Bioessays. 2005, 27: 849-857.CrossRefPubMed

Demiroglu A, Steer EJ, Heath C, Taylor K, Bentley M, Allen SL, Koduru P, Brody JP, Hawson G, Rodwell R, Doody ML, Carnicero F, Reiter A, Goldman JM, Melo JV, Cross NC: The t(8;22) in chronic myeloid leukemia fuses BCR to FGFR1: transforming activity and specific inhibition of FGFR1 fusion proteins. Blood. 2001, 98: 3778-3783.CrossRefPubMed

Guasch G, Mack GJ, Popovici C, Dastugue N, Birnbaum D, Rattner JB, Pebusque MJ: FGFR1 is fused to the centrosome-associated protein CEP110 in the 8p12 stem cell myeloproliferative disorder with t(8;9)(p12;q33). Blood. 2000, 95: 1788-1796.PubMed

Guasch G, Popovici C, Mugneret F, Chaffanet M, Pontarotti P, Birnbaum D, Pebusque MJ: Endogenous retroviral sequence is fused to FGFR1 kinase in the 8p12 stem-cell myeloproliferative disorder with t(8;19)(p12;q13.3). Blood. 2003, 101: 286-288.CrossRefPubMed

Popovici C, Zhang B, Gregoire MJ, Jonveaux P, Lafage-Pochitaloff M, Birnbaum D, Pebusque MJ: The t(6;8)(q27;p11) translocation in a stem cell myeloproliferative disorder fuses a novel gene, FOP, to fibroblast growth factor receptor 1. Blood. 1999, 93: 1381-1389.PubMed

Walz C, Chase A, Schoch C, Weisser A, Schlegel F, Hochhaus A, Fuchs R, Schmitt-Graff A, Hehlmann R, Cross NC, Reiter A: The t(8;17)(p11;q23) in the 8p11 myeloproliferative syndrome fuses MYO18A to FGFR1. Leukemia. 2005, 19: 1005-1009.CrossRefPubMed

Belloni E, Trubia M, Gasparini P, Micucci C, Tapinassi C, Confalonieri S, Nuciforo P, Martino B, Lo-Coco F, Pelicci PG, Di Fiore PP: 8p11 myeloproliferative syndrome with a novel t(7;8) translocation leading to fusion of the FGFR1 and TIF1 genes. Genes Chromosomes Cancer. 2005, 42: 320-325.CrossRefPubMed

Popovici C, Adelaide J, Ollendorff V, Chaffanet M, Guasch G, Jacrot M, Leroux D, Birnbaum D, Pebusque MJ: Fibroblast growth factor receptor 1 is fused to FIM in stem-cell myeloproliferative disorder with t(8;13). Proc Natl Acad Sci U S A. 1998, 95: 5712-5717.PubMedCentralCrossRefPubMed

Guasch G, Ollendorff V, Borg JP, Birnbaum D, Pebusque MJ: 8p12 stem cell myeloproliferative disorder: the FOP-fibroblast growth factor receptor 1 fusion protein of the t(6;8) translocation induces cell survival mediated by mitogen-activated protein kinase and phosphatidylinositol 3-kinase/Akt/mTOR pathways. Mol Cell Biol. 2001, 21: 8129-8142.PubMedCentralCrossRefPubMed

10.

Rordorf-Nikolic T, Van Horn DJ, Chen D, White MF, Backer JM: Regulation of phosphatidylinositol 3'-kinase by tyrosyl phosphoproteins. Full activation requires occupancy of both SH2 domains in the 85-kDa regulatory subunit. J Biol Chem. 1995, 270: 3662-3666.CrossRefPubMed

11.

Andersen JS, Wilkinson CJ, Mayor T, Mortensen P, Nigg EA, Mann M: Proteomic characterization of the human centrosome by protein correlation profiling. Nature. 2003, 426: 570-574.CrossRefPubMed

12.

Yan X, Habedanck R, Nigg EA: A complex of two centrosomal proteins, CAP350 and FOP, cooperates with EB1 in microtubule anchoring. Mol Biol Cell. 2006, 17: 634-644.PubMedCentralCrossRefPubMed

13.

Delaval B, Letard S, Lelievre H, Chevrier V, Daviet L, Dubreuil P, Birnbaum D: Oncogenic tyrosine kinase of malignant hemopathy targets the centrosome. Cancer Res. 2005, 65: 7231-7240.CrossRefPubMed

14.

Delaval B, Lelievre H, Birnbaum D: Myeloproliferative disorders: the centrosome connection. Leukemia. 2005, 19: 1739-1744.CrossRefPubMed

15.

Doxsey S, Zimmerman W, Mikule K: Centrosome control of the cell cycle. Trends Cell Biol. 2005, 15: 303-311.CrossRefPubMed

16.

Chevrier V, Piel M, Collomb N, Saoudi Y, Frank R, Paintrand M, Narumiya S, Bornens M, Job D: The Rho-associated protein kinase p160ROCK is required for centrosome positioning. J Cell Biol. 2002, 157: 807-817.PubMedCentralCrossRefPubMed

17.

Hoppeler-Lebel A, Celati C, Bellett G, Mogensen MM, Klein-Hitpass L, Bornens M, Tassin AM: Centrosomal CAP350 protein stabilises microtubules associated with the Golgi complex. J Cell Sci. 2007, 120: 3299-3308.CrossRefPubMed

18.

Furdui CM, Lew ED, Schlessinger J, Anderson KS: Autophosphorylation of FGFR1 kinase is mediated by a sequential and precisely ordered reaction. Mol Cell. 2006, 21: 711-717.CrossRefPubMed

19.

Lamothe B, Yamada M, Schaeper U, Birchmeier W, Lax I, Schlessinger J: The docking protein Gab1 is an essential component of an indirect mechanism for fibroblast growth factor stimulation of the phosphatidylinositol 3-kinase/Akt antiapoptotic pathway. Mol Cell Biol. 2004, 24: 5657-5666.PubMedCentralCrossRefPubMed

20.

Ong SH, Hadari YR, Gotoh N, Guy GR, Schlessinger J, Lax I: Stimulation of phosphatidylinositol 3-kinase by fibroblast growth factor receptors is mediated by coordinated recruitment of multiple docking proteins. Proc Natl Acad Sci U S A. 2001, 98: 6074-6079.PubMedCentralCrossRefPubMed

21.

Kapeller R, Toker A, Cantley LC, Carpenter CL: Phosphoinositide 3-kinase binds constitutively to alpha/beta-tubulin and binds to gamma-tubulin in response to insulin. J Biol Chem. 1995, 270: 25985-25991.CrossRefPubMed

22.

Carpenter CL, Cantley LC: Phosphoinositide kinases. Biochemistry. 1990, 29: 11147-11156.CrossRefPubMed

23.

Susa M, Keeler M, Varticovski L: Platelet-derived growth factor activates membrane-associated phosphatidylinositol 3-kinase and mediates its translocation from the cytosol. Detection of enzyme activity in detergent-solubilized cell extracts. J Biol Chem. 1992, 267: 22951-22956.PubMed

24.

Kelly KL, Ruderman NB: Insulin-stimulated phosphatidylinositol 3-kinase. Association with a 185-kDa tyrosine-phosphorylated protein (IRS-1) and localization in a low density membrane vesicle. J Biol Chem. 1993, 268: 4391-4398.PubMed

25.

De Nadai C, Huitorel P, Chiri S, Ciapa B: Effect of wortmannin, an inhibitor of phosphatidylinositol 3-kinase, on the first mitotic divisions of the fertilized sea urchin egg. J Cell Sci. 1998, 111 (17): 2507-2518.PubMed

26.

Hinchcliffe EH, Li C, Thompson EA, Maller JL, Sluder G: Requirement of Cdk2-cyclin E activity for repeated centrosome reproduction in Xenopus egg extracts. Science. 1999, 283: 851-854.CrossRefPubMed

27.

Lacey KR, Jackson PK, Stearns T: Cyclin-dependent kinase control of centrosome duplication. Proc Natl Acad Sci U S A. 1999, 96: 2817-2822.PubMedCentralCrossRefPubMed

28.

Henry MK, Nimbalkar D, Hohl RJ, Quelle FW: Cytokine-induced phosphoinositide 3-kinase activity promotes Cdk2 activation in factor-dependent hematopoietic cells. Exp Cell Res. 2004, 299: 257-266.CrossRefPubMed

29.

Takahashi M, Mukai H, Oishi K, Isagawa T, Ono Y: Association of immature hypophosphorylated protein kinase cepsilon with an anchoring protein CG-NAP. J Biol Chem. 2000, 275: 34592-34596.CrossRefPubMed

30.

Newton AC: Regulation of the ABC kinases by phosphorylation: protein kinase C as a paradigm. Biochem J. 2003, 370: 361-371.PubMedCentralCrossRefPubMed

Title: Myeloproliferative disorder FOP-FGFR1 fusion kinase recruits phosphoinositide-3 kinase and phospholipase Cγ at the centrosome
Authors: Hélène Lelièvre
Véronique Chevrier
Anne-Marie Tassin
Daniel Birnbaum
Publication date: 01-12-2008
Publisher: BioMed Central
Published in: Molecular Cancer / Issue 1/2008
Electronic ISSN: 1476-4598
DOI: https://doi.org/10.1186/1476-4598-7-30

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Abstract

Background

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Conclusion

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