Myeloproliferative disorder FOP-FGFR1 fusion kinase recruits phosphoinositide-3 kinase and phospholipase Cγ at the centrosome
<p>Abstract</p> <p>Background</p> <p>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 t...
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| Format: | Article |
| Language: | English |
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BMC
2008-04-01
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| Series: | Molecular Cancer |
| Online Access: | http://www.molecular-cancer.com/content/7/1/30 |
| _version_ | 1818528158044913664 |
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| author | Tassin Anne-Marie Chevrier Véronique Lelièvre Hélène Birnbaum Daniel |
| author_facet | Tassin Anne-Marie Chevrier Véronique Lelièvre Hélène Birnbaum Daniel |
| author_sort | Tassin Anne-Marie |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>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.</p> <p>Results</p> <p>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.</p> <p>Conclusion</p> <p>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.</p> |
| first_indexed | 2024-12-11T06:46:01Z |
| format | Article |
| id | doaj.art-2d7e0ff0f245478cbec11f31811ab836 |
| institution | Directory Open Access Journal |
| issn | 1476-4598 |
| language | English |
| last_indexed | 2024-12-11T06:46:01Z |
| publishDate | 2008-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Cancer |
| spelling | doaj.art-2d7e0ff0f245478cbec11f31811ab8362022-12-22T01:17:04ZengBMCMolecular Cancer1476-45982008-04-01713010.1186/1476-4598-7-30Myeloproliferative disorder FOP-FGFR1 fusion kinase recruits phosphoinositide-3 kinase and phospholipase Cγ at the centrosomeTassin Anne-MarieChevrier VéroniqueLelièvre HélèneBirnbaum Daniel<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Results</p> <p>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.</p> <p>Conclusion</p> <p>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.</p>http://www.molecular-cancer.com/content/7/1/30 |
| spellingShingle | Tassin Anne-Marie Chevrier Véronique Lelièvre Hélène Birnbaum Daniel Myeloproliferative disorder FOP-FGFR1 fusion kinase recruits phosphoinositide-3 kinase and phospholipase Cγ at the centrosome Molecular Cancer |
| title | Myeloproliferative disorder FOP-FGFR1 fusion kinase recruits phosphoinositide-3 kinase and phospholipase Cγ at the centrosome |
| title_full | Myeloproliferative disorder FOP-FGFR1 fusion kinase recruits phosphoinositide-3 kinase and phospholipase Cγ at the centrosome |
| title_fullStr | Myeloproliferative disorder FOP-FGFR1 fusion kinase recruits phosphoinositide-3 kinase and phospholipase Cγ at the centrosome |
| title_full_unstemmed | Myeloproliferative disorder FOP-FGFR1 fusion kinase recruits phosphoinositide-3 kinase and phospholipase Cγ at the centrosome |
| title_short | Myeloproliferative disorder FOP-FGFR1 fusion kinase recruits phosphoinositide-3 kinase and phospholipase Cγ at the centrosome |
| title_sort | myeloproliferative disorder fop fgfr1 fusion kinase recruits phosphoinositide 3 kinase and phospholipase cγ at the centrosome |
| url | http://www.molecular-cancer.com/content/7/1/30 |
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