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Blood, 1 July 2005, Vol. 106, No. 1, pp. 328-337. Prepublished online as a Blood First Edition Paper on March 22, 2005; DOI 10.1182/blood-2004-09-3686. This Article Full Text (PDF) All Versions of this Article: 2004-09-3686v1 106/1/328    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Chen, J. Articles by Gilliland, D G Search for Related Content PubMed PubMed Citation Articles by Chen, J. Articles by Gilliland, D G Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted September 24, 2004 Accepted March 9, 2005 Constitutively activated FGFR3 mutants signal through PLC-dependent and -independent pathways for hematopoietic transformation Jing Chen*, Ifor R Williams, Benjamin H Lee, Nicole Duclos, Brian J Huntly, Daniel J Donoghue, and D G Gilliland Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA Department of Pathology, Emory University, Atlanta, GA, USA Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA Department of Chemistry and Biochemistry, Univeristy of California-San Diego, La Jolla, CA, USA * Corresponding author; email: jchen{at}rics.bwh.harvard.edu. Ectopic expression of FGFR3 associated with t(4;14) has been implicated in the pathogenesis of human multiple myeloma. Some t(4;14) patients have activating mutations of FGFR3 of which a minority are K650E (TDII). To investigate the role of autophosphorylated tyrosine residues in FGFR3 signal transduction and transformation, we characterized a series of FGFR3 TDII mutants with single or multiple YF substitutions. Phenylalanine substitution of Y760, essential for PLC binding and activation, significantly attenuated FGFR3 TDII-mediated PLC activation, as well as transformation in Ba/F3 cells and a murine bone marrow transplant leukemia model. In contrast, single substitution of Y577, Y724 or Y770 had minimal to moderate effects on TDII-dependent transformation. Substitution of all the four non-activation loop tyrosine residues significantly attenuated, but did not abolish TDII transforming activity. Similar observations were obtained in the context of a constitutively activated fusion TEL-FGFR3 associated with t(4;12)(p16;p13) peripheral T-cell lymphomas. Moreover, two independent EµSR-FGFR3 TDII transgenic mouse lines developed a pro-B cell lymphoma, and PLC was highly activated in primary lymphoma cells as assessed by tyrosine phosphorylation. These data indicate that engagement of multiple signaling pathways, including PLC-dependent and PLC-independent pathways, is required for full hematopoietic transformation by constitutively activated FGFR3 mutants. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. R. St-Germain, P. Taylor, J. Tong, L. L. Jin, A. Nikolic, I. I. Stewart, R. M. Ewing, M. Dharsee, Z. Li, S. Trudel, et al. Multiple myeloma phosphotyrosine proteomic profile associated with FGFR3 expression, ligand activation, and drug inhibition PNAS, November 24, 2009; 106(47): 20127 - 20132. [Abstract] [Full Text] [PDF] L. Salazar, T. Kashiwada, P. Krejci, P. Muchowski, D. Donoghue, W. R. Wilcox, and L. M. Thompson A novel interaction between fibroblast growth factor receptor 3 and the p85 subunit of phosphoinositide 3-kinase: activation-dependent regulation of ERK by p85 in multiple myeloma cells Hum. Mol. Genet., June 1, 2009; 18(11): 1951 - 1961. [Abstract] [Full Text] [PDF] J. Y. Cha, S. Maddileti, N. Mitin, T. K. Harden, and C. J. Der Aberrant Receptor Internalization and Enhanced FRS2-dependent Signaling Contribute to the Transforming Activity of the Fibroblast Growth Factor Receptor 2 IIIb C3 Isoform J. Biol. Chem., March 6, 2009; 284(10): 6227 - 6240. [Abstract] [Full Text] [PDF] M. M. Loriaux, R. L. Levine, J. W. Tyner, S. Frohling, C. Scholl, E. P. Stoffregen, G. Wernig, H. Erickson, C. A. Eide, R. Berger, et al. High-throughput sequence analysis of the tyrosine kinome in acute myeloid leukemia Blood, May 1, 2008; 111(9): 4788 - 4796. [Abstract] [Full Text] [PDF] S. Dong, S. Kang, T.-L. Gu, S. Kardar, H. Fu, S. Lonial, H. J. Khoury, F. Khuri, and J. Chen 14-3-3 integrates prosurvival signals mediated by the AKT and MAPK pathways in ZNF198-FGFR1-transformed hematopoietic cells Blood, July 1, 2007; 110(1): 360 - 369. [Abstract] [Full Text] [PDF] J. L. Rocnik, R. Okabe, J.-C. Yu, B. H. Lee, N. Giese, D. P. Schenkein, and D. G. Gilliland Roles of tyrosine 589 and 591 in STAT5 activation and transformation mediated by FLT3-ITD Blood, August 15, 2006; 108(4): 1339 - 1345. [Abstract] [Full Text] [PDF]

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