Constitutively activated FGFR3 mutants signal through PLCgamma-dependent and -independent pathways for hematopoietic transformation.

Abstract

Ectopic expression of fibroblast growth factor receptor 3 (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 (thanatophoric dysplasia type II [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 Y-->F substitutions. Phenylalanine substitution of Y760, essential for phospholipase Cgamma (PLCgamma) binding and activation, significantly attenuated FGFR3 TDII-mediated PLCgamma 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 4 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, 2 independent EmuSR-FGFR3 TDII transgenic mouse lines developed a pro-B-cell lymphoma, and PLCgamma was highly activated in primary lymphoma cells as assessed by tyrosine phosphorylation. These data indicate that engagement of multiple signaling pathways, including PLCgamma-dependent and PLCgamma-independent pathways, is required for full hematopoietic transformation by constitutively activated FGFR3 mutants.

• Authors: Jing Chen, Ifor R Williams, Benjamin H Lee, Nicole Duclos, Brian J P Huntly, Daniel J Donoghue, D Gary Gilliland
• Journal: Blood (Blood) Vol. 106 Issue 1 Pg. 328-37 (Jul 01 2005) ISSN: 0006-4971 [Print] United States
• PMID: 15784730 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Oncogene Proteins, Fusion
• Receptors, Fibroblast Growth Factor
• Tyrosine
• Fgfr3 protein, mouse
• Protein-Tyrosine Kinases
• Receptor, Fibroblast Growth Factor, Type 3
• Type C Phospholipases
• Phospholipase C gamma

Topics

• Amino Acid Substitution
• Animals
• Cell Transformation, Neoplastic
• Cells, Cultured
• Gene Expression Regulation, Neoplastic
• Mice
• Mice, Transgenic
• Multiple Myeloma (pathology, physiopathology)
• Mutagenesis, Site-Directed
• Oncogene Proteins, Fusion (genetics)
• Phospholipase C gamma
• Protein-Tyrosine Kinases (genetics, metabolism)
• Receptor, Fibroblast Growth Factor, Type 3
• Receptors, Fibroblast Growth Factor (genetics, metabolism)
• Signal Transduction (physiology)
• Type C Phospholipases (metabolism)
• Tyrosine (genetics)