FGFR3 Activates RSK2 to Mediate Hematopoietic Transformation through Tyrosine Phosphorylation of RSK2 and Activation of the MEK/ERK Pathway

To better understand the signaling properties of oncogenic FGFR3, we performed phospho-proteomics studies to identify potential downstream signaling effectors that are tyrosine phosphorylated in hematopoietic cells expressing constitutively activated leukemogenic FGFR3 mutants. We found that FGFR3 d...

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Bibliographic Details
Published in:Cancer cell 2007-09, Vol.12 (3), p.201-214
Main Authors: Kang, Sumin, Dong, Shaozhong, Gu, Ting-Lei, Guo, Ailan, Cohen, Michael S., Lonial, Sagar, Khoury, Hanna Jean, Fabbro, Doriano, Gilliland, D. Gary, Bergsagel, P. Leif, Taunton, Jack, Polakiewicz, Roberto D., Chen, Jing
Format: Article
Language:English
Subjects:
Apoptosis
Binding Sites
Cell Line, Tumor
Cell Proliferation
Cell Transformation, Neoplastic - metabolism
CELLCYCLE
Enzyme Activation
Extracellular Signal-Regulated MAP Kinases - metabolism
Humans
MAP Kinase Signaling System
Mitogen-Activated Protein Kinase Kinases - metabolism
Models, Biological
Multiple Myeloma - enzymology
Multiple Myeloma - metabolism
Phosphorylation
Receptor, Fibroblast Growth Factor, Type 3 - physiology
Ribosomal Protein S6 Kinases, 90-kDa - antagonists & inhibitors
Ribosomal Protein S6 Kinases, 90-kDa - metabolism
RNA Interference
SIGNALING
Tyrosine - metabolism
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Summary:To better understand the signaling properties of oncogenic FGFR3, we performed phospho-proteomics studies to identify potential downstream signaling effectors that are tyrosine phosphorylated in hematopoietic cells expressing constitutively activated leukemogenic FGFR3 mutants. We found that FGFR3 directly tyrosine phosphorylates the serine/threonine kinase p90RSK2 at Y529, which consequently regulates RSK2 activation by facilitating inactive ERK binding to RSK2 that is required for ERK-dependent phosphorylation and activation of RSK2. Moreover, inhibition of RSK2 by siRNA or a specific RSK inhibitor fmk effectively induced apoptosis in FGFR3-expressing human t(4;14)-positive myeloma cells. Our findings suggest that FGFR3 mediates hematopoietic transformation by activating RSK2 in a two-step fashion, promoting both the ERK-RSK2 interaction and subsequent phosphorylation of RSK2 by ERK.
ISSN:1535-6108
1878-3686
DOI:10.1016/j.ccr.2007.08.003