Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis
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Binding Sites
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Cell Line, Tumor
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Cell Proliferation
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Cell Transformation, Neoplastic / metabolism*
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Enzyme Activation
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Humans
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MAP Kinase Signaling System*
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Mitogen-Activated Protein Kinase Kinases / metabolism
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Models, Biological
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Multiple Myeloma / enzymology*
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Multiple Myeloma / metabolism
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Phosphorylation
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RNA Interference
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Receptor, Fibroblast Growth Factor, Type 3 / physiology*
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Ribosomal Protein S6 Kinases, 90-kDa / antagonists & inhibitors
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Ribosomal Protein S6 Kinases, 90-kDa / metabolism*
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Tyrosine / metabolism
Substances
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Tyrosine
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FGFR3 protein, human
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Receptor, Fibroblast Growth Factor, Type 3
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Ribosomal Protein S6 Kinases, 90-kDa
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ribosomal protein S6 kinase, 90kDa, polypeptide 3
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Extracellular Signal-Regulated MAP Kinases
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Mitogen-Activated Protein Kinase Kinases