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FGFR3 activates RSK2 to mediate hematopoietic transformation through tyrosine phosphorylation of RSK2 and activation of the MEK/ERK pathway.

Cancer cell | Sep 5, 2007

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.

Pubmed ID: 17785202 RIS Download

Mesh terms: Apoptosis | Binding Sites | Cell Line, Tumor | Cell Proliferation | Cell Transformation, Neoplastic | Enzyme Activation | Extracellular Signal-Regulated MAP Kinases | Humans | MAP Kinase Signaling System | Mitogen-Activated Protein Kinase Kinases | Models, Biological | Multiple Myeloma | Phosphorylation | RNA Interference | Receptor, Fibroblast Growth Factor, Type 3 | Ribosomal Protein S6 Kinases, 90-kDa | Tyrosine

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