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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 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

Authors

  • Kang S
  • Dong S
  • Gu TL
  • Guo A
  • Cohen MS
  • Lonial S
  • Khoury HJ
  • Fabbro D
  • Gilliland DG
  • Bergsagel PL
  • Taunton J
  • Polakiewicz RD
  • Chen J

Journal

Cancer cell

Publication Data

September 5, 2007

Associated Grants

  • Agency: NCI NIH HHS, Id: CA120272
  • Agency: NCI NIH HHS, Id: R01 CA120272
  • Agency: NCI NIH HHS, Id: R01 CA120272-02

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