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

Sumin Kang, Shaozhong Dong, Ting Lei Gu, Ailan Guo, Michael S. Cohen, Sagar Lonial, Hanna Jean Khoury, Doriano Fabbro, D. Gary Gilliland, P. Leif Bergsagel, Jack Taunton, Roberto D. Polakiewicz, Jing Chen

Research output: Contribution to journalArticle

104 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)201-214
Number of pages14
JournalCancer Cell
Volume12
Issue number3
DOIs
StatePublished - Sep 11 2007

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Keywords

  • CELLCYCLE
  • SIGNALING

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

Cite this

Kang, S., Dong, S., Gu, T. L., Guo, A., Cohen, M. S., Lonial, S., Khoury, H. J., Fabbro, D., Gilliland, D. G., Bergsagel, P. L., Taunton, J., Polakiewicz, R. D., & Chen, J. (2007). FGFR3 Activates RSK2 to Mediate Hematopoietic Transformation through Tyrosine Phosphorylation of RSK2 and Activation of the MEK/ERK Pathway. Cancer Cell, 12(3), 201-214. https://doi.org/10.1016/j.ccr.2007.08.003