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Molecular and Cellular Biology, April 2009, p. 2105-2117, Vol. 29, No. 8
0270-7306/09/$08.00+0 doi:10.1128/MCB.00998-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
Fibroblast Growth Factor Receptor 3 Associates with and Tyrosine Phosphorylates p90 RSK2, Leading to RSK2 Activation That Mediates Hematopoietic Transformation
Sumin Kang,1
Shannon Elf,1
Shaozhong Dong,1
Taro Hitosugi,1
Katherine Lythgoe,1
Ailan Guo,2
Hong Ruan,2
Sagar Lonial,1
Hanna J. Khoury,1
Ifor R. Williams,3
Benjamin H. Lee,4
Johannes L. Roesel,5
Gerard Karsenty,6
André Hanauer,7
Jack Taunton,8
Titus J. Boggon,9
Ting-Lei Gu,2 and
Jing Chen1*
Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322,1 Cell Signaling Technology, Inc., Danvers, Massachusetts 01923,2 Department of Pathology, Emory University School of Medicine, Atlanta, Georgia 30322,3 Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139,4 Novartis Pharma AG, Basel, Switzerland,5 Department of Genetics and Development, Columbia University, New York, New York 10032,6 Institut de Génétique et de Biologie Moléculaire et Cellulaire, C.U. de Strasbourg, France,7 Department of Cellular and Molecular Pharmacology, University of California—San Francisco, San Francisco, California 94107,8 Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 065209
Received 24 June 2008/ Returned for modification 20 August 2008/ Accepted 21 January 2009
Dysregulation of the receptor tyrosine kinase fibroblast growth factor receptor 3 (FGFR3) plays a pathogenic role in a number of human hematopoietic malignancies and solid tumors. These include t(4;14) multiple myeloma associated with ectopic expression of FGFR3 and t(4;12)(p16;p13) acute myeloid leukemia associated with expression of a constitutively activated fusion tyrosine kinase, TEL-FGFR3. We recently reported that FGFR3 directly tyrosine phosphorylates RSK2 at Y529, which consequently regulates RSK2 activation. Here we identified Y707 as an additional tyrosine in RSK2 that is phosphorylated by FGFR3. Phosphorylation at Y707 contributes to RSK2 activation, through a putative disruption of the autoinhibitory 
L-helix on the C terminus of RSK2, unlike Y529 phosphorylation, which facilitates ERK binding. Moreover, we found that FGFR3 interacts with RSK2 through residue W332 in the linker region of RSK2 and that this association is required for FGFR3-dependent phosphorylation of RSK2 at Y529 and Y707, as well as the subsequent RSK2 activation. Furthermore, in a murine bone marrow transplant assay, genetic deficiency in RSK2 resulted in a significantly delayed and attenuated myeloproliferative syndrome induced by TEL-FGFR3 as compared with wild-type cells, suggesting a critical role of RSK2 in FGFR3-induced hematopoietic transformation. Our current and previous findings represent a paradigm for tyrosine phosphorylation-dependent regulation of serine-threonine kinases.
* Corresponding author. Mailing address: Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322. Phone: (404) 778-5274. Fax: (404) 778-5520. E-mail: jchen{at}emory.edu
Published ahead of print on 17 February 2009.
Molecular and Cellular Biology, April 2009, p. 2105-2117, Vol. 29, No. 8
0270-7306/09/$08.00+0 doi:10.1128/MCB.00998-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
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