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Author Notes:

Correspondence: Jing Chen, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322; Email: jchen@emory.edu

Acknowledgments: We gratefully acknowledge the critical reading of the manuscript by Drs. Benjamin Lee and Brian Huntly.

We thank Claire Torre for the generous help with primary patient sample analysis.

Drs. Ruan Hong and Qingyuan Ge (Cell Signaling Technology, Inc.) kindly helped us with generation of phospho-RSK2 (Y529) antibody.

Disclosures: J.C. is a Georgia Cancer Coalition Distinguished Cancer Scholar.

T.-L.G., A.G., and R.D.P. are employed by Cell Signaling Technology, Inc., whose product was studied in the present work.

D.F. is employed by Novartis Pharma AG.

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Research Funding:

This work was supported in part by NIH grant CA120272 (J.C.), the Leukemia and Lymphoma Society (J.C.), and the Multiple Myeloma Research Foundation (J.C. and S.L.).

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

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Journal Title:

Cancer Cell

Volume:

Volume 12, Number 3

Publisher:

, Pages 201-214

Type of Work:

Article | Post-print: After Peer Review

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.

Copyright information:

© 2007 Elsevier Inc.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommerical-NoDerivs 3.0 Unported License (http://creativecommons.org/licenses/by-nc-nd/3.0/).

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