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

doi:10.1016/j.ccr.2007.08.003

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 journal › Article › peer-review

129 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 language	English (US)
Pages (from-to)	201-214
Number of pages	14
Journal	Cancer Cell
Volume	12
Issue number	3
DOIs	https://doi.org/10.1016/j.ccr.2007.08.003
State	Published - Sep 11 2007
Externally published	Yes

Funding

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. 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.). 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.

Funders	Funder number
Author National Institutes of Health National Institutes of Health National Institutes of Health National Institutes of Health The Bev Hartig Huntington's Disease Foundation National Institutes of Health
National Institute of Health-National Cancer Institute	R01CA120272
Multiple Myeloma Research Foundation
Leukemia and Lymphoma Society

Keywords

CELLCYCLE
SIGNALING

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1016/j.ccr.2007.08.003

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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

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 2007, 'FGFR3 Activates RSK2 to Mediate Hematopoietic Transformation through Tyrosine Phosphorylation of RSK2 and Activation of the MEK/ERK Pathway', Cancer Cell, vol. 12, no. 3, pp. 201-214. https://doi.org/10.1016/j.ccr.2007.08.003

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

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.",

keywords = "CELLCYCLE, SIGNALING",

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

note = "Funding Information: 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. 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.). 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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doi = "10.1016/j.ccr.2007.08.003",

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AU - Kang, Sumin

AU - Dong, Shaozhong

AU - Gu, Ting Lei

AU - Guo, Ailan

AU - Cohen, Michael S.

AU - Lonial, Sagar

AU - Khoury, Hanna Jean

AU - Fabbro, Doriano

AU - Gilliland, D. Gary

AU - Bergsagel, P. Leif

AU - Taunton, Jack

AU - Polakiewicz, Roberto D.

AU - Chen, Jing

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PY - 2007/9/11

Y1 - 2007/9/11

N2 - 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.

AB - 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.

KW - CELLCYCLE

KW - SIGNALING

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

Abstract

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