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.
Kang
Sumin
S
Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA.
Dong
Shaozhong
S
Gu
Ting-Lei
TL
Guo
Ailan
A
Cohen
Michael S
MS
Lonial
Sagar
S
Khoury
Hanna Jean
HJ
Fabbro
Doriano
D
Gilliland
D Gary
DG
Bergsagel
P Leif
PL
Taunton
Jack
J
Polakiewicz
Roberto D
RD
Chen
Jing
J
D017209:Apoptosis; D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D008954:Models, Biological; D009101:Multiple Myeloma / Q000201:enzymology* / Q000378:metabolism; D010766:Phosphorylation; D034622:RNA Interference; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000502:physiology*; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism