Fibroblast growth factor receptor 3 associates with and tyrosine phosphorylates p90 RSK2, leading to RSK2 activation that mediates hematopoietic transformation.
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 alphaL-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.
Kang
Sumin
S
Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA.
Elf
Shannon
S
Dong
Shaozhong
S
Hitosugi
Taro
T
Lythgoe
Katherine
K
Guo
Ailan
A
Ruan
Hong
H
Lonial
Sagar
S
Khoury
Hanna J
HJ
Williams
Ifor R
IR
Lee
Benjamin H
BH
Roesel
Johannes L
JL
Karsenty
Gerard
G
Hanauer
André
A
Taunton
Jack
J
Boggon
Titus J
TJ
Gu
Ting-Lei
TL
Chen
Jing
J
D000818:Animals; D001665:Binding Sites; D016026:Bone Marrow Transplantation; D006410:Hematopoiesis; D051379:Mice; D009196:Myeloproliferative Disorders / Q000209:etiology; D010766:Phosphorylation; D011485:Protein Binding / Q000502:physiology; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000378:metabolism*; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism
D014443:Tyrosine; D051498:Receptor, Fibroblast Growth Factor, Type 3; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C069330:ribosomal protein S6 kinase, 90kDa, polypeptide 3