Fibroblast Growth Factor Receptor 3 Associates with and Tyrosine Phosphorylates p90 RSK2, Leading to RSK2 Activation That Mediates Hematopoietic Transformation

Abstract

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.

Targeting p90 Ribosomal S6 Kinase Eliminates Tumor-Initiating Cells by Inactivating Y-Box Binding Protein-1 in Triple-Negative Breast Cancers

“…We found that RSK inhibition demonstrated specific/increased toxicity to breast TICs when compared with normal hematopoietic stem cells. This is in line with a study by Kang et al, which showed that loss of RSK2 via knockout also had no affect on the hematopoietic stem cell subpopulation [44]. Collectively, these data indicate that RSK inhibition is effective at eliminating breast cancer TICs but unlike conventional chemotherapies has little effect on normal stem cells.…”

Coffin–Lowry syndrome

“…21 In addition, it has recently been shown that FGFR3, by interacting with, and phosphorylating two tyrosine residues within the C-terminal region of RSK2, influences RSK2 activation. 23 Altogether, the data provide evidence that RSKs have an important role in cell-cycle progression, differentiation, and cell survival. 21 In the cytosol, RSK proteins have been shown to phosphorylate many substrates, including GSK3, L1CAM, the Ras GEF-Sos, IkB, the p34cdc2-inhibitory kinase Myt1, the translation factors eEF2, eIF4B, and the pro-apoptotic protein BAD (Figure 2).…”

p90RSK2 is essential for FLT3-ITD– but dispensable for BCR-ABL–induced myeloid leukemia

“…9 TEL-FGFR3 is a constitutively activated fusion tyrosine kinase that is associated with t(4;12)(p16;p13) AML. 43 Genetic deficiency of RSK2 resulted in a significantly delayed and attenuated myeloproliferative syndrome induced by TEL-FGFR3 compared with wild type cells, suggesting that RSK2 may be required in TEL-FGFR3-induced pathogenesis and disease progression, but not lineage determination in hematopoietic transformation.…”

“…16,30 We recently found that oncogenic FGFR3 phosphorylates and activates RSK2 to induce hematopoietic transformation. 7,9 Targeting RSK2 but not RSK1 by siRNA or treatment with a specific RSK inhibitor fmk 31,32 effectively induced apoptosis in FGFR3-expressing human t(4;14)-positive myeloma cells and primary patient myeloma cells. These findings suggest a critical role for RSK2 in FGFR3-induced hematopoietic transformation.…”

“…2 We recently reported that tyrosine phosphorylation of RSK2 facilitates inactive ERK binding to RSK2 in the initial activation step, and disrupts an autoinhibitory region of RSK2 to achieve full activation. [7][8][9] RSK2 phosphorylates multiple signaling effectors that possess RRXS/T or RXRXXS/T motifs. 10 These RSK2 phosphorylation targets include transcriptional regulators such as cAMP-response element-binding protein (CREB), 11 c-Fos, 12,13 NFATc4, 14 NFAT3, 15 ATF4, 16 and Nur77.…”