IntroductionRSK2 is a Ser/Thr kinase that belongs to a family containing 4 members, RSK1 to 4, all of which are downstream substrates of ERK and play a role in various cellular processes including gene expression, cell cycle, survival, and proliferation. RSK family members share both structural and functional similarities, and are uniquely characterized by the presence of 2 distinct kinase domains, both of which are catalytically functional 1-3 (reviewed in Blenis, 4 Frodin and Gammeltoft, 5 and Anjum and Blenis 6 ). The carboxyl-terminal kinase (CTK) domain is responsible for autophosphorylation at Ser386 (numbering based on the murine RSK2 amino acid sequence), which is critical for RSK activation, while the N-terminal kinase (NTK) domain phosphorylates RSK substrates. 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. 17 Phosphorylation and activation of these transcription factors are important for regulation of gene expression. RSK2 also phosphorylates histone H3, which contributes to chromatin remodeling during mitosis and transcriptional activation. 18 In addition, RSK2 promotes cell survival by phosphorylating and inhibiting proapoptotic protein factors including BAD,19 Bim, 20 and death-associated protein kinase (DAPK). 21 Moreover, RSK2 promotes proliferation by phosphorylating GSK3, 22 NHE-1, 23 and p27 kip1 . 24 Therefore, RSK2 may serve as a key regulator by activating multiple signaling effectors in a signaling network that promotes cell survival and proliferation.Defects in the human RSK2 gene are associated with CoffinLowry syndrome (CLS), an X-linked mental retardation. 25,26 Although there is no evidence that RSK2 is mutated in human cancers, RSK2 signaling has been demonstrated to play a key role in the pathogenesis and disease progression of some human malignancies, including metastatic head and neck cancer, 27 FGFR1-expressing prostate cancer, 28,29 and osteosarcoma. 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.In this report, we focus on the role of RSK2 in other hematopoietic malignancies induced by different leukemogenic tyrosine kinases (LTKs) including BCR-ABL and FMS-like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) mutant. BCR-ABL is a constitutively active fus...
1716 p90 ribosomal S6 kinase 2 (p90RSK2) is a serine/threonine kinase that plays an active role in diverse cellular processes, including gene expression, cell proliferation, and survival. We previously demonstrated that RSK2 signaling plays a key role in the pathogenesis and disease progression of leukemogenic FGFR3 associated hematopoietic malignancies, including FGFR3-expressing t(4;14) multiple myeloma and TEL-FGFR3-expressing t(4;12)(p16;p13) peripheral T cell lymphoma. In this study, we found that p90RSK2 is commonly activated in diverse leukemia cell lines expressing different leukemogenic tyrosine kinases, including K562 (BCR-ABL), Molm14 and Mv4;11 (FLT3-ITD), HEL (JAK2 V617F), and EOL-1(FIP1L1-PDGFR alpha). We next examined the role of RSK2 in myeloid transformation induced by BCR-ABL and FLT3-ITD due to their high frequency of occurrence in CML and AML, respectively. Interestingly, although RSK2 is activated by BCR-ABL in both stably transduced Ba/F3 cells and K562 human leukemia cells, we found that genetic deficiency of RSK2 does not affect the pathogenesis or disease progression of myeloproliferative disease induced by BCR-ABL in a murine bone marrow transplant (BMT) model using wild type or RSK2-/- donor bone marrow cells. This finding suggests that RSK2 is dispensable for BCR-ABL induced myeloproliferative disease. Moreover, targeting RSK2 by treatment with potent and highly specific RSK inhibitor fmk did not effectively induce apoptosis in K562 human leukemia cells expressing BCR-ABL, or in primary leukemia cells from BCR-ABL positive CML patients. In contrast, we found that targeting RSK2 may represent an effective therapy to treat patients with FLT3-ITD positive AML. Treatment with fmk induced significant apoptotic cell death in Molm14 and Mv4;11 human leukemia cells expressing FLT3-ITD, as well as in primary leukemia cells from FLT3-ITD positive AML patients. In consonance with these results, FLT3-ITD induced T-cell lymphoma in a BMT assay using RSK2-/- donor bone marrow cells, phenotypically distinct from the myeloproliferative disease induced by FLT3-ITD using wild type donor bone marrow cells. These results suggest that RSK2 is required for FLT3-ITD induced hematopoietic transformation, likely playing a role in pathogenesis and lineage determination. Together these findings suggest that the role of RSK2 in hematopoietic transformation may depend on different upstream oncogenic signals mediated by different leukemogenic tyrosine kinases. Our data also demonstrate that RSK2 may represent an alternative therapeutic target in the treatment of FLT3-ITD positive leukemia. Disclosures: No relevant conflicts of interest to declare.
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