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

Abstract

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...

RSK2Ser227 at N-Terminal Kinase Domain Is a Potential Therapeutic Target for Multiple Myeloma

“…Recent studies have shown that RSK2 acts as the key regulator for cellular transformation and metastasis by mediating signaling through oncogenic tyrosine kinases (TK; refs. [10][11][12]. As for myeloma, previous studies have suggested the importance of RSK2 signaling associated with fibroblast growth factor receptor 3 (FGFR3) activation by t(4;14) (13,14).…”

The Prometastatic Ribosomal S6 Kinase 2-cAMP Response Element-binding Protein (RSK2-CREB) Signaling Pathway Up-regulates the Actin-binding Protein Fascin-1 to Promote Tumor Metastasis

“…Our data supports the notion that targeting RSK2 with specific small molecule drugs may represent a potential therapeutic strategy to attenuate metastatic cancer cell invasion and tumor metastasis. We previously demonstrated that targeting RSK2 effectively induces apoptotic cell death and attenuates cell proliferation in t(4;14) FGFR3-positive multiple myeloma cells or FLT3-ITD-positive acute myeloid leukemia cells (29,46). We also showed that RSK specific inhibitors such as fmk might have minimal nonspecific cytotoxicity in human cells (29).…”

Targeting RSK2 in myeloid leukemia: Right for FLT3 but wrong for BCR-ABL

“…6,7 We found that both BCR-ABL and FLT3-ITD activate RSK2 in human leukemia cells, implying that RSK2 may represent a common downstream signaling node that is responsible for cell proliferation and survival in hematopoietic malignancies associated with leukemogenic tyrosine kinases. 8 Surprisingly however, genetic deficiency of RSK2 did not affect the pathogenesis and progression of myeloproliferative disease induced by BCR-ABL in a murine bone marrow transplant (BMT) assay, indicating that RSK2 is dispensable for BCR-ABL-induced myeloid transformation. In marked contrast, the absence of RSK2 abrogated the ability of FLT3-ITD to induce myeloproliferative disease in the same BMT assay, but rather induced a disease of T-cell ALL.…”

“…1B). 8,11 Future studies exploring the critical role of RSK2 in FLT3-ITD transformed hematopoietic cells may provide further insights toward developing more effective therapies in FLT3-ITD-associated disease.…”