Critical role for Rsk2 in T-lymphocyte activation

Lin, Jian-Xin; Spolski, Rosanne

doi:10.1182/blood-2007-02-072207

Cited by 35 publications

(40 citation statements)

References 63 publications

(69 reference statements)

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“…BCR-ABL or FLT3-ITD were retrovirally transduced into donor BM cells from either WT Balb/C mice or mice that are genetically deficient of RSK2 (RSK2 KO) 35 ( Figure 2A). The transduced cells were subsequently injected into lethally irradiated syngeneic WT Balb/C recipient mice.…”

Section: Genetic Deficiency Of Rsk2 Does Not Affect Bcr-abl-induced Mmentioning

confidence: 99%

“…35 Murine BMT assays were performed as described previously. 36 In brief, retroviral supernatants were generated by transient cotransfection of 293T cells with the MSCV2.2-Gateway-IRES-GFP-BCR-ABL 37 or FLT3-ITD/51 38 constructs and packaging construct using Superfect (QIAGEN).…”

Section: Micementioning

confidence: 99%

“…on April 7, 2019. by guest www.bloodjournal.org From for normal lymphoid development and RSK2 KO animals had normal numbers of Gr-1 ϩ and Mac-1 ϩ cells in the spleen. 35 Therefore, the change in disease phenotype and attenuation of disease burden seen in FLT3-ITD-and TEL-FGFR3-induced disease using RSK2-deficient BM cells in BMT mice, respectively, is most likely because of impairment of RSK2-mediated signal transduction rather than abnormalities in the target cell populations. It is possible that, although RSK2 may not be required for normal myelopoiesis, these 3 leukemogenic tyrosine kinases activate distinct signaling pathways to induce hematopoietic transformation.…”

mentioning

confidence: 99%

“…16,44 However, RSK2 KO mice have a normal lifespan and no histologic or metabolic evidence of internal organ dysfunction. 16,35,44 Lin et al demonstrated that RSK2 is dispensable 6890 ELF et al BLOOD, 23 JUNE 2011 ⅐ VOLUME 117, NUMBER 25 For personal use only. on April 7, 2019. by guest www.bloodjournal.org From For personal use only.…”

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confidence: 99%

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

Elf¹,

Blevins²,

Jin³

et al. 2011

Blood

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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...

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Section: Genetic Deficiency Of Rsk2 Does Not Affect Bcr-abl-induced Mmentioning

confidence: 99%

Section: Micementioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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

Elf¹,

Blevins²,

Jin³

et al. 2011

Blood

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“…In hematopoietic system, RSK2 is phosphorylated in B and T lymphocytes in physiologic condition, whereas its further phosphorylation has been shown to be essential in their activation (7,8). It is located downstream of the RAS/ERK1/2 signaling cascade, which is activated in response to oncogenic signalings and/or growth factor stimuli (6,9).…”

Section: Introductionmentioning

confidence: 99%

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

Shimura

Kuroda

et al. 2012

Molecular Cancer Therapeutics

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Multiple myeloma is an entity of cytogenetically and genetically heterogenous plasma cell neoplasms. Despite recent improvement in the treatment outcome of multiple myeloma by novel molecular-targeted chemotherapeutics, multiple myeloma remains incurable. The identification of a therapeutic target molecule in which various signaling for cell-survival converge is a core component for the development of new therapeutic strategies against multiple myeloma. RSK2 is an essential mediator of the ERK1/2 signaling pathway for cell survival and proliferation. In this study, we discovered that RSK2 Ser227 , which is located at the N-terminal kinase domain and is one site responsible for substrate phosphorylation, is activated through phosphorylation regardless of the type of cytogenetic abnormalities or upstream molecular signaling in all 12 multiple myeloma-derived cell lines examined and 6 of 9 patient-derived CD138-positive primary myeloma cells. The chemical inhibition of RSK2Ser227 by BI-D1870 or gene knockdown of RSK2 inhibits myeloma cell proliferation through apoptosis induction, and this anti-myeloma effect was accompanied by downregulation of c-MYC, cyclin D, p21 WAF1/CIP1 , and MCL1. RSK2 Ser227 inhibition resulting from BI-D1870 treatment restored lenalidomide-induced direct cytotoxicity of myeloma cells from interleukin-6-mediated cell protection, showed no cross-resistance to bortezomib, and exerted additive/synergistic antiproliferative effects in conjunction with the mTOR, histone deacetylase, and BH3-mimicking BCL2/BCLX L inhibitors. These results suggest that RSK2 Ser227 is a potential therapeutic target not only for newly diagnosed but also for patients with later phase multiple myeloma who are resistant or refractory to currently available anti-myeloma therapies.

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Aberrant expression of RSK1 characterizes high‐grade gliomas with immune infiltration

Hajj¹,

Silva

Bellis

et al. 2019

Molecular Oncology

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The p90 ribosomal S6 kinase (RSK) family, a downstream target of Ras/extracellular signal-regulated kinase signaling, can mediate cross-talk with the mammalian target of rapamycin complex 1 pathway. As RSK connects two oncogenic pathways in gliomas, we investigated the protein levels of the RSK isoforms RSK1-4 in nontumoral brain (NB) and grade I-IV gliomas. When compared to NB or low-grade gliomas (LGG), a group of glioblastomas (GBMs) that excluded long-survivor cases expressed higher levels of RSK1 (RSK1 hi). No difference was observed in RSK2 median-expression levels among NB and gliomas; however, high levels of RSK2 in GBM (RSK2 hi) were associated with worse survival. RSK4 expression was not detected in any brain tissues, whereas RSK3 expression was very low, with GBM demonstrating the lowest RSK3 protein levels. RSK1 hi and, to a lesser extent, RSK2 hi GBMs showed higher levels of phosphorylated RSK, which reveals RSK activation. Transcriptome analysis indicated that most RSK1 hi GBMs belonged to the mesenchymal subtype, and RSK1 expression strongly correlated with gene expression signature of immune infiltrates, in particular of activated natural killer cells and M2 macrophages. In an independent cohort, we confirmed that RSK1 hi GBMs exclude long survivors, and RSK1 expression was associated with high protein levels of the mesenchymal subtype marker lysosomal protein transmembrane 5, as well as with high expression of CD68, which indicated the presence of infiltrating immune cells. An RSK1 signature was obtained based on differentially expressed mRNAs and validated in public glioma datasets. Enrichment of RSK1 signature followed glioma progression, recapitulating RSK1 protein expression, and was associated with worse survival not only in GBM but also in LGG. In conclusion, both RSK1 and RSK2 associate with glioma malignity, but displaying

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Critical role for Rsk2 in T-lymphocyte activation

Cited by 35 publications

References 63 publications

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

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

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

Aberrant expression of RSK1 characterizes high‐grade gliomas with immune infiltration

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