Serine/Arginine Protein–Specific Kinase 2 Promotes Leukemia Cell Proliferation by Phosphorylating Acinus and Regulating Cyclin A1

Jang, Sung-Wuk; Yang, Seung-Ju; Ehlén, Åsa; Dong, Suchuan; Khoury, H. Jean; Chen, Jing; Persson, Jenny L.; Ye, Keqiang

doi:10.1158/0008-5472.can-08-0021

Cited by 83 publications

(106 citation statements)

References 36 publications

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“…Most recently, we show that SRPK2 binds and phosphorylates acinus and redistributes it from the nuclear speckles to the nucleoplasm, resulting in cyclin A1 but not A2 up-regulation and leukemia cell proliferation (18). Nevertheless, acinus does not implicate in SRPK2-mediated cyclin D1 expression in cortical neurons (supplemental Fig.…”

Section: Discussionmentioning

confidence: 89%

“…14-3-3 Inhibits SRPK2-provoked Cell Cycle Progression in Neurons-Our recent study demonstrates that acinus is a physiological substrate of SRPK2, which phosphorylates acinus on Ser-422 (18). To assess the effect of Akt phosphorylation on SRPK2 kinase activity toward acinus, we conducted an in vitro kinase assay using purified acinus protein as a substrate.…”

Section: Resultsmentioning

confidence: 99%

“…14-3-3 Suppresses the SRPK2 Effect on Cyclin D1 Expression and Apoptosis-SRPK2 robustly provoked cyclin A1 expression in leukemia cells, and it also weakly enhanced cyclin D1 expression in other cells in addition to leukemia (18). To explore whether Akt phosphorylation and SRPK2 kinase activity play any role in provoking cyclin D1 expression, we conducted a luciferase assay with cyclin D1 promoter construct.…”

Section: Resultsmentioning

confidence: 99%

“…Both SRPK1 and SRPK2 are primarily localized in the cytoplasm despite having putative nuclear localization signals (17). Most recently we show that SRPK2 binds and phosphorylates acinus, an SR protein essential for RNA splicing, and redistributes it from the nuclear speckles to the nucleoplasm, resulting in cyclin A1 but not A2 up-regulation (18). Ablation of acinus or SRPK2 abrogates cyclin A1 expression in leukemia cells and arrests cells at the G 1 phase.…”

mentioning

confidence: 81%

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Interaction of Akt-phosphorylated SRPK2 with 14-3-3 Mediates Cell Cycle and Cell Death in Neurons

Jang

Liu²,

Fu³

et al. 2009

Journal of Biological Chemistry

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108

109

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Terminally differentiated neurons are unable to reenter the cell cycle. Aberrant cell cycle activation provokes neuronal cell death, whereas cell cycle inhibition elevates neuronal survival. However, the molecular mechanism regulating the cell cycle and cell death in mature neurons remains elusive. Here we show that SRPK2, a protein kinase specific for the serine/arginine (SR) family of splicing factors, triggers cell cycle progression in neurons and induces apoptosis through regulation of nuclear cyclin D1. Akt phosphorylates SRPK2 on Thr-492 and promotes its nuclear translocation leading to cyclin D1 up-regulation, cell cycle reentry, and neuronal apoptosis. In addition, SRPK2 phosphorylates SC35 and, thus, inactivates p53, resulting in cyclin D1 up-regulation. 14-3-3 binding to SRPK2, regulated by Akt phosphorylation, inhibits these events. We find that SRPK2 is phosphorylated in ischemia-attacked brain, correlating with the observed increase in cyclin D1 levels. Hence, phosphatidylinositol 3-kinase/Akt mediates the cell cycle and cell death machinery in the nervous system through phosphorylation of SRPK2.In the central nervous system the nascent neuroblasts leave ventricular zone or subventricular zone and migrate to the destination where they differentiate and become permanently post-mitotic cells (1). It is well established that terminally differentiated neurons are unable to reenter the cell cycle, but accumulating evidence has demonstrated the up-regulation of cell cycle regulatory proteins in degenerating neurons of Alzheimer disease (AD) 2 brain (2). Elevated levels of Cdc2, Cdk4, p16, Ki-67, cyclin B1, and cyclin D have been found in pathologically affected or vulnerable neurons in AD (3-7). Moreover, several of these regulators have been observed in vulnerable neurons before lesion formation (8). Together these findings suggest that the activity of certain cell cycle regulators plays a critical upstream role in the AD neurodegenerative process. Greene and co-workers (9 -12) have shown that drugs that block cell cycle advances are efficient in preventing the death of PC12 cells as well as sympathetic neurons. Dominant negative forms of the Cdk4 and Cdk6 preventing the cell death induced by camptothecin (a topoisomerase inhibitor) are effectively blocked by the G 1 /S blockers, such as deferoxamine and mimosine, as well as by the cyclin-dependent kinases (Cdk) inhibitors flavopiridol and olomoucine. In addition, they show that neurons treated with DNA-damaging agents such as UV irradiation or camptothecin also require cyclin D and Cdk4/6 activity to induce neuronal death (13). Thus, this evidence supports that mature neurons might retain certain elements of the cell cycle and have the capability of reactivating additional aspects of the replication mechanism when under stresses. Any events that force a mature neuron back into the cell cycle are lethal rather than mitogenic for the neuron.SRPK, a family of cell cycle-regulated protein kinases, phosphorylate serine/arginine (SR) domain-containing protein...

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Section: Discussionmentioning

confidence: 89%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 81%

See 2 more Smart Citations

Interaction of Akt-phosphorylated SRPK2 with 14-3-3 Mediates Cell Cycle and Cell Death in Neurons

Jang

Liu²,

Fu³

et al. 2009

Journal of Biological Chemistry

Self Cite

108

109

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“…Acinus L belongs to the "peripheral" components of the EJC (87). Interestingly, the EJC core component mago nashi homolog 2 (MAGOHB) (88), the peripheral EJC component pinin and the NMD factors UPF1, UPF2, and UPF3B (85) scored also as highly significant in our mTOR-interactome analysis.…”

Section: Discussionmentioning

confidence: 97%

Functional Proteomics Identifies Acinus L as a Direct Insulin- and Amino Acid-Dependent Mammalian Target of Rapamycin Complex 1 (mTORC1) Substrate

Schwarz

Wiese

Tölle

et al. 2015

Molecular & Cellular Proteomics

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The serine/threonine kinase mammalian target of rapamycin (mTOR) governs growth, metabolism, and aging in response to insulin and amino acids (aa), and is often activated in metabolic disorders and cancer. Much is known about the regulatory signaling network that encompasses mTOR, but surprisingly few direct mTOR substrates have been established to date. To tackle this gap in our knowledge, we took advantage of a combined quantitative phosphoproteomic and interactomic strategy. We analyzed the insulin-and aa-responsive phosphoproteome upon inhibition of the mTOR complex 1 (mTORC1) component raptor, and investigated in parallel the interactome of endogenous mTOR. By overlaying these two datasets, we identified acinus L as a potential novel mTORC1 target. We confirmed acinus L as a direct mTORC1 substrate by co-immunoprecipitation and MSenhanced kinase assays. Our study delineates a triple proteomics strategy of combined phosphoproteomics, interactomics, and MS-enhanced kinase assays for the de novo-identification of mTOR network components, and provides a rich source of potential novel mTOR interactors and targets for future investigation. Molecular &

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Functions of SRPK, CLK and DYRK kinases in stem cells, development, and human developmental disorders

Hogg,

Findlay

2023

FEBS Letters

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Human developmental disorders encompass a wide range of debilitating physical conditions and intellectual disabilities. Perturbation of protein kinase signalling underlies the development of some of these disorders. For example, disrupted SRPK signalling is associated with intellectual disabilities, and the gene dosage of DYRKs can dictate the pathology of disorders including Down's syndrome. Here, we review the emerging roles of the CMGC kinase families SRPK, CLK, DYRK, and sub‐family HIPK during embryonic development and in developmental disorders. In particular, SRPK, CLK, and DYRK kinase families have key roles in developmental signalling and stem cell regulation, and can co‐ordinate neuronal development and function. Genetic studies in model organisms reveal critical phenotypes including embryonic lethality, sterility, musculoskeletal errors, and most notably, altered neurological behaviours arising from defects of the neuroectoderm and altered neuronal signalling. Further unpicking the mechanisms of specific kinases using human stem cell models of neuronal differentiation and function will improve our understanding of human developmental disorders and may provide avenues for therapeutic strategies.

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Serine/Arginine Protein–Specific Kinase 2 Promotes Leukemia Cell Proliferation by Phosphorylating Acinus and Regulating Cyclin A1

Cited by 83 publications

References 36 publications

Interaction of Akt-phosphorylated SRPK2 with 14-3-3 Mediates Cell Cycle and Cell Death in Neurons

Interaction of Akt-phosphorylated SRPK2 with 14-3-3 Mediates Cell Cycle and Cell Death in Neurons

Functional Proteomics Identifies Acinus L as a Direct Insulin- and Amino Acid-Dependent Mammalian Target of Rapamycin Complex 1 (mTORC1) Substrate

Functions of SRPK, CLK and DYRK kinases in stem cells, development, and human developmental disorders

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