Regulated Cellular Partitioning of SR Protein-specific Kinases in Mammalian Cells

Ding, Jingzhong; Zhong, Xiang-Yang; Hagopian, Jonathan C.; Cruz, Marissa M.; Ghosh, Gourisankar; Feramisco, James R.; Adams, Joseph A.; Fu, Xiang‐Dong

doi:10.1091/mbc.e05-10-0963

Cited by 109 publications

(186 citation statements)

References 55 publications

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“…Enzymatic analysis reveals that SRPKs use a highly processive mechanism to phosphorylate a defined region in the RS domain in each SR protein (Aubol et al 2003;Ngo et al 2008), and Clk/Sty can further phosphorylate the remaining sites in the RS domain (Ngo et al 2005;Velazquez-Dones et al 2005), suggesting the possibility that these kinases may catalyze a cooperative phosphorylation relay to modulate SR protein function at different biochemical steps and/or in various cellular locations (Ngo et al 2005;Hagopian et al 2008). This idea is consistent with their cellular distributions: While members of the Clk/Sty family of kinases are predominately localized in the nucleus (Colwill et al 1996;Nayler et al 1998), the SRPK family of kinases are detected in both the cytoplasm and the nucleus (Wang et al 1998;Ding et al 2006).…”

supporting

confidence: 80%

Regulation of SR protein phosphorylation and alternative splicing by modulating kinetic interactions of SRPK1 with molecular chaperones

Zhong¹,

Ding²,

Adams³

et al. 2009

Genes Dev.

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172

189

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Phosphorylation is essential for the SR family of splicing factors/regulators to function in constitutive and regulated pre-mRNA splicing; yet both hypo-and hyperphosphorylation of SR proteins are known to inhibit splicing, indicating that SR protein phosphorylation must be tightly regulated in the cell. However, little is known how SR protein phosphorylation might be regulated during development or in response to specific signaling events. Here, we report that SRPK1, a ubiquitously expressed SR protein-specific kinase, directly binds to the cochaperones Hsp40/DNAjc8 and Aha1, which mediate dynamic interactions of the kinase with the major molecular chaperones Hsp70 and Hsp90 in mammalian cells. Inhibition of the Hsp90 ATPase activity induces dissociation of SRPK1 from the chaperone complexes, which can also be triggered by a stress signal (osmotic shock), resulting in translocation of the kinase from the cytoplasm to the nucleus, differential phosphorylation of SR proteins, and alteration of splice site selection. These findings connect the SRPK to the molecular chaperone system that has been implicated in numerous signal transduction pathways and provide mechanistic insights into complex regulation of SR protein phosphorylation and alternative splicing in response to developmental cues and cellular signaling.[Keywords: SR protein-specific kinase; molecular chaperones; stress signaling; SR protein phosphorylation alternative splicing] Supplemental material is available at http://www.genesdev.org.

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supporting

confidence: 80%

Regulation of SR protein phosphorylation and alternative splicing by modulating kinetic interactions of SRPK1 with molecular chaperones

Zhong¹,

Ding²,

Adams³

et al. 2009

Genes Dev.

Self Cite

172

189

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“…19). In comparison to SF2/ASF, SRPK1 spends only a short time in the nucleus, which is at G 2 /M transition (39). We found that PfSRPK1 is predominantly inside the parasite nucleus during the early stages of development of asexual parasites.…”

Section: Discussionmentioning

confidence: 71%

PfSRPK1, a Novel Splicing-related Kinase from Plasmodium falciparum

Dixit

Singh

Sharma

et al. 2010

Journal of Biological Chemistry

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Even though it is increasingly evident that post-transcriptional events like mRNA processing and splicing may regulate gene expression and proteome diversity of malaria parasite Plasmodium, molecular mechanisms that regulate events like mRNA splicing in malaria parasite are poorly understood. Protein kinases control a wide variety of cellular events in almost all eukaryotes, including modulation of mRNA splicing, transport, and stability. We have identified a novel splicing-related protein kinase from Plasmodium falciparum, PfSRPK1. PfSRPK1 when incubated with parasite nuclear extracts inhibited RNA splicing, suggesting that it may control mRNA splicing in the parasite. PfSR1, a putative splicing factor from P. falciparum, was identified as a substrate of PfSRPK1. PfSR1 interacts with RNA and PfSRPK1 modulates its RNA binding. Early in the parasite development, PfSRPK1 and PfSR1 are present in the nucleus. These studies provide useful insights into the function of two potentially key components of P. falciparum mRNA splicing machinery.Malaria is one of the most serious infectious diseases and causes several million deaths and clinical illness in hundreds of millions of people every year (1). One of the major problems of recent times has been the emergence of new drugresistant strains of the malaria parasite Plasmodium falciparum. After invasion of the erythrocytes, the parasite can propagate asexually, giving rise to several new merozoites that invade fresh erythrocytes, which serve as hosts for the parasite to propagate. The blood stage infection is the cause of malaria pathogenesis. The parasite also undergoes sexual differentiation, which leads to the formation of male and female gametocytes. Upon ingestion of gametocytes by the Anopheles mosquito, further development continues inside the vector host. It is well known that signal transduction events mediated by protein kinases regulate diverse cellular processes. The importance of protein kinases in malaria parasite has been highlighted by a series of recent reports (2, 3), as these enzymes have been implicated in wide ranging events in both asexual and sexual stages of the parasite life cycle and, therefore, are considered as potential drug targets. Despite these reports, the information regarding signaling networks in the parasite is very limited.Although it is clear that metazoan protein kinase cascades control gene expression by regulating transcriptional or posttranscriptional events, this area in P. falciparum biology is largely unexplored. Plasmodium displays a high degree of developmental control of gene expression (4). Strikingly, only a few transcription factors have been identified in the parasite leading to the speculation that post-transcriptional events may be pivotal in regulating gene expression in the parasite (5). Translational repression of some genes (6) and control of gene expression by antisense RNA are some of the post-transcriptional (7) events that have been implicated in regulating gene expression in the parasite. mRNA splicing is on...

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“…SRPK1 was first identified as a serine kinase regulating intracellular localization of splicing factors in the cell cycle (15). It translocates to the nucleus before initiation of M phase, indicating that it may play a role in cell cycle progression (41). A previous study shows that both SRPK1 and SRPK2 are the substrates of caspases.…”

Section: Discussionmentioning

confidence: 99%

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

110

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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Regulated Cellular Partitioning of SR Protein-specific Kinases in Mammalian Cells

Cited by 109 publications

References 55 publications

Regulation of SR protein phosphorylation and alternative splicing by modulating kinetic interactions of SRPK1 with molecular chaperones

Regulation of SR protein phosphorylation and alternative splicing by modulating kinetic interactions of SRPK1 with molecular chaperones

PfSRPK1, a Novel Splicing-related Kinase from Plasmodium falciparum

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

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