Interplay between SRPK and Clk/Sty Kinases in Phosphorylation of the Splicing Factor ASF/SF2 Is Regulated by a Docking Motif in ASF/SF2

Ngo, Jacky Chi Ki; Chakrabarti, Sutapa; Ding, Jingzhong; Velazquez-Dones, Adolfo; Nolen, Brad J.; Aubol, Brandon E.; Adams, Joseph A.; Fu, Xiang‐Dong; Ghosh, Gourisankar

doi:10.1016/j.molcel.2005.08.025

Cited by 188 publications

(294 citation statements)

References 49 publications

(53 reference statements)

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“…GST-⌬PfSRPK1 was able to phosphorylate myelin basic protein (MBP) in vitro, indicating that this spacer region-deleted version of the kinase was active (Fig. 1C) as was also the case with human SRPK1 (17). GST-⌬PfS-RPK1 also exhibited autophosphorylation, which was reduced in the presence of MBP, most likely due to competition for the substrate binding site, thus suggesting that ⌬PfSRPK1 may undergo trans-autophosphorylation.…”

Section: Resultsmentioning

confidence: 66%

“…SR protein function is regulated by phosphorylation of their RS domains by multiple kinases, including a family of evolutionarily conserved SR protein-specific kinases (SRPKs). The SRPK family of kinases is unique as the kinases are capable of phosphorylating repetitive RS domains with remarkable specificity and efficiency (16,17). In mammals and yeast, SRPKs have been implicated in several key functions like regulation of mRNA processing, nuclear import, germ line development, polyamine transport, and ion homeostasis (18 -20).…”

mentioning

confidence: 99%

“…In mammals and yeast, SRPKs have been implicated in several key functions like regulation of mRNA processing, nuclear import, germ line development, polyamine transport, and ion homeostasis (18 -20). In addition to SRPKs, SR proteins are also phosphorylated by cdc28/cdc2-like kinases (Clk/Sty) (17). The cooperative phosphorylation of SR proteins is considered important for modulating its function and cellular localization (19).…”

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confidence: 99%

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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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Section: Resultsmentioning

confidence: 66%

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confidence: 99%

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confidence: 99%

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PfSRPK1, a Novel Splicing-related Kinase from Plasmodium falciparum

Dixit

Singh

Sharma

et al. 2010

Journal of Biological Chemistry

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“…SRPK1 phosphorylates only the N-terminal region of the RS domain before dissociating, while Clk/Sty remains attached and phosphorylates the entire RS domain. For SRPK1, this substrate specificity is governed by a docking motif N-terminal to the RS domains, which restricts the number of serines in ASF/SF2 that can be phosphorylated [74] (Figure 2). In the cell, SRPK1 is found in the cytoplasm, while Clk/Sty is localized in the nucleus [66,[75][76][77].…”

Section: Processive Phosphorylation Of Asf/sf2mentioning

confidence: 99%

“…The current model is that SRPK1 phosphorylates ASF/SF2 in the cytoplasm, triggering nuclear entry and recruitment to speckles. Subsequent phosphorylation by Clk/Sty promotes release of ASF/SF2 from speckles, at which point the protein can participate in splicing [74].…”

Section: Processive Phosphorylation Of Asf/sf2mentioning

confidence: 99%

Processive phosphorylation: Mechanism and biological importance

Patwardhan

Miller

2007

Cellular Signalling

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Recent proteomic data indicate that a majority of the phosphorylated proteins in a eucaryotic cell contain multiple sites of phosphorylation. In many signaling events, a single kinase phosphorylates multiple sites on a target protein. Processive phosphorylation occurs when a protein kinase binds once to a substrate and phosphorylates all of the available sites before dissociating. In this review, we discuss examples of processive phosphorylation by serine/threonine kinases and tyrosine kinases. We describe current experimental approaches for distinguishing processive from non-processive phosphorylation. Finally, we contrast the biological situations that are suited to regulation by processive and non-processive phosphorylation.

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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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Interplay between SRPK and Clk/Sty Kinases in Phosphorylation of the Splicing Factor ASF/SF2 Is Regulated by a Docking Motif in ASF/SF2

Cited by 188 publications

References 49 publications

PfSRPK1, a Novel Splicing-related Kinase from Plasmodium falciparum

PfSRPK1, a Novel Splicing-related Kinase from Plasmodium falciparum

Processive phosphorylation: Mechanism and biological importance

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

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