Protein Kinase A-Dependent Phosphorylation of Serine 119 in the Proto-Oncogenic Serine/Arginine-Rich Splicing Factor 1 Modulates Its Activity as a Splicing Enhancer Protein

Aksaas, Anne Kristin; Eikvar, Sissel; Akusjärvi, Göran; Skålhegg, Bjørn Steen; Kvissel, Anne Katrine

doi:10.1177/1947601911430226

Cited by 9 publications

(8 citation statements)

References 78 publications

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“…SRSF1 is involved in the regulation of constitutive and alternative splicing. In a recent review it was noted that SRSF1 has also been shown to promote tumor transformation and growth by several mechanisms; for example, by stabilizing mRNA of anti-apoptotic factors 21 and by generating inactive tumor suppressor proteins by alternative splicing [ 41 ]. Reversible phosphorylation cascades are able to rapidly conduct signals throughout the cell and are probably important in mediating extracellular signals to the spliceosome [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

Effects of mycophenolate mofetil on kidney function and phosphorylation status of renal proteins in Alport COL4A3-deficient mice

Petrova

Schultze²,

Brandhorst³

et al. 2014

Proteome Sci

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BackgroundWe investigated the effects of mycophenolate mofetil (MMF) on kidney function and on protein phosphorylation in a mouse model for the human Alport syndrome.MethodsCOL4A3-deficient (COL4A3−/−) mice were randomly allocated to receive a placebo (PLC COL4A3−/−) or MMF treatment (MMF COL4A3−/−). Wild type mice (WT) were used as controls. Changes in serum creatinine, total protein and blood urea nitrogen (BUN), concentrations of mycophenolic acid (MPA) and its glucuronide metabolite (MPAG), serum protein electrophoresis, urine dipstick chemistry and sediment were measured. Changes in the phosphorylation status of renal proteins and histology were analyzed.ResultsMMF influenced kidney function and protein phosphorylation. Serum creatinine and BUN were lower in MMF treated compared to PLC treated COL4A3−/− mice. Serum albumin and alpha-1 globulins were significantly decreased while serum creatinine, alpha-2 globulins, urine dipstick protein, leukocyte esterase, hemoglobin and red blood cells were all increased in both COL4A3−/− groups compared to WT. Differential 2DE-gel analysis identified six phosphorylated kidney protein spots that were significantly altered by MMF.ConclusionsThese data suggest that the MMF treatment in this murine model moderately improved kidney function and reversed the phosphorylation status of six renal phosphoprotein spots to that seen in WT mice.Electronic supplementary materialThe online version of this article (doi:10.1186/s12953-014-0056-z) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Effects of mycophenolate mofetil on kidney function and phosphorylation status of renal proteins in Alport COL4A3-deficient mice

Petrova

Schultze²,

Brandhorst³

et al. 2014

Proteome Sci

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“…Table 4 lists examples of PKA CM sites (61)(62)(63)(64)(65)(66)(67)(68)(69)(70)(71) that are all located in the loops, but their corresponding overall protein conformations are clearly incompatible with the PKA conformation. Thus, despite the exposed CMs, these proteins may use their distinct overall conformations to prevent their access to relevant kinases, and mechanisms may exist to temporally alter the protein conformations to allow their access to kinases, thereby leading to regulated phosphorylation and subsequent specific cellular responses.…”

Section: Resultsmentioning

confidence: 99%

A Mechanism of Global Shape-dependent Recognition and Phosphorylation of Filamin by Protein Kinase A

Ithychanda

Mohan

Zhu

et al. 2015

Journal of Biological Chemistry

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Background:The mechanism of filamin Ser 2152 phosphorylation by PKA is unclear. Results: Autoinhibitory filamin is resistant to phosphorylation despite exposed Ser 2152 , but ligand binding alters the filamin conformation, triggering PKA recognition. Conclusion: Filamin Ser2152 phosphorylation is conformation-dependent on ligand binding. Significance: The overall conformation of substrate, not just the exposed phosphorylation site, regulates the kinase substrate recognition in signaling.

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“…SFSR17A targets PKA in close proximity to several members of the SR family of proteins. Furthermore, several independent reports show that the PKA C subunit interacts with the SR protein SRSF1 ( 159 – 161 ). PKA-dependent phosphorylation of SRSF1 was found to enhance its RNA-binding capacity ( 159 ), and to modulate its activity as a splicing regulator ( 159 – 161 ).…”

Section: Kinase Anchoring Proteins—c-kapsmentioning

confidence: 99%

The Molecular Basis for Specificity at the Level of the Protein Kinase a Catalytic Subunit

Søberg

Skålhegg

2018

Front. Endocrinol.

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Assembly of multi enzyme complexes at subcellular localizations by anchoring- and scaffolding proteins represents a pivotal mechanism for achieving spatiotemporal regulation of cellular signaling after hormone receptor targeting [for review, see (1)]. In the 3′ 5′-cyclic adenosine monophosphate (cAMP) dependent protein kinase (PKA) signaling pathway it is generally accepted that specificity is secured at several levels. This includes at the first level stimulation of receptors coupled to heterotrimeric G proteins which through stimulation of adenylyl cyclase (AC) forms the second messenger cAMP. Cyclic AMP has several receptors including PKA. PKA is a tetrameric holoenzyme consisting of a regulatory (R) subunit dimer and two catalytic (C) subunits. The R subunit is the receptor for cAMP and compartmentalizes cAMP signals through binding to cell and tissue-specifically expressed A kinase anchoring proteins (AKAPs). The current dogma tells that in the presence of cAMP, PKA dissociates into an R subunit dimer and two C subunits which are free to phosphorylate relevant substrates in the cytosol and nucleus. The release of the C subunit has raised the question how specificity of the cAMP and PKA signaling pathway is maintained when the C subunit no longer is attached to the R subunit-AKAP complex. An increasing body of evidence points toward a regulatory role of the cAMP and PKA signaling pathway by targeting the C subunits to various C subunit binding proteins in the cytosol and nucleus. Moreover, recent identification of isoform specific amino acid sequences, motifs and three dimensional structures have together provided new insight into how PKA at the level of the C subunit may act in a highly isoform-specific fashion. Here we discuss recent understanding of specificity of the cAMP and PKA signaling pathway based on C subunit subcellular targeting as well as evolution of the C subunit structure that may contribute to the dynamic regulation of C subunit activity.

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Protein Kinase A-Dependent Phosphorylation of Serine 119 in the Proto-Oncogenic Serine/Arginine-Rich Splicing Factor 1 Modulates Its Activity as a Splicing Enhancer Protein

Cited by 9 publications

References 78 publications

Effects of mycophenolate mofetil on kidney function and phosphorylation status of renal proteins in Alport COL4A3-deficient mice

Effects of mycophenolate mofetil on kidney function and phosphorylation status of renal proteins in Alport COL4A3-deficient mice

A Mechanism of Global Shape-dependent Recognition and Phosphorylation of Filamin by Protein Kinase A

The Molecular Basis for Specificity at the Level of the Protein Kinase a Catalytic Subunit

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