Splicing Factor Arginine/Serine-rich 17A (SFRS17A) Is an A-kinase Anchoring Protein That Targets Protein Kinase A to Splicing Factor Compartments

Jarnæss, Elisabeth; Stokka, Anne Jorunn; Kvissel, Anne Katrine; Skålhegg, Bjørn Steen; Torgersen, Knut Martin; Scott, John D.; Carlson, Catherine R.; Taskén, Kjetil

doi:10.1074/jbc.m109.056465

Cited by 23 publications

(22 citation statements)

References 56 publications

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“…2–4). Anchored PKA has been shown to be important in various cellular processes including hormone‐mediated insulin secretion from pancreatic islet B‐cells,5 vasopressin‐induced aquaporin shuttle in renal principal cells,6 and regulation of pre‐mRNA splicing 7. It is also heavily involved in the proper functioning of cardiomyocytes 8…”

Section: Introductionmentioning

confidence: 99%

Sphingosine Kinase Interacting Protein is an A‐Kinase Anchoring Protein Specific for Type I cAMP‐Dependent Protein Kinase

et al. 2010

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The compartmentalization of kinases and phosphatases plays an important role in the specificity of second-messenger-mediated signaling events. Localization of the cAMP-dependent protein kinase is mediated by interaction of its regulatory subunit (PKA-R) with the versatile family of A-kinase-anchoring proteins (AKAPs). Most AKAPs bind avidly to PKA-RII, while some have dual specificity for both PKA-RI and PKA-RII; however, no mammalian PKA-RI-specific AKAPs have thus far been assigned. This has mainly been attributed to the observation that PKA-RI is more cytosolic than the more heavily compartmentalized PKA-RII. Chemical proteomics screens of the cAMP interactome in mammalian heart tissue recently identified sphingosine kinase type 1-interacting protein (SKIP, SPHKAP) as a putative novel AKAP. Biochemical characterization now shows that SPHKAP can be considered as the first mammalian AKAP that preferentially binds to PKA-RIalpha. Recombinant human SPHKAP functions as an RI-specific AKAP that utilizes the characteristic AKAP amphipathic helix for interaction. Further chemical proteomic screening utilizing differential binding characteristics of specific cAMP resins confirms SPHKAPs endogenous specificity for PKA-RI directly in mammalian heart and spleen tissue. Immunolocalization studies revealed that recombinant SPHKAP is expressed in the cytoplasm, where PKA-RIalpha also mainly resides. Alignment of SPHKAPs' amphipathic helix with peptide models of PKA-RI- or PKA-RII-specific anchoring domains shows that it has largely only PKA-RIalpha characteristics. Being the first mammalian PKA-RI-specific AKAP with cytosolic localization, SPHKAP is a very promising model for studying the function of the less explored cytosolic PKA-RI signaling nodes.

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Section: Introductionmentioning

confidence: 99%

Sphingosine Kinase Interacting Protein is an A‐Kinase Anchoring Protein Specific for Type I cAMP‐Dependent Protein Kinase

et al. 2010

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“…The first evidence of a possible involvement of PKA in the regulation of AS came from the observation that a fraction of the C subunit translocates into the nucleus, colocalizes with SRSF2 (previously reported as SC35) in splicing speckles, and phosphorylates several SR proteins, at least in vitro [78]. Localization of the C subunit in nuclear speckles seems to be related to its interaction with the C-subunit binding protein HA95 [78] and to the SR protein SRSF17A, which was shown to be a novel AKAP required to anchor PKA C subunit in splicing speckles [79]. Importantly, modulation of E1A reporter minigene splicing by SRSF17A is dependent on its interaction with PKA [79].…”

Section: Signaling-activated Splicing Factor Kinasesmentioning

confidence: 99%

“…Localization of the C subunit in nuclear speckles seems to be related to its interaction with the C-subunit binding protein HA95 [78] and to the SR protein SRSF17A, which was shown to be a novel AKAP required to anchor PKA C subunit in splicing speckles [79]. Importantly, modulation of E1A reporter minigene splicing by SRSF17A is dependent on its interaction with PKA [79]. Moreover, nuclear PKA itself is able to modulate AS of the E1A reporter minigene, even in the absence of the cAMP stimulation [78].…”

Section: Signaling-activated Splicing Factor Kinasesmentioning

confidence: 99%

Phosphorylation-Mediated Regulation of Alternative Splicing in Cancer

Naro

Sette

2013

International Journal of Cell Biology

130

132

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Alternative splicing (AS) is one of the key processes involved in the regulation of gene expression in eukaryotic cells. AS catalyzes the removal of intronic sequences and the joining of selected exons, thus ensuring the correct processing of the primary transcript into the mature mRNA. The combinatorial nature of AS allows a great expansion of the genome coding potential, as multiple splice-variants encoding for different proteins may arise from a single gene. Splicing is mediated by a large macromolecular complex, the spliceosome, whose activity needs a fine regulation exerted by cis-acting RNA sequence elements and trans-acting RNA binding proteins (RBP). The activity of both core spliceosomal components and accessory splicing factors is modulated by their reversible phosphorylation. The kinases and phosphatases involved in these posttranslational modifications significantly contribute to AS regulation and to its integration in the complex regulative network that controls gene expression in eukaryotic cells. Herein, we will review the major canonical and noncanonical splicing factor kinases and phosphatases, focusing on those whose activity has been implicated in the aberrant splicing events that characterize neoplastic transformation.

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“…They are anchored to defined compartments, such as the plasma membrane, organelles and specific sites in the cytosol where they create focal points for signal transduction [5][6][7][8][9][10]. Up to now, only two AKAPs are found inside the nucleus, that is, AKAP8 and a splicing factor SFRS17A (also known as AKAP17A), binding type II and both type I and type II PKA regulatory subunits, respectively [11][12][13]. Besides, in the nucleus, the homologue of AKAP8, referred to as A-kinase anchoring protein 8 like (AKAP8L) or HA95, is present [14][15][16].…”

Section: Introductionmentioning

confidence: 99%

PKA‐binding domain of AKAP8 is essential for direct interaction with DPY30 protein

et al. 2018

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The main function of the A kinase-anchoring proteins (AKAPs) is to target the cyclic AMP-dependent protein kinase A (PKA) to its cellular substrates through the interaction with its regulatory subunits. Besides anchoring of PKA, AKAP8 participates in regulating the histone H3 lysine 4 (H3K4) histone methyltransferase (HMT) complexes. It is also involved in DNA replication, apoptosis, transcriptional silencing of rRNA genes, alternative splicing, and chromatin condensation during mitosis. In this study, we focused on the interaction between AKAP8 and the core subunit of all known H3K4 HMT complexes-DPY30 protein. Here, we demonstrate that the PKA-binding domain of AKAP8 and the C-terminal domain of DPY30, also called Dpy-30 motif, are crucial for the interaction between these proteins. We show that a single amino acid substitution in DPY30 L69D affects its dimerization and completely abolishes its interaction with AKAP8 and another DPY30-binding partner brefeldin A-inhibited guanine nucleotide-exchange protein 1 (BIG1), which is also AKAP domain-containing protein. We further demonstrate that AKAP8 interacts with DPY30 and the RII alpha regulatory subunit of PKA both in the interphase and in mitotic cells, and we show evidences that AKAP8L, a homologue of AKAP8, interacts with core subunits of the H3K4 HMT complexes, which suggests its role as a potential regulator of these complexes. The results presented here reinforce the analogy between AKAP8-RII alpha and AKAP8-DPY30 interactions, postulated before, and improve our understanding of the complexity of the cellular functions of the AKAP8 protein.Abbreviations AKAP8, A-kinase anchoring protein 8; AKAP8L, A-kinase anchoring protein 8 like; ASH2L, absent, small, or homeotic 2-like protein; BAP18, BPTF-associated protein of 18 kDa; BIG1, brefeldin A-inhibited guanine nucleotide-exchange protein; co-IP, co-immunoprecipitation; DBM, DPY30-binding motif; GST, glutathione S-transferase; H3K4, histone H3 lysine 4; HDAC3, histone deacetylase 3; HEK293, human embryonic kidney 293 cell line; His-tag, polyhistidine-tag; HMT, histone methyltransferase; Kif2A, kinesin family member 2A; KMT, histone lysine methyltransferase; MLL, mixed lineage leukemia; PI, propidium iodide; PKA, cAMP-dependent protein kinase; PRKAR2a, protein kinase cAMP-dependent type II regulatory subunit alpha; RbBP5, retinoblastoma-binding protein 5; RIIa, cAMP-dependent protein kinase type IIalpha regulatory subunit; SAC, spindle assembly checkpoint; TAP tag, tandem affinity purification tag; TPR, translocated promoter region protein; WB, Western blot; WDR5, WD repeat domain 5; WRAD, WDR5-RbBP5-ASH2L-DPY30 complex.

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Splicing Factor Arginine/Serine-rich 17A (SFRS17A) Is an A-kinase Anchoring Protein That Targets Protein Kinase A to Splicing Factor Compartments

Cited by 23 publications

References 56 publications

Sphingosine Kinase Interacting Protein is an A‐Kinase Anchoring Protein Specific for Type I cAMP‐Dependent Protein Kinase

Sphingosine Kinase Interacting Protein is an A‐Kinase Anchoring Protein Specific for Type I cAMP‐Dependent Protein Kinase

Phosphorylation-Mediated Regulation of Alternative Splicing in Cancer

PKA‐binding domain of AKAP8 is essential for direct interaction with DPY30 protein

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