Proto-oncoprotein tls/fus is associated to the nuclear matrix and complexed with splicing factors ptb, srm160, and sr proteins

Meißner, Michael; Lopato, Sergiy; Gotzmann, Josef; Sauermann, Georg; Barta, Andrea

doi:10.1016/s0014-4827(02)00046-0

Cited by 94 publications

(73 citation statements)

References 54 publications

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“…It is also known to impact signaling pathways in a specific manner as shown with its specific activation of the MAPK pathway [93]. The phosphorylation of TLS-FUS, a nuclear transcription factor that also functions in splicing, demonstrates the versatility of PKCβII functions [94,95]. The observation that PKCβII acts to phosphorylate Akt on Ser473 and acts as a PDK2 (phosphoinositide dependent kinase type 2) activity [96], underscores the role of PKCβII in signaling pathways.…”

Section: Pkcβiimentioning

confidence: 95%

Specific protein kinase C isoforms as transducers and modulators of insulin signaling

Sampson

Cooper

2006

Molecular Genetics and Metabolism

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Recent studies implicate specific PKC isoforms in the insulin-signaling cascade. Insulin activates PKCsα, βII, δ and ζ in several cell types. In addition, as will be documented in this review, certain members of the PKC family may also be activated and act upstream of PI3 and MAP kinases. Each of these isoforms has been shown one way or another either to mimic or to modify insulin-stimulated effects in one or all of the insulin-responsive tissues. Moreover, each of the isoforms has been shown to be activated by insulin stimulation or conditions important for effective insulin stimulation. Studies attempting to demonstrate a definitive role for any of the isoforms have been performed on different cells, ranging from appropriate model systems for skeletal muscle, liver and fat, such as primary cultures, and cell lines and even in vivo studies, including transgenic mice with selective deletion of specific PKC isoforms. In addition, studies have been done on certain expression systems such as CHO or HEK293 cells, which are far removed from the tissues themselves and serve mainly as vessels for potential protein-protein interactions. Thus, a clear picture for many of the isoforms remains elusive in spite of over two decades of intensive research. The recent intrusion of transgenic and precise molecular biology technologies into the research armamentarium has opened a wide range of additional possibilities for direct involvement of individual isoforms in the insulin signaling cascade. As we hope to discuss within the context of this review, whereas many of the long soughtafter answers to specific questions are not yet clear, major advances have been made in our understanding of precise roles for individual PKC isoforms in mediation of insulin effects. In this review, in which we shall focus our attention on isoforms in the conventional and novel categories, a clear case will be made to show that these isoforms are not only expressed but are importantly involved in regulation of insulin metabolic effects.

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Section: Pkcβiimentioning

confidence: 95%

Specific protein kinase C isoforms as transducers and modulators of insulin signaling

Sampson

Cooper

2006

Molecular Genetics and Metabolism

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“…The protein is a member of the TET (TLS, EWS, and TAF15) family of proteins, which is implicated in both transcription and splicing (Tan and Manley 2009;Dormann and Haass 2013). TET proteins share similar domain organization and copurify or interact with transcription factors (TFIID and RNA polymerase II [RNAP II]) (Bertolotti et al 1996;Law et al 2006;Kwon et al 2013) on the one hand and the spliceosome and SR protein-splicing factors (Yang et al 1998;Rappsilber et al 2002;Zhou et al 2002;Meissner et al 2003;Leichter et al 2011) on the other, suggesting possible roles in coupling transcription and splicing. Considerable evidence implicates TET proteins in splicing control in vivo (Paronetto et al 2011;Blechingberg et al 2012), and FUS was shown to enhance RNAP II transcription while repressing RNAP III transcription in vitro (Tan and Manley 2010) and increase RNAP II phosphorylation, and thereby transcription elongation, in vivo (Schwartz et al 2012).…”

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confidence: 99%

ALS mutations in TLS/FUS disrupt target gene expression

Coady

Manley

2015

Genes Dev.

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Amyotrophic lateral sclerosis (ALS) is caused by mutations in a number of genes, including the gene encoding the RNA/DNA-binding protein translocated in liposarcoma or fused in sarcoma (TLS/FUS or FUS). Previously, we identified a number of FUS target genes, among them MECP2. To investigate how ALS mutations in FUS might impact target gene expression, we examined the effects of several FUS derivatives harboring ALS mutations, such as R521C (FUS C ), on MECP2 expression in transfected human U87 cells. Strikingly, FUS C and other mutants not only altered MECP2 alternative splicing but also markedly increased mRNA abundance, which we show resulted from sharply elevated stability. Paradoxically, however, MeCP2 protein levels were significantly reduced in cells expressing ALS mutant derivatives. Providing a parsimonious explanation for these results, biochemical fractionation and in vivo localization studies revealed that MECP2 mRNA colocalized with cytoplasmic FUS C in insoluble aggregates, which are characteristic of ALS mutant proteins. Together, our results establish that ALS mutations in FUS can strongly impact target gene expression, reflecting a dominant effect of FUS-containing aggregates.

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“…For example, the translation-coupled assembly of focal adhesions at the cell membrane is regulated by hnRNP P2 (28). Notably, both nuclear hnRNA processing (41,42) and localized protein synthesis at the plasma membrane (28) provide opportunities for P2 to join Sm and SR proteins, well-known RNP autoantigens (43,44).…”

Section: Discussionmentioning

confidence: 99%

Heterogeneous Nuclear Ribonucleoprotein P2 Is an Autoantibody Target in Mice Deficient for Mer, Axl, and Tyro3 Receptor Tyrosine Kinases

Radic

Shah

Zhang

et al. 2006

The Journal of Immunology

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Deficiencies in clearance of apoptotic cells predispose to the development of autoimmune disease. This is evident in mice lacking the receptor tyrosine kinases Tyro3, Axl, and Mer. Deficient mice exhibit an increased abundance of apoptotic cells in tissues and manifest diverse autoimmune conditions. To test these mice for the presence of autoantibodies to apoptotic cells, we generated spontaneous splenic B cell hybridomas and used a novel microscopy screen to detect Ab binding to apoptotic Jurkat cells. From hybridomas secreting IgG Abs reactive with apoptotic cells, we selected one that recreated the major serum specificity for apoptotic cells. The Ab LHC7.15 bound to an Ag that is differentially distributed between the nucleus and the cytoplasm in live and apoptotic cells. In late apoptotic cells, the Ag coalesces into aggregates that bleb from the cell surface. Immunopurification of the Ag, followed by mass spectrometry, identified a protein of 69 kDa whose partial sequence matched heterogeneous nuclear ribonucleoprotein P2. This multifunctional protein binds DNA, RNA, and several known ribonucleoprotein autoantigens. Our observations indicate that a ribonucleoprotein complex, formed and translocated to the cell surface in apoptosis, represents a potent stimulus for breaking tolerance and inducing systemic autoimmunity in mice with defective clearance of cell remnants.

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Proto-oncoprotein tls/fus is associated to the nuclear matrix and complexed with splicing factors ptb, srm160, and sr proteins

Cited by 94 publications

References 54 publications

Specific protein kinase C isoforms as transducers and modulators of insulin signaling

Specific protein kinase C isoforms as transducers and modulators of insulin signaling

ALS mutations in TLS/FUS disrupt target gene expression

Heterogeneous Nuclear Ribonucleoprotein P2 Is an Autoantibody Target in Mice Deficient for Mer, Axl, and Tyro3 Receptor Tyrosine Kinases

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