Nuclear ARVCF Protein Binds Splicing Factors and Contributes to the Regulation of Alternative Splicing

Rappe, Ulrike; Schlechter, Tanja; Aschoff, Moritz; Hotz‐Wagenblatt, Agnes; Hofmann, Ilse

doi:10.1074/jbc.m113.530717

Cited by 10 publications

(11 citation statements)

References 72 publications

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“…NDUFV3 appeared in evolution around the time that lobe-finned fishes developed, as a homologue could not be identified in jawless fish, insects, nematodes or fungi. Analysis of the structure of the human NDUFV3 gene revealed the same splicing pattern as in rat (consistent with detection of NDUFV3L in human U2OS cells) and the alternative splicing is known to involve the catenin protein known as ‘Armadillo Repeat gene deleted in Velo-Cardio-Facial syndrome’ (ARVCF) [56] . NDUFV3L itself is present in many species from fish to humans — and it is possible that for some species RNA sequencing has not yet been deep enough to identify it.…”

Section: Discussionsupporting

confidence: 62%

Subunit NDUFV3 is present in two distinct isoforms in mammalian complex I

Bridges

Mohammed

Harbour

et al. 2017

Biochimica et Biophysica Acta (BBA) - Bioenergetics

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Complex I (NADH:ubiquinone oxidoreductase) is the first enzyme of the electron transport chain in mammalian mitochondria. Extensive proteomic and structural analyses of complex I from Bos taurus heart mitochondria have shown it comprises 45 subunits encoded on both the nuclear and mitochondrial genomes; 44 of them are different and one is present in two copies. The bovine heart enzyme has provided a model for studying the composition of complex I in other mammalian species, including humans, but the possibility of additional subunits or isoforms in other species or tissues has not been explored. Here, we describe characterization of the complexes I purified from five rat tissues and from a rat hepatoma cell line. We identify a ~ 50 kDa isoform of subunit NDUFV3, for which the canonical isoform is only ~ 10 kDa in size. We combine LC-MS and MALDI-TOF mass spectrometry data from two different purification methods (chromatography and immuno-purification) with information from blue native PAGE analyses to show the long isoform is present in the mature complex, but at substoichiometric levels. It is also present in complex I in cultured human cells. We describe evidence that the long isoform is more abundant in both the mitochondria and purified complexes from brain (relative to in heart, liver, kidney and skeletal muscle) and more abundant still in complex I in cultured cells. We propose that the long 50 kDa isoform competes with its canonical 10 kDa counterpart for a common binding site on the flavoprotein domain of complex I.

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Section: Discussionsupporting

confidence: 62%

Subunit NDUFV3 is present in two distinct isoforms in mammalian complex I

Bridges

Mohammed

Harbour

et al. 2017

Biochimica et Biophysica Acta (BBA) - Bioenergetics

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“…When not bound to cadherin, ARVCF may regulate the cytoskeleton by interacting with small-GTPases such as Rho and Rac [107, 108]. Like most catenins, ARVCF also translocates to the nucleus where it may be involved in alternative mRNA splicing [109, 110]. ARVCF is expressed in the human forebrain ganglionic eminences; mouse Arvcf is expressed in the brainstem, hippocampus, cerebral cortex, and heart (Fig.…”

Section: Main Textmentioning

confidence: 99%

In the line-up: deleted genes associated with DiGeorge/22q11.2 deletion syndrome: are they all suspects?

Motahari

Moody

Maynard

et al. 2019

J Neurodevelop Disord

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Background 22q11.2 deletion syndrome (22q11DS), a copy number variation (CNV) disorder, occurs in approximately 1:4000 live births due to a heterozygous microdeletion at position 11.2 (proximal) on the q arm of human chromosome 22 (hChr22) (McDonald-McGinn and Sullivan, Medicine 90:1-18, 2011). This disorder was known as DiGeorge syndrome, Velo-cardio-facial syndrome (VCFS) or conotruncal anomaly face syndrome (CTAF) based upon diagnostic cardiovascular, pharyngeal, and craniofacial anomalies (McDonald-McGinn and Sullivan, Medicine 90:1-18, 2011; Burn et al., J Med Genet 30:822-4, 1993) before this phenotypic spectrum was associated with 22q11.2 CNVs. Subsequently, 22q11.2 deletion emerged as a major genomic lesion associated with vulnerability for several clinically defined behavioral deficits common to a number of neurodevelopmental disorders (Fernandez et al., Principles of Developmental Genetics, 2015; Robin and Shprintzen, J Pediatr 147:90-6, 2005; Schneider et al., Am J Psychiatry 171:627-39, 2014). Results The mechanistic relationships between heterozygously deleted 22q11.2 genes and 22q11DS phenotypes are still unknown. We assembled a comprehensive “line-up” of the 36 protein coding loci in the 1.5 Mb minimal critical deleted region on hChr22q11.2, plus 20 protein coding loci in the distal 1.5 Mb that defines the 3 Mb typical 22q11DS deletion. We categorized candidates based upon apparent primary cell biological functions. We analyzed 41 of these genes that encode known proteins to determine whether haploinsufficiency of any single 22q11.2 gene—a one gene to one phenotype correspondence due to heterozygous deletion restricted to that locus—versus complex multigenic interactions can account for single or multiple 22q11DS phenotypes. Conclusions Our 22q11.2 functional genomic assessment does not support current theories of single gene haploinsufficiency for one or all 22q11DS phenotypes. Shared molecular functions, convergence on fundamental cell biological processes, and related consequences of individual 22q11.2 genes point to a matrix of multigenic interactions due to diminished 22q11.2 gene dosage. These interactions target fundamental cellular mechanisms essential for development, maturation, or homeostasis at subsets of 22q11DS phenotypic sites. Electronic supplementary material The online version of this article (10.1186/s11689-019-9267-z) contains supplementary material, which is available to authorized users.

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“…ARVCF is also localized to the nucleus [38,39]. Both p120ctn and ARVCF have splice variants that include an alternative exon, exon C, that allows for an insertion within the polyK sequence.…”

Section: Expression and Localization Of P120ctn Family Of Proteinsmentioning

confidence: 99%

“…This insertion can disrupt the intrinsic nuclear localization ability of the polyK sequence from p120ctn [40]. However, an ARVCF isoform that includes exon C is still able to localize to the nucleus [39], suggesting that there may be other determinants in these proteins that regulate nuclear localization [25,38,39]. …”

Section: Expression and Localization Of P120ctn Family Of Proteinsmentioning

confidence: 99%

Functional roles of p120ctn family of proteins in central neurons

Arikkath

2017

Seminars in Cell & Developmental Biology

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The cadherin-catenin complex in central neurons is associated with a variety of cytosolic partners, collectively called catenins. The p120ctn members are a family of catenins that are distinct from the more ubiquitously expressed α- and β-catenins. It is becoming increasingly clear that the functional roles of the p120ctn family of catenins in central neurons extend well beyond their functional roles in non-neuronal cells in partnering with cadherin to regulate adhesion. In this review, we will provide an overview of the p120ctn family in neurons and their varied functional roles in central neurons. Finally, we will examine the emerging roles of this family of proteins in neurodevelopmental disorders.

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Nuclear ARVCF Protein Binds Splicing Factors and Contributes to the Regulation of Alternative Splicing

Cited by 10 publications

References 72 publications

Subunit NDUFV3 is present in two distinct isoforms in mammalian complex I

Subunit NDUFV3 is present in two distinct isoforms in mammalian complex I

In the line-up: deleted genes associated with DiGeorge/22q11.2 deletion syndrome: are they all suspects?

Functional roles of p120ctn family of proteins in central neurons

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