Deciphering the Cross Talk between hnRNP K and c-Src: the c-Src Activation Domain in hnRNP K Is Distinct from a Second Interaction Site

Adolph, Dörte; Flach, Nadine; Mueller, Katharina; Ostareck, Dirk H.; Ostareck-Lederer, Antje

doi:10.1128/mcb.02014-06

Cited by 35 publications

(43 citation statements)

References 62 publications

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“…Abolishment of mRNA silencing requires coordinated post-translational modifications of hnRNP K in erythroid differentiation. HnRNP K activates cSrc (Ostareck-Lederer et al 2002;Adolph et al 2007), and c-Src-dependent tyrosine phosphorylation diminishes DICE binding activity of hnRNP K and consequently its function as inhibitor of mRNA translation (Messias et al 2006). For several mRNAs, which are equally expressed in untreated and activated macrophages, a stronger enrichment on hnRNP K was determined in noninduced RAW 264.7 cells and BMDMs compared to cells induced with LPS for 6 h (Fig.…”

Section: Discussionmentioning

confidence: 99%

Translation control of TAK1 mRNA by hnRNP K modulates LPS-induced macrophage activation

Liepelt

Mossanen

Denecke

et al. 2014

RNA

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Macrophage activation by bacterial lipopolysaccharides (LPS) is induced through Toll-like receptor 4 (TLR4). The synthesis and activity of TLR4 downstream signaling molecules modulates the expression of pro-and anti-inflammatory cytokines. To address the impact of post-transcriptional regulation on that process, we performed RIP-Chip analysis. Differential association of mRNAs with heterogeneous nuclear ribonucleoprotein K (hnRNP K), an mRNA-specific translational regulator in differentiating hematopoietic cells, was studied in noninduced and LPS-activated macrophages. Analysis of interactions affected by LPS revealed several mRNAs encoding TLR4 downstream kinases and their modulators. We focused on transforming growth factor-β-activated kinase 1 (TAK1) a central player in TLR4 signaling. HnRNP K interacts specifically with a sequence in the TAK1 mRNA 3 ′ UTR in vitro. Silencing of hnRNP K does not affect TAK1 mRNA synthesis or stability but enhances TAK1 mRNA translation, resulting in elevated TNF-α, IL-1β, and IL-10 mRNA expression. Our data suggest that the hnRNP K-3 ′ UTR complex inhibits TAK1 mRNA translation in noninduced macrophages. LPS-dependent TLR4 activation abrogates translational repression and newly synthesized TAK1 boosts macrophage inflammatory response.

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Section: Discussionmentioning

confidence: 99%

Translation control of TAK1 mRNA by hnRNP K modulates LPS-induced macrophage activation

Liepelt

Mossanen

Denecke

et al. 2014

RNA

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“…Although hnRNP K is abundantly expressed in neurons (Blanchette et al, 2006;Liu et al, 2008;Thyagarajan and Szaro, 2004), its cellular functions are known mostly from studies in cell lines, which indicate that it shuttles between the nucleus and cytoplasm and participates in multiple aspects of RNA metabolism, from splicing and nuclear export to translation and turnover. As the substrate of numerous kinases, hnRNP K is ideally suited for coupling the fates of its RNA targets with cell signaling (Adolph et al, 2007;Collier et al, 1998;Habelhah et al, 2001;Mikula et al, 2006;Ostareck-Lederer et al, 2002). Current models propose that hnRNP K is a scaffolding protein, controlling its target RNAs through combinatorial interactions with multiple partners, which can either bind hnRNP K directly, depending on its phosphorylation state, or interact indirectly through steric hindrance and competition while binding (Bomsztyk et al, 1997;Bomsztyk et al, 2004;Makeyev and Liebhaber, 2002;Ostareck et al, 1997;Ostareck-Lederer et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

hnRNP K post-transcriptionally co-regulates multiple cytoskeletal genes needed for axonogenesis

Liu

Szaro

2011

Development

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SUMMARYThe RNA-binding protein, hnRNP K, is essential for axonogenesis. Suppressing its expression in Xenopus embryos yields terminally specified neurons with severely disorganized microtubules, microfilaments and neurofilaments, raising the hypothesis that hnRNP K post-transcriptionally regulates multiple transcripts of proteins that organize the axonal cytoskeleton. To identify downstream candidates for this regulation, RNAs that co-immunoprecipitated from juvenile brain with hnRNP K were identified on microarrays. A substantial number of these transcripts were linked to the cytoskeleton and to intracellular localization, trafficking and transport. Injection into embryos of a non-coding RNA bearing multiple copies of an hnRNP K RNA-binding consensus sequence found within these transcripts largely phenocopied hnRNP K knockdown, further supporting the idea that it regulates axonogenesis through its binding to downstream target RNAs. For further study of regulation by hnRNP K of the cytoskeleton during axon outgrowth, we focused on three validated RNAs representing elements associated with all three polymers -Arp2, tau and an -internexin-like neurofilament. All three were co-regulated post-transcriptionally by hnRNP K, as hnRNP K knockdown yielded comparable defects in their nuclear export and translation but not transcription. Directly knocking down expression of all three together, but not each one individually, substantially reproduced the axonless phenotype, providing further evidence that regulation of axonogenesis by hnRNP K occurs largely through pleiotropic effects on cytoskeletal-associated targets. These experiments provide evidence that hnRNP K is the nexus of a novel post-transcriptional regulatory module controlling the synthesis of proteins that integrate all three cytoskeletal polymers to form the axon.KEY WORDS: Microtubule associated protein tau, Actin-related protein 2, -Internexin, Xenopus laevis hnRNP K post-transcriptionally co-regulates multiple cytoskeletal genes needed for axonogenesis

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“…Plasmids Venus1C, Venus2-HA-MS2BP, Luc-Dzip-6MS2, and GFP-NLS-MS2BP were kindly provided by S. Hü ttelmaier (Department of Medicine, Martin-Luther-University Halle-Wittenberg, Halle, Germany) (Stöhr et al 2006). To create Venus1-Flag-hnRNP K, a Flag-tag was cloned between XhoI/EcoRI of Venus1-hnRNP K (Adolph et al 2007). To generate Venus1-Flag-DDX6 as well as domains -D1 and -D2, first the Flag-tag was cloned into Venus1C, and DDX6 was amplified from pET16b-DDX6 with primers DDX6-KpnI-fw and DDX6-KpnI-rv.…”

Section: Methodsmentioning

confidence: 99%

DDX6 recruits translational silenced human reticulocyte 15-lipoxygenase mRNA to RNP granules

Naarmann¹,

Harnisch²,

Müller‐Newen³

et al. 2010

RNA

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Erythroid precursor cells lose the capacity for mRNA synthesis due to exclusion of the nucleus during maturation. Therefore, the stability and translation of mRNAs that code for specific proteins, which function in late stages of maturation when reticulocytes become erythrocytes, are controlled tightly. Reticulocyte 15-lipoxygenase (r15-LOX) initiates the breakdown of mitochondria in mature reticulocytes. Through the temporal restriction of mRNA translation, the synthesis of r15-LOX is prevented in premature cells. The enzyme is synthesized only in mature reticulocytes, although r15-LOX mRNA is already present in erythroid precursor cells. Translation of r15-LOX mRNA is inhibited by hnRNP K and hnRNP E1, which bind to the differentiation control element (DICE) in its 39 untranslated region (39UTR). The hnRNP K/E1-DICE complex interferes with the joining of the 60S ribosomal subunit to the 40S subunit at the AUG. We took advantage of the inducible human erythroid K562 cell system that fully recapitulates this process to identify so far unknown factors, which are critical for DICE-dependent translational regulation. Applying RNA chromatography with the DICE as bait combined with hnRNP K immunoprecipitation, we specifically purified the DEAD-box RNA helicase 6 (DDX6) that interacts with hnRNP K and hnRNP E1 in a DICE-dependent manner. Employing RNA interference and fluorescence in situ hybridization, we show that DDX6 colocalizes with endogenous human (h)r15-LOX mRNA to P-body-like RNP granules, from which 60S ribosomal subunits are excluded. Our data suggest that in premature erythroid cells translational silencing of hr15-LOX mRNA is maintained by DDX6 mediated storage in these RNP granules.

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Deciphering the Cross Talk between hnRNP K and c-Src: the c-Src Activation Domain in hnRNP K Is Distinct from a Second Interaction Site

Cited by 35 publications

References 62 publications

Translation control of TAK1 mRNA by hnRNP K modulates LPS-induced macrophage activation

Translation control of TAK1 mRNA by hnRNP K modulates LPS-induced macrophage activation

hnRNP K post-transcriptionally co-regulates multiple cytoskeletal genes needed for axonogenesis

DDX6 recruits translational silenced human reticulocyte 15-lipoxygenase mRNA to RNP granules

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