Molecular characterization of protein kinase C‐α binding to lamin A

Martelli, Alberto M.; Bortul, Roberta; Tabellini, Giovanna; Faenza, Irene; Cappellini, Alessandra; Bareggi, Renato; Manzoli, Lucia; Cocco, Lucio

doi:10.1002/jcb.10227

Cited by 43 publications

(38 citation statements)

References 43 publications

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“…Alternatively, it may also protect binding sites for stress-relevant partners that interact with the lamin A tail. These include SREBP (Lloyd et al, 2002), PKCa (Tang et al, 2000), 12(5)-lipoxygenase (Martelli et al, 2002), c-fos (Ivorra et al, 2006) and ERK (Gonzalez et al,2008). Indeed, our observation that some of the single mutants (C522A and C588A) promote multiple intermolecular interactions supports the notion that the conserved cysteine residues form cross-linkages with several different proteins.…”

Section: Cysteine Modifications and Cellular Agingsupporting

confidence: 79%

Conserved cysteine residues in the mammalian lamin A tail are essential for cellular responses to ROS generation

et al. 2011

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SummaryPre-lamin A and progerin have been implicated in normal aging, and the pathogenesis of age-related degenerative diseases is termed 'laminopathies'. Here, we show that mature lamin A has an essential role in cellular fitness and that oxidative damage to lamin A is involved in cellular senescence. Primary human dermal fibroblasts (HDFs) aged replicatively or by pro-oxidants acquire a range of dysmorphic nuclear shapes. We observed that conserved cysteine residues in the lamin A tail domain become hyperoxidized in senescent fibroblasts, which inhibits the formation of lamin A inter-and intramolecular disulfide bonds. Both in the absence of lamin A and in the presence of a lamin A cysteine-toalanine mutant, which eliminates these cysteine residues (522, 588, and 591), mild oxidative stress induced nuclear disorganization and led to premature senescence as a result of decreased tolerance to ROS stimulators. Human dermal fibroblasts lacking lamin A or expressing the lamin A cysteine-to-alanine mutant displayed a gene expression profile of ROS-responsive genes characteristic of chronic ROS stimulation. Our findings suggest that the conserved C-terminal cysteine residues are essential for lamin A function and that loss or oxidative damage to these cysteine residues promotes cellular senescence.

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Section: Cysteine Modifications and Cellular Agingsupporting

confidence: 79%

Conserved cysteine residues in the mammalian lamin A tail are essential for cellular responses to ROS generation

et al. 2011

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“…To determine whether PLC␤ was involved in nuclear mGlu5-mediated Ca 2ϩ responses, siRNA targeted against PLC␤1, the most prevalent nuclear isoform (41), was used to knockdown expression. Western blotting of striatal lysates prepared 48 and 72 h after siRNA transfection showed that there was at least a 60 -70% knockdown of PLC␤1 using the targeted siRNA versus a scrambled control (Fig.…”

Section: Mglu5 Receptors Are Localized At Both the Plasma Andmentioning

confidence: 99%

Activated Nuclear Metabotropic Glutamate Receptor mGlu5 Couples to Nuclear Gq/11 Proteins to Generate Inositol 1,4,5-Trisphosphate-mediated Nuclear Ca2+ Release

Kumar

Jong

O’Malley

2008

Journal of Biological Chemistry

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Recently we have shown that the metabotropic glutamate 5 (mGlu5) receptor can be expressed on nuclear membranes of heterologous cells or endogenously on striatal neurons where it can mediate nuclear Ca 2؉ changes. Here, pharmacological, optical, and genetic techniques were used to show that upon activation, nuclear mGlu5 receptors generate nuclear inositol 1,4,5-trisphosphate (IP 3 ) in situ. Specifically, expression of an mGlu5 F767S mutant in HEK293 cells that blocks G q/11 coupling or introduction of a dominant negative G␣ q construct in striatal neurons prevented nuclear Ca 2؉ changes following receptor activation. These data indicate that nuclear mGlu5 receptors couple to G q/11 to mobilize nuclear Ca 2؉ . Nuclear mGlu5-mediated Ca 2؉ responses could also be blocked by the phospholipase C (PLC) inhibitor, U73122, the phosphatidylinositol (PI) PLC inhibitor 1-O-octadecyl-2-O-methyl-sn-glycero-3-phosphorylcholine (ET-18-OCH 3 ), or by using small interfering RNA targeted against PLC␤1 demonstrating that PI-PLC is involved. Direct assessment of inositol phosphate production using a PIP2/IP 3 "biosensor" revealed for the first time that IP 3 can be generated in the nucleus following activation of nuclear mGlu5 receptors. Finally, both IP 3 and ryanodine receptor blockers prevented nuclear mGlu5-mediated increases in intranuclear Ca 2؉ . Collectively, this study shows that like plasma membrane receptors, activated nuclear mGlu5 receptors couple to G q/11 and PLC to generate IP 3 -mediated release of Ca 2؉ from Ca 2؉ -release channels in the nucleus. Thus the nucleus can function as an autonomous organelle independent of signals originating in the cytoplasm, and nuclear mGlu5 receptors play a dynamic role in mobilizing Ca 2؉ in a specific, localized fashion. Many cells produce Ca2ϩ signals both in the cytoplasm as well as the nucleus. Nuclear Ca 2ϩ is thought to play a vital role in a variety of nuclear functions such as cell division, proliferation, protein import, apoptosis, and gene transcription (1).Nuclear Ca 2ϩ may be mobilized from a number of sources including diffusion of cytosolic Ca 2ϩ waves through nuclear pore complexes (2), release into the nucleoplasm from the nuclear lumen (3, 4), or release from the so-called nucleoplasmic reticulum, invaginations of the nuclear envelope into the nucleoplasm itself (5). Presumably Ca 2ϩ release from the lumen of the nuclear membrane and/or the nucleoplasmic reticulum would either amplify Ca 2ϩ signals arriving via the nuclear pore complex and/or independently generate nucleoplasmic Ca 2ϩ transients. Such a model of nuclear Ca 2ϩ release is bolstered by data documenting the presence and activation of the inositol 1,4,5-trisphosphate receptors (IP 3 Rs) 2 and ryanodine receptors (RyRs) on inner nuclear membranes and the nucleoplasmic reticulum (3, 4, 6 -9). Thus these Ca 2ϩ -release channels are perfectly poised to independently regulate nucleoplasmic Ca 2ϩ levels.Despite the importance of IP 3 Rs and RyRs in controlling the release of nuclear Ca 2ϩ , very little ...

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“…Three signaling proteins are known to bind A-type lamins in vivo; lamin filaments might therefore provide a structural basis for signaling. Protein kinase C α (PKCα) -a serine-threonine kinase activated by many signals, including diacylglycerol (DAG) and 12(S)-hydroxyeicosatetraenoic acid [12(S)-HETE] -binds to the C-terminal half of the lamin A/C tail (Martelli et al, 2002) (Fig. 1).…”

Section: Signaling Partnersmentioning

confidence: 99%

Proteins that bind A-type lamins: integrating isolated clues

Zastrow

Vlcek

Wilson

2004

Journal of Cell Science

202

189

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What do such diverse molecules as DNA, actin, retinoblastoma protein and protein kinase Cα all have in common? They and additional partners bind `A-type' lamins, which form stable filaments in animal cell nuclei. Mutations in A-type lamins cause a bewildering range of tissue-specific diseases, termed `laminopathies', including Emery-Dreifuss muscular dystrophy and the devastating Hutchinson-Gilford progeria syndrome, which mimics premature aging. Considered individually and collectively, partners for A-type lamins form four loose groups: architectural partners, chromatin partners, gene-regulatory partners and signaling partners. We describe 16 partners in detail, summarize their binding sites in A-type lamins, and sketch portraits of ternary complexes and functional pathways that might depend on lamins in vivo. On the basis of our limited current knowledge, we propose lamin-associated complexes with multiple components relevant to nuclear structure (e.g. emerin, nesprin 1α, actin) or signaling and gene regulation (e.g. LAP2α, retinoblastoma, E2F-DP heterodimers, genes) as `food for thought'. Testing these ideas will deepen our understanding of nuclear function and human disease.

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Molecular characterization of protein kinase C‐α binding to lamin A

Cited by 43 publications

References 43 publications

Conserved cysteine residues in the mammalian lamin A tail are essential for cellular responses to ROS generation

Conserved cysteine residues in the mammalian lamin A tail are essential for cellular responses to ROS generation

Activated Nuclear Metabotropic Glutamate Receptor mGlu5 Couples to Nuclear Gq/11 Proteins to Generate Inositol 1,4,5-Trisphosphate-mediated Nuclear Ca2+ Release

Proteins that bind A-type lamins: integrating isolated clues

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