c‐Abl acetylation by histone acetyltransferases regulates its nuclear–cytoplasmic localization

Bari, Maria Giovanna di; Ciuffini, Laura; Mingardi, Michele; Testi, Roberto; Soddu, Silvia; Barilá, Daniela

doi:10.1038/sj.embor.7400700

Cited by 53 publications

(40 citation statements)

References 30 publications

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“…Although it will require further investigations to determine the role of this specific PTM on c-Src, it may be conceivable that N ε -lysine acetylation could affect c-Src turnover or function (25), influencing Cx43 phosphorylation in mdx. Intriguingly, c-Abl, another c-Src family member, has been previously reported as acetylated on lysine, with important consequences on its intracellular localization and function (26).…”

Section: Resultsmentioning

confidence: 99%

N ^ε -lysine acetylation determines dissociation from GAP junctions and lateralization of connexin 43 in normal and dystrophic heart

Colussi

Rosati

Straino

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

107

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Wanting to explore the epigenetic basis of Duchenne cardiomyopathy, we found that global histone acetylase activity was abnormally elevated and the acetylase P300/CBP-associated factor (PCAF) coimmunoprecipitated with connexin 43 (Cx43), which was N ε -lysine acetylated and lateralized in mdx heart. This observation was paralleled by Cx43 dissociation from N-cadherin and zonula occludens 1, whereas pp60-c-Src association was unaltered. In vivo treatment of mdx with the pan-histone acetylase inhibitor anacardic acid significantly reduced Cx43 N ε -lysine acetylation and restored its association to GAP junctions (GJs) at intercalated discs. Noteworthy, in normal as well as mdx mice, the class IIa histone deacetylases 4 and 5 constitutively colocalized with Cx43 either at GJs or in the lateralized compartments. The class I histone deacetylase 3 was also part of the complex. Treatment of normal controls with the histone deacetylase pan-inhibitor suberoylanilide hydroxamic acid (MC1568) or the class IIa-selective inhibitor 3-{4-[3-(3-fluorophenyl)-3-oxo-1-propen-1-yl]-1-methyl-1H-pyrrol-2-yl}-N-hydroxy-2-propenamide (MC1568) determined Cx43 hyperacetylation, dissociation from GJs, and distribution along the long axis of ventricular cardiomyocytes. Consistently, the histone acetylase activator pentadecylidenemalonate 1b (SPV106) hyperacetylated cardiac proteins, including Cx43, which assumed a lateralized position that partly reproduced the dystrophic phenotype. In the presence of suberoylanilide hydroxamic acid, cell to cell permeability was significantly diminished, which is in agreement with a Cx43 close conformation in the consequence of hyperacetylation. Additional experiments, performed with Cx43 acetylation mutants, revealed, for the acetylated form of the molecule, a significant reduction in plasma membrane localization and a tendency to nuclear accumulation. These results suggest that Cx43 N ε -lysine acetylation may have physiopathological consequences for cell to cell coupling and cardiac function. muscular dystrophy | protein acetylation

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Section: Resultsmentioning

confidence: 99%

N ^ε -lysine acetylation determines dissociation from GAP junctions and lateralization of connexin 43 in normal and dystrophic heart

Colussi

Rosati

Straino

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

107

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“…Acetylation of sites in and around NLS sequences has been shown to inhibit the nuclear localization of a small number of proteins, including c-Abl, RECQL4, E1A, Skp2 and IFI16 (di Bari et al, 2006;Dietschy et al, 2009;Inuzuka et al, 2012;Li et al, 2012;Madison et al, 2002). Given that K83 and K95 are adjacent to or contained within the NLS2 of Net1A, respectively, we examined whether treatment of cells with TSA stimulated Net1A relocalization.…”

Section: Net1a Acetylation Stimulates Its Relocalization Outside the mentioning

confidence: 99%

Acetylation of the RhoA GEF Net1A controls its subcellular localization and activity

Song

Ulu

et al. 2015

Journal of Cell Science

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Net1 isoform A (Net1A) is a RhoA GEF that is required for cell motility and invasion in multiple cancers. Nuclear localization of Net1A negatively regulates its activity, and we have recently shown that Rac1 stimulates Net1A relocalization to the plasma membrane to promote RhoA activation and cytoskeletal reorganization. However, mechanisms controlling the subcellular localization of Net1A are not well understood. Here, we show that Net1A contains two nuclear localization signal (NLS) sequences within its Nterminus and that residues surrounding the second NLS sequence are acetylated. Treatment of cells with deacetylase inhibitors or expression of active Rac1 promotes Net1A acetylation. Deacetylase inhibition is sufficient for Net1A relocalization outside the nucleus, and replacement of the N-terminal acetylation sites with arginine residues prevents cytoplasmic accumulation of Net1A caused by deacetylase inhibition or EGF stimulation. By contrast, replacement of these sites with glutamine residues is sufficient for Net1A relocalization, RhoA activation and downstream signaling. Moreover, the N-terminal acetylation sites are required for rescue of F-actin accumulation and focal adhesion maturation in Net1 knockout MEFs. These data indicate that Net1A acetylation regulates its subcellular localization to impact on RhoA activity and actin cytoskeletal organization.

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“…[40][41][42] c-Abl shuttles between the cytoplasm and nucleus, 43,44 and acetylation and/or binding to 14-3-3 proteins promotes its cytoplasmic retention. [45][46][47] Activation of nuclear c-Abl by DNA-damaging agents c-Abl and Arg during solid tumor progression / Ganguly and Plattner M Monographs induces G1 arrest and/or apoptosis, [48][49][50][51][52][53][54] whereas activation of the membrane and cytoplasmic pools of c-Abl and Arg by growth factors promotes membrane ruffling and motility of fibroblasts and endothelial cells, as well as endothelial tubule formation. 6,10,22,33,36,[55][56][57][58][59][60][61] In contrast, inhibition or knockout of c-Abl promotes wound-healing motility and migration toward collagen, fibronectin, or insulin.…”

Section: Biological Function Of C-abl/arg In Nontransformed Cellsmentioning

confidence: 99%

Activation of Abl Family Kinases in Solid Tumors

Ganguly

Plattner

2012

Genes & Cancer

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Although c-Abl and Arg non-receptor tyrosine kinases are well known for driving leukemia development, their role in solid tumors has not been appreciated until recently. Accumulating evidence now indicates that c-Abl and/or Arg are activated in some solid tumor cell lines via unique mechanisms that do not involve gene mutation/translocation, and c-Abl/Arg activation promotes matrix degradation, invasion, proliferation, tumorigenesis, and/ or metastasis, depending on the tumor type. However, some data suggest that c-Abl also may suppress invasion, proliferation, and tumorigenesis in certain cell contexts. Thus, c-Abl/Arg may serve as molecular switches that suppress proliferation and invasion in response to some stimuli (e.g., ephrins) or when inactive/regulated, or as promote invasion and proliferation in response to other signals (e.g., activated growth factor receptors, loss of inhibitor expression), which induce sustained activation. Clearly, more data are required to determine the extent and prevalence of c-Abl/Arg activation in primary tumors and during progression, and additional animal studies are needed to substantiate in vitro findings. Furthermore, c-Abl/ Arg inhibitors have been used in numerous solid tumor clinical trials; however, none of these trials were restricted to patients whose tumors expressed highly activated c-Abl/Arg (targeted trial). Targeted trials are critical for determining whether c-Abl/Arg inhibitors can be effective treatment options for patients whose tumors are driven by c-Abl/Arg.

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c‐Abl acetylation by histone acetyltransferases regulates its nuclear–cytoplasmic localization

Cited by 53 publications

References 30 publications

N ^ε -lysine acetylation determines dissociation from GAP junctions and lateralization of connexin 43 in normal and dystrophic heart

N ^ε -lysine acetylation determines dissociation from GAP junctions and lateralization of connexin 43 in normal and dystrophic heart

Acetylation of the RhoA GEF Net1A controls its subcellular localization and activity

Activation of Abl Family Kinases in Solid Tumors

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c‐Abl acetylation by histone acetyltransferases regulates its nuclear–cytoplasmic localization

Cited by 53 publications

References 30 publications

N ε -lysine acetylation determines dissociation from GAP junctions and lateralization of connexin 43 in normal and dystrophic heart

N ε -lysine acetylation determines dissociation from GAP junctions and lateralization of connexin 43 in normal and dystrophic heart

Acetylation of the RhoA GEF Net1A controls its subcellular localization and activity

Activation of Abl Family Kinases in Solid Tumors

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Product

Resources

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N ^ε -lysine acetylation determines dissociation from GAP junctions and lateralization of connexin 43 in normal and dystrophic heart

N ^ε -lysine acetylation determines dissociation from GAP junctions and lateralization of connexin 43 in normal and dystrophic heart