Specific phosphorylation of Ser458 of A-type lamins in <i>LMNA</i>-associated myopathy patients

Mitsuhashi, Hiroaki; Hayashi, Yukiko; Matsuda, Chie; Noguchi, S.; Wakatsuki, Soichi; Araki, Toshiyuki; Nishino, Ichizo

doi:10.1242/dev.061374

Cited by 6 publications

(8 citation statements)

References 9 publications

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“…49 In contrast, S458 has been reported to be specifically phosphorylated in muscle biopsies from myopathy patients with mutations in the Igfold of lamin A but not from patients with other lamin A mutations or healthy controls. 50 The authors speculate that mutations in the Ig-fold opens the lamin structure and exposes S458 to Akt1 which was shown to target this site. 50 Our identification of phosphorylation of the same site from interphase HeLa cells suggests that the phosphorylation also have a nonpathological role and that this modification is regulated in a cell specific manner.…”

Section: Lessons From Laminopathiesmentioning

confidence: 99%

“…50 The authors speculate that mutations in the Ig-fold opens the lamin structure and exposes S458 to Akt1 which was shown to target this site. 50 Our identification of phosphorylation of the same site from interphase HeLa cells suggests that the phosphorylation also have a nonpathological role and that this modification is regulated in a cell specific manner.…”

Section: Lessons From Laminopathiesmentioning

confidence: 99%

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Phosphorylation of lamins determine their structural properties and signaling functions

Torvaldson

Kochin

Eriksson

2015

Nucleus

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Section: Lessons From Laminopathiesmentioning

confidence: 99%

Section: Lessons From Laminopathiesmentioning

confidence: 99%

Phosphorylation of lamins determine their structural properties and signaling functions

Torvaldson

Kochin

Eriksson

2015

Nucleus

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“…While B-type lamins relocate exclusively to the periphery of the newly forming sister nuclei, A-type lamins initially accumulate within the nuclear interior during telophase and early G1 (Moir et al 2000;Dechat et al 2004). Besides their mitotic phosphorylation, lamins become also phosphorylated during interphase, which appears to be important for the regulation of their nuclear import and their solubility (Hennekes et al 1993;Schneider et al 1999;Cenni et al 2005;Kuga et al 2010;Mitsuhashi et al 2010;ZarembaCzogalla et al 2012;Buxboim et al 2014;Kochin et al 2014).…”

mentioning

confidence: 99%

Lamins at the crossroads of mechanosignaling

2015

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The intermediate filament proteins, A-and B-type lamins, form the nuclear lamina scaffold adjacent to the inner nuclear membrane. B-type lamins confer elasticity, while A-type lamins lend viscosity and stiffness to nuclei. Lamins also contribute to chromatin regulation and various signaling pathways affecting gene expression. The mechanical roles of lamins and their functions in gene regulation are often viewed as independent activities, but recent findings suggest a highly cross-linked and interdependent regulation of these different functions, particularly in mechanosignaling. In this newly emerging concept, lamins act as a ''mechanostat'' that senses forces from outside and responds to tension by reinforcing the cytoskeleton and the extracellular matrix. A-type lamins, emerin, and the linker of the nucleoskeleton and cytoskeleton (LINC) complex directly transmit forces from the extracellular matrix into the nucleus. These mechanical forces lead to changes in the molecular structure, modification, and assembly state of A-type lamins. This in turn activates a tension-induced ''inside-out signaling'' through which the nucleus feeds back to the cytoskeleton and the extracellular matrix to balance outside and inside forces. These functions regulate differentiation and may be impaired in lamin-linked diseases, leading to cellular phenotypes, particularly in mechanical load-bearing tissues.

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“…However, lamins are stably phosphorylated in interphase cells and even in post-mitotic nuclei, such as those of muscle fibers, where phosphorylation is dependent on the insulin pathway [Cenni et al, 2005]. Moreover, we found that reduced lamin A N-terminal phosphorylation is associated with LMNA-linked muscle diseases [Cenni et al, 2005], while it has been recently reported that specific phosphorylation at serine 458 of A-type lamins occurs in muscle laminopathies [Mitsuhashi et al, 2010]. Phosphoserine 458 is not found in normal cells or in nonmuscular laminopathies [Mitsuhashi et al, 2010].…”

Section: Nuclear Envelope Proteins and Signaling A Type Laminsmentioning

confidence: 58%

“…Moreover, we found that reduced lamin A N-terminal phosphorylation is associated with LMNA-linked muscle diseases [Cenni et al, 2005], while it has been recently reported that specific phosphorylation at serine 458 of A-type lamins occurs in muscle laminopathies [Mitsuhashi et al, 2010]. Phosphoserine 458 is not found in normal cells or in nonmuscular laminopathies [Mitsuhashi et al, 2010]. Thus, lamin A/C phosphorylation at specific sites plays a major role in muscle function, possibly interfering with lamin intermolecular interactions.…”

Section: Nuclear Envelope Proteins and Signaling A Type Laminsmentioning

confidence: 62%

Laminopathies and lamin‐associated signaling pathways

Maraldi

Capanni

Cenni

et al. 2011

J of Cellular Biochemistry

101

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Laminopathies are genetic diseases due to mutations or altered post-translational processing of nuclear envelope/lamina proteins. The majority of laminopathies are caused by mutations in the LMNA gene, encoding lamin A/C, but manifest as diverse pathologies including muscular dystrophy, lipodystrophy, neuropathy, and progeroid syndromes. Lamin-binding proteins implicated in laminopathies include lamin B2, nuclear envelope proteins such as emerin, MAN1, LBR, and nesprins, the nuclear matrix protein matrin 3, the lamina-associated polypeptide, LAP2alpha and the transcriptional regulator FHL1. Thus, the altered functionality of a nuclear proteins network appears to be involved in the onset of laminopathic diseases. The functional interplay among different proteins involved in this network implies signaling partners. The signaling effectors may either modify nuclear envelope proteins and their binding properties, or use nuclear envelope/lamina proteins as platforms to regulate signal transduction. In this review, both aspects of lamin-linked signaling are presented and the major pathways so far implicated in laminopathies are summarized.

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Specific phosphorylation of Ser458 of A-type lamins in LMNA-associated myopathy patients

Cited by 6 publications

References 9 publications

Phosphorylation of lamins determine their structural properties and signaling functions

Phosphorylation of lamins determine their structural properties and signaling functions

Lamins at the crossroads of mechanosignaling

Laminopathies and lamin‐associated signaling pathways

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