Phosphorylation of lamins determine their structural properties and signaling functions

Torvaldson, Elin; Kochin, Vitaly; Eriksson, John E.

doi:10.1080/19491034.2015.1017167

Cited by 71 publications

(77 citation statements)

References 52 publications

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“…Our observation that macrophage survival/growth is induced MINCLE-independently by several TDM-related glycolipids after 24h, but MINCLE-dependently further enhanced by the cord factor after 48h, suggests that both pathways contribute to TDM-induced macrophage growth and survival. Phosphorylation of lamins, such as of LMNA observed here, contributes to regulation of the cell cycle (73). Thus, these data suggest that TDM promotes the survival and/or proliferation of macrophages and may thereby contribute to the dynamics of the granuloma response during mycobacterial infection.…”

Section: Discussionsupporting

confidence: 54%

Macrophage Phosphoproteome Analysis Reveals MINCLE-dependent and -independent Mycobacterial Cord Factor Signaling

Hansen

Peltier

Killy

et al. 2019

Molecular & Cellular Proteomics

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First quantitative phosphoproteome analysis of TDM-activated macrophages reveals new insights in biological processes of macrophages stimulated with the mycobacterial cord factor. Surprisingly, the bioinformatic results revealed Mincle-dependent and-independent phosphorylation, which appear to affect different biological processes. Whereas PI3K/AKT signaling, dependent on Mincle, is involved in TDM-induced cytokine regulation, Mincle-independent phosphorylation and transcriptomic changes were linked to cell cycle regulation. Collectively, the observed reprogramming of macrophages by TDM might be relevant in the mycobacteriamacrophage interaction.

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Section: Discussionsupporting

confidence: 54%

Macrophage Phosphoproteome Analysis Reveals MINCLE-dependent and -independent Mycobacterial Cord Factor Signaling

Hansen

Peltier

Killy

et al. 2019

Molecular & Cellular Proteomics

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“…Lamin A/C phosphorylation on S22 was also elevated in OE hearts ( Figure 4I). This mechanosensitive phosphorylation was shown to promote Lamin A solubilization into the nucleoplasm and is associated with mitotic NEBD (Torvaldson et al 2015) (Ward and Kirschner, 1990) (Heald and McKeon, 1990) (Buxboim et al, 2014). Likewise, analysis of the proteome revealed an elevation in several cytoplasmic membrane-bound and nuclear-envelope bound force sensors and transducers in OE hearts ( Figure 4J) (Elosegui-artola et al, 2016).…”

Section: Erbb2 Signaling Induces An Altered Mechanical State In Cmsmentioning

confidence: 89%

ERBB2 drives YAP activation and EMT-like processes during cardiac regeneration

Aharonov

Shakked

Umansky

et al. 2020

Preprint

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Cardiomyocyte (CM) loss after injury results in adverse remodelling and fibrosis, which inevitably lead to heart failure. ERBB2-Neuregulin and Hippo-YAP signaling pathways are key mediators of CM proliferation and regeneration, yet the crosstalk between these pathways is unclear. Here, we demonstrate in adult mice that transient over-expression (OE) of activated ERBB2 in CMs promotes cardiac regeneration in a heart failure model. OE CMs present an EMT-like regenerative response manifested by cytoskeletal remodelling, junction dissolution, migration, and ECM turnover. Molecularly, we identified YAP as a critical mediator of ERBB2 signaling. In OE CMs, YAP interacts with nuclear envelope and cytoskeletal components, reflecting the altered mechanic state elicited by ERBB2. Hippoindependent activating phosphorylation on YAP at S352 and S274 were enriched in OE CMs, peaking during metaphase, and viral overexpression of YAP phospho-mutants dampened the proliferative competence of OE CMs. Taken together, we demonstrate a potent ERBB2mediated YAP mechanosensory signaling, involving EMT-like characteristics, resulting in heart regeneration. Highlights1. ERBB2-driven regeneration of scarred hearts recapitulates core-EMT processes 2. YAP is activated and required downstream to ERBB2 signaling in CMs 3. YAP activity is mechanically driven by cytoskeleton and nuclear envelope remodeling 4. YAP S274 and S352 phosphorylation is essential for CM mitosis

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“…Early studies reported that phosphorylation of S22 and S392 begins at late G2 stage and is mediated by CDK1/Cyclin B, a kinase complex that promotes cell-cycle progression from G2 to mitosis (Georgatos et al, 1997;Heald and McKeon, 1990;Ward and Kirschner, 1990). More recently, S22 and S392 phosphorylation have been reported in the nuclear interior of interphase cells (Kochin et 75 al., 2014), suggesting that S22/S392-phosphorylated, non-polymerized LMNA may represent a nuclearinterior pool of LMNA in interphase cells (Torvaldson et al, 2015). Separate studies proposed that S22 and S392 phosphorylation are increased upon changes in the mechanical environment of the cell and promote LMNA disassembly and degradation (Buxboim et al, 2014;Swift et al, 2013).…”

mentioning

confidence: 99%

Phosphorylated Lamin A/C in the nuclear interior binds active enhancers associated with abnormal transcription in progeria

Ikegami

Secchia

Almakki

et al. 2019

Preprint

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20LMNA encodes nuclear lamin A/C that tethers lamina-associated domains (LADs) to the nuclear lamina.Hutchinson-Gilford progeria is a premature aging disorder caused by heterozygous LMNA point mutations, however, the mechanism by which LMNA mutations cause progeria is unclear. We report that Ser22-phosphorylated LMNA (pS22-LMNA) was localized to the interior of the nucleus in human fibroblasts throughout the cell cycle. pS22-LMNA interacted with a specific subset of putative active 25 enhancers, not LADs, primarily at locations co-bound by the transcriptional activator c-Jun. In progeriapatient fibroblasts, some pS22-LMNA-binding sites were lost whereas new pS22-LMNA-binding sites emerged at abnormal locations. New pS22-LMNA-binding in progeria cells was accompanied by increased H3K27 acetylation, increased c-Jun binding, and upregulated expression of genes implicated in coronary artery diseases, hypertension, and cardiomegaly, clinical components of progeria. Thus, 30 pS22-LMNA bound to enhancers and progeria mutations affected pS22-LMNA-bound enhancer function.These observations expand the genomic role of LMNA to include direct enhancer binding and modulation, and introduce a novel molecular mechanism whereby LMNA mutation may contribute to disease distinct from LMNA's role at the nuclear lamina. 35interior was soluble and highly mobile (Broers et al., 1999;Shimi et al., 2008) thus present as a nonpolymerized form and not constituting a scaffold structure. The specific function of LMNA in the nuclear interior has been difficult to ascertain, mainly due to a lack of understanding about how LMNA is directed 65 to the nuclear interior, and a lack of laboratory approaches to isolate nuclear-interior LMNA.Polymerization and depolymerization of nuclear lamins, required for nuclear envelope breakdown and the cell cycle, are regulated by phosphorylation of specific serine residues (Gerace and Blobel, 1980;Heald and McKeon, 1990;Peter et al., 1990;Ward and Kirschner, 1990). Ser22 (S22) and Ser392 (S392) of LMNA are well characterized and are known as "mitotic sites" because they are phosphorylated during 70 mitosis, leading to LMNA depolymerization (Heald and McKeon, 1990;Peter et al., 1990;Ward and Kirschner, 1990). Early studies reported that phosphorylation of S22 and S392 begins at late G2 stage and is mediated by CDK1/Cyclin B, a kinase complex that promotes cell-cycle progression from G2 to mitosis (Georgatos et al., 1997;Heald and McKeon, 1990;Ward and Kirschner, 1990). More recently, S22 and S392 phosphorylation have been reported in the nuclear interior of interphase cells (Kochin et 75 al., 2014), suggesting that S22/S392-phosphorylated, non-polymerized LMNA may represent a nuclearinterior pool of LMNA in interphase cells (Torvaldson et al., 2015). Separate studies proposed that S22 and S392 phosphorylation are increased upon changes in the mechanical environment of the cell and promote LMNA disassembly and degradation (Buxboim et al., 2014;Swift et al., 2013). Therefore, LMNA S22/S392 phosphorylation has b...

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Phosphorylation of lamins determine their structural properties and signaling functions

Cited by 71 publications

References 52 publications

Macrophage Phosphoproteome Analysis Reveals MINCLE-dependent and -independent Mycobacterial Cord Factor Signaling

Macrophage Phosphoproteome Analysis Reveals MINCLE-dependent and -independent Mycobacterial Cord Factor Signaling

ERBB2 drives YAP activation and EMT-like processes during cardiac regeneration

Phosphorylated Lamin A/C in the nuclear interior binds active enhancers associated with abnormal transcription in progeria

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