ADAM12 localizes with c-Src to actin-rich structures at the cell periphery and regulates Src kinase activity

Stautz, Dorte; Sanjay, Archana; Hansen, Matilde Thye; Albrechtsen, Reidar; Wewer, Ulla M.; Kveiborg, Marie

doi:10.1016/j.yexcr.2009.09.017

Cited by 35 publications

(35 citation statements)

References 50 publications

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“…Under normal conditions, inactive ADAM12 resides mainly in the perinuclear area, and it translocates to the cytoplasm when activated. This process may be induced by extracellular stimuli, such as TGF-β 33,34 . In UT HC-MSC, the ADAM12 immunolocalization was in perinuclear regions.…”

Section: Rheumatologymentioning

confidence: 99%

Perivascular Cells in Diffuse Cutaneous Systemic Sclerosis Overexpress Activated ADAM12 and Are Involved in Myofibroblast Transdifferentiation and Development of Fibrosis

Cipriani

Benedetto²,

Ruscitti³

et al. 2016

J Rheumatol

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Objective.Microvascular damage is pivotal in the pathogenesis of systemic sclerosis (SSc), preceding fibrosis, and whose trigger is not still fully understood. Perivascular progenitor cells, with profibrotic activity and function, are identified by the expression of the isoform 12 of ADAM (ADAM12) and this molecule may be upregulated by transforming growth factor-β (TGF-β). The goal of this work was to evaluate whether pericytes in the skin of patients with diffuse cutaneous SSc (dcSSc) expressed ADAM12, suggesting their potential contribution to the fibrotic process, and whether TGF-β might modulate this molecule.Methods.After ethical approval, mesenchymal stem cells (MSC) and fibroblasts (FB) were isolated from bone marrow and skin samples collected from 20 patients with dcSSc. ADAM12 expression was investigated in the skin and in isolated MSC and FB treated with TGF-β by immunofluorescence, quantitative real-time PCR, and western blot. Further, we silenced ADAM12 expression in both dcSSc-MSC and -FB to confirm the TGF-β modulation.Results.Pericytes and FB of dcSSc skin showed an increased expression of ADAM12 when compared with healthy control skin. TGF-β in vitro treatment induced a significant increase of ADAM12 in both SSc-MSC and -FB, with the higher levels observed in dcSSc cells. After ADAM12 silencing, the TGF-β ability to upregulate α-smooth muscle actin in both SSc-MSC and SSc-FB was inhibited.Conclusion.Our results suggest that in SSc, pericytes that transdifferentiate toward activated FB are present in the vascular tree, and TGF-β, while increasing ADAM12 expression, may modulate this transdifferentiation.

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Section: Rheumatologymentioning

confidence: 99%

Perivascular Cells in Diffuse Cutaneous Systemic Sclerosis Overexpress Activated ADAM12 and Are Involved in Myofibroblast Transdifferentiation and Development of Fibrosis

Cipriani

Benedetto²,

Ruscitti³

et al. 2016

J Rheumatol

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“…The in silico mapping allowed for a significant refinement of the QTL on Chromosome 7 from 60 Mb to 0.22 Mb. The only gene in the region, Adam12, is a metalloproteinase that is upregulated in liver fibrogenesis and has been implicated in modulating signaling via c-SRC and the TGF-␤ type II receptor (5,59). Other members of the TGF-␤ receptor family, the BMP type I and type II receptors, which transduce their signal via SMAD proteins, are intimately involved in liver iron homeostasis (17).…”

Section: Comparison Of Qtl Regions Associated With Liver Iron Levels mentioning

confidence: 99%

In silico QTL mapping of basal liver iron levels in inbred mouse strains

McLachlan

Lee

Steele

et al. 2011

Physiological Genomics

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Both iron deficiency and iron excess are detrimental in many organisms, and previous studies in both mice and humans suggest that genetic variation may influence iron status in mammals. However, these genetic factors are not well defined. To address this issue, we measured basal liver iron levels in 18 inbred strains of mice of both sexes on a defined iron diet and found ∼4-fold variation in liver iron in males (lowest 153 μg/g, highest 661 μg/g) and ∼3-fold variation in females (lowest 222 μg/g, highest 658 μg/g). We carried out a genome-wide association mapping to identify haplotypes underlying differences in liver iron and three other related traits (copper and zinc liver levels, and plasma diferric transferrin levels) in a subset of 14 inbred strains for which genotype information was available. We identified two putative quantitative trait loci (QTL) that contain genes with a known role in iron metabolism: Eif2ak1 and Igf2r. We also identified four putative QTL that reside in previously identified iron-related QTL and 22 novel putative QTL. The most promising putative QTL include a 0.22 Mb region on Chromosome 7 and a 0.32 Mb region on Chromosome 11 that both contain only one candidate gene, Adam12 and Gria1, respectively. Identified putative QTL are good candidates for further refinement and subsequent functional studies.

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“…Our immunostainings of ADAM15 and FAK in the focal contacts comprising of transmembrane integrins and cytoplasmic proteins linking the ECM to the cytoskeleton provide evidence that the spatial requirements for such interactions are fulfilled. Likewise, colocalization with Src at the cell periphery and Src interaction has been shown for another ADAM family member (ADAM12 (36,37)). It is tempting to speculate in the light of data presented here and the compiled work of others that upregulation of ADAM15 in (patho)physiologic conditions might have a dual impact on integrin-associated signaling.…”

Section: Discussionmentioning

confidence: 79%

ADAM15 Protein Amplifies Focal Adhesion Kinase Phosphorylation under Genotoxic Stress Conditions

Fried¹,

Böhm²,

Krause

et al. 2012

Journal of Biological Chemistry

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Background: ADAM15 confers apoptosis resistance to chondrocytes upon exposure to genotoxic stress. Results: Apoptosis induction provokes direct ADAM15 binding to focal adhesion kinase (FAK) and an associated enhanced phosphorylation of the FAK-Src complex. Conclusion: ADAM15 interacts with FAK-Src, thereby enhancing survival signals. Significance: The anti-apoptotic ADAM15 signaling has potential relevance to tumorigenesis beyond its impact on chondrocyte survival.

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ADAM12 localizes with c-Src to actin-rich structures at the cell periphery and regulates Src kinase activity

Cited by 35 publications

References 50 publications

Perivascular Cells in Diffuse Cutaneous Systemic Sclerosis Overexpress Activated ADAM12 and Are Involved in Myofibroblast Transdifferentiation and Development of Fibrosis

Perivascular Cells in Diffuse Cutaneous Systemic Sclerosis Overexpress Activated ADAM12 and Are Involved in Myofibroblast Transdifferentiation and Development of Fibrosis

In silico QTL mapping of basal liver iron levels in inbred mouse strains

ADAM15 Protein Amplifies Focal Adhesion Kinase Phosphorylation under Genotoxic Stress Conditions

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