Cysteine-rich protein 2 alters p130Cas localization and inhibits vascular smooth muscle cell migration

Chen, Chung-Huang; Ho, Yen‐Chun; Ho, Hua-Hui; Chang, I–Shou; Kirsch, Kathrin H.; Chuang, Yung-Jen; Layne, Matthew D.; Yet, Shaw‐Fang

doi:10.1093/cvr/cvt207

Cited by 25 publications

(24 citation statements)

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“…MUC18 (CD146) is a glycoprotein detected in endothelial cells as a surface receptor that triggers a transient increase in the intracellular calcium concentration . Cysteine‐rich protein (CRP) 2 is a member of the LIM‐only CRP family, also expressed in vascular smooth muscle cells (VSMCs) of blood vessels . Its role is to repress VSMC migration and vascular remodelling, because it was demonstrated that the absence of CRP2 increases neointima formation, correlating with increased VSMC migration .…”

Section: Discussionmentioning

confidence: 99%

Protein profiling of human lung telocytes and microvascular endothelial cells using iTRAQ quantitative proteomics

Zheng

Crețoiu

Yan

et al. 2014

J Cellular Molecular Medi

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Telocytes (TCs) are described as a particular type of cells of the interstitial space (www.telocytes.com). Their main characteristics are the very long telopodes with alternating podoms and podomers. Recently, we performed a comparative proteomic analysis of human lung TCs with fibroblasts, demonstrating that TCs are clearly a distinct cell type. Therefore, the present study aims to reinforce this idea by comparing lung TCs with endothelial cells (ECs), since TCs and ECs share immunopositivity for CD34. We applied isobaric tag for relative and absolute quantification (iTRAQ) combined with automated 2-D nano-ESI LC-MS/MS to analyse proteins extracted from TCs and ECs in primary cell cultures. In total, 1609 proteins were identified in cell cultures. 98 proteins (the 5th day), and 82 proteins (10th day) were confidently quantified (screened by two-sample t-test, P < 0.05) as up- or down-regulated (fold change >2). We found that in TCs there are 38 up-regulated proteins at the 5th day and 26 up-regulated proteins at the 10th day. Bioinformatics analysis using Panther revealed that the 38 proteins associated with TCs represented cellular functions such as intercellular communication (via vesicle mediated transport) and structure morphogenesis, being mainly cytoskeletal proteins and oxidoreductases. In addition, we found 60 up-regulated proteins in ECs e.g.: cell surface glycoprotein MUC18 (15.54-fold) and von Willebrand factor (5.74-fold). The 26 up-regulated proteins in TCs at 10th day, were also analysed and confirmed the same major cellular functions, while the 56 down-regulated proteins confirmed again their specificity for ECs. In conclusion, we report here the first extensive comparison of proteins from TCs and ECs using a quantitative proteomics approach. Our data show that TCs are completely different from ECs. Protein expression profile showed that TCs play specific roles in intercellular communication and intercellular signalling. Moreover, they might inhibit the oxidative stress and cellular ageing and may have pro-proliferative effects through the inhibition of apoptosis. The group of proteins identified in this study needs to be explored further for the role in pathogenesis of lung disease.

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Section: Discussionmentioning

confidence: 99%

Protein profiling of human lung telocytes and microvascular endothelial cells using iTRAQ quantitative proteomics

Zheng

Crețoiu

Yan

et al. 2014

J Cellular Molecular Medi

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“…These expression levels are relevant to IMT and plaque, as BCAR1 has been shown to be expressed at the protein level in cells involved in atherosclerosis. 25 Although analysis could not be separated by sex in GTEx, further analysis of tissue expression data in ASAP 8 did not indicate the association of rs4888378 with TMEM170A and LDHD to be specific to women; the relationship was significant in men but not in women ( Figure VI in the Data Supplement). However, the small sample size of women precluded assessment of any association.…”

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confidence: 95%

“…It has since been shown that BCAR1 is involved in PDGF stimulation of VSMC migration, and its expression and phosphorylation promote formation of neointima after arterial injury. 25 We therefore hypothesize that the risk G allele increases expression of BCAR1 stimulating VSMC migration and increasing the formation of neointima in the vessel wall, resulting in larger plaques and greater cIMT.The implication of BCAR1 in the phenotype is particularly interesting when we consider the sex-specific associations with common cIMT, IMT progression, and vascular events. Men have a higher overall risk of CHD, 28 and although differences between the sexes in traditional risk factors contribute to this disparity, sex remains associated over and above the known risk factors.…”

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confidence: 98%

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confidence: 99%

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Functional Analysis of a Carotid Intima-Media Thickness Locus Implicates BCAR1 and Suggests a Causal Variant

Boardman-Pretty

Smith

Palmen

et al. 2015

Circ Cardiovasc Genet

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C ardiovascular disease (CVD) is the most common cause of death in the developed world, 1 and identification of those at high risk and strategies to reduce its incidence are important goals. Risk factors for CVD are numerous and well characterized, allowing groups at higher risk to be identified. Markers of preclinical disease may provide greater use for studying the development of CVD compared with traditional clinical and lifestyle-related risk factors.2 Carotid intima-media thickness is one such marker that can be used as a surrogate for subclinical atherosclerosis 3 because it is easily measured with noninvasive standardized ultrasound techniques and is predictive of coronary events. 2,4,5 Clinical Perspective on p 706Background-Carotid intima-media thickness (IMT) is a marker of subclinical atherosclerosis that can predict cardiovascular disease events over traditional risk factors. This study examined the BCAR1-CFDP1-TMEM170A locus on chromosome 16, associated with carotid IMT and coronary artery disease in the IMT and IMT-Progression as Predictors of Vascular Events (IMPROVE) cohort, to identify the functional variant. Methods and Results-In analysis of the locus lead single nucleotide polymorphism (SNP; rs4888378, intronic in CFDP1) in Progressione della Lesione Intimale Carotidea (PLIC), the protective AA genotype was associated with slower IMT progression in women (P=0.04) but not in men. Meta-analysis of 5 cohort studies also supported a protective effect of the A allele on common carotid IMT in women only (women: β=−0.0047, P=1.63×10 -4 ; men: β=−0.0029, P=0.0678). Two hundred fourteen noncoding variants in strong linkage disequilibrium (r 2 ≥0.8) with rs4888378 were identified from 1000 Genome Project. ENCODE regulatory chromatin marks were used to create a shortlist of 6 possible regulatory variants. Electrophoretic mobility shift assays on the shortlist detected allele-specific protein binding to the lead SNP rs4888378; multiplexed competitor electrophoretic mobility shift assays implicated FOXA as the protein. Luciferase reporter assays on rs4888378 showed a significant 35% to 92% (P=0.0057; P=4.0×10 -22 ) decrease in gene expression with the A allele. Expression quantitative trait loci analysis confirmed previously reported associations of rs4888378 with BCAR1 in vascular tissues. Conclusions-Molecular studies suggest the lead SNP as a potentially causal SNP at the BCAR1-CFDP1-TMEM170Alocus, and expression quantitative trait loci studies implicate BCAR1 as the causal gene. This variant showed stronger effects on common carotid IMT in women, raising questions about the mechanism of the causal SNP on atherosclerosis. Boardman-Pretty et al Analysis of cIMT Locus: BCAR1 and Causal Variant 697Genome-wide association studies have identified numerous loci implicated in CVD and related traits, 6 but translating these initial findings into information about molecular processes and clinical utility has often been problematic 7 ; several CV risk factors have been identified which predict the developmen...

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“…Cas is associated with the development and progression of pulmonary disease (8), cardiovascular disease (9), and particularly cancer (1,4,10,11). Increased p130…”

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confidence: 99%

Identification of Novel Crk-associated Substrate (p130Cas) Variants with Functionally Distinct Focal Adhesion Kinase Binding Activities

Kumbrink

Soni

Laumbacher³

et al. 2015

Journal of Biological Chemistry

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Background: The tumor promoter p130Cas utilizes its SH3 domain to control cell adhesion and migration. Results: We identified N-terminal extended p130Cas variants with enhanced SH3 domain binding activity which modulates cell migration and invasion. Conclusion: Naturally occurring p130Cas variants exhibit differential biological activities. Significance: Knowledge on these variants may explain how p130Cas controls cellular programs and drives carcinogenesis.

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Cysteine-rich protein 2 alters p130Cas localization and inhibits vascular smooth muscle cell migration

Abstract: These studies demonstrate that CRP2 sequesters p130Cas at FAs, thereby reducing lamellipodia formation and blunting VSMC migration.

Cited by 25 publications

References 44 publications

Protein profiling of human lung telocytes and microvascular endothelial cells using iTRAQ quantitative proteomics

Protein profiling of human lung telocytes and microvascular endothelial cells using iTRAQ quantitative proteomics

Functional Analysis of a Carotid Intima-Media Thickness Locus Implicates BCAR1 and Suggests a Causal Variant

Identification of Novel Crk-associated Substrate (p130Cas) Variants with Functionally Distinct Focal Adhesion Kinase Binding Activities

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