Integrin <i>α</i>1β1 Controls Reactive Oxygen Species Synthesis by Negatively Regulating Epidermal Growth Factor Receptor-Mediated Rac Activation

Chen, Xiwu; Abair, Tristin D.; Ibanez, R.; Su, Yan; Frey, Mark R.; Dise, Rebecca S.; Polk, D. Brent; Singh, Amar; Harris, Raymond C.; Zent, Roy; Pozzi, Ambra

doi:10.1128/mcb.01476-06

Cited by 99 publications

(103 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…3 They play opposite functions when activated by collagen, and they can also affect the functions of the other. 26 Although loss of integrin a1b1 leads to increased levels of EGF receptor activation, ROS production, and consequent collagen synthesis/deposition compared with WT cells and/or mice, 3,6,7 loss of integrin a2b1 does not seem to have a protective role because of decreased EGF receptor activation or ROS production; no differences in EGF receptor phosphorylation (not shown) or ROS levels ( Figure 5C) were observed between WT and integrin a2-null cells.…”

Section: Discussionmentioning

confidence: 88%

“…6 Briefly, 1.5310 5 primary WT, a1-null, and a2-null mesangial cells were plated in sixwell plates in DMEM containing 10% FCS. After 2 days, the cells were washed and incubated in serum-free medium with 2 mM dehydroethidium (Sigma).…”

Section: Ros Evaluationmentioning

confidence: 99%

“…3 Immortalized mesangial cells were obtained by crossing WTor integrin a2KO mice with the immorto mouse as previously described. 6 Immortalized mesangial cells were propagated at 33°C in the presence of 100 IU/ml IFN-g. For experiments, cells were cultured at 37°C without IFN-g for at least 3 days before use, because this time is optimal for conditionally immortalized mesangial cells to acquire a phenotype similar to the phenotype of freshly isolated primary mesangial cells. 6 To generate Stat3C-expressing mesangial cells, 3310 5 immortalized a2KO mesangial cells were transfected with 2 mg mouse pRCStat3C (plasmid 8722; Addgene) or pcDNA-neo empty vector using Lipofectamine Plus (Invitrogen, Grand Island, NY) followed by G418 (0.6 mg/ml) selection and analysis of Stat3C expression by Western blot with anti-FLAG antibodies.…”

Section: Cell Culture and Transfectionmentioning

confidence: 99%

“…3,5 We also showed that integrin a1b1 negatively regulates EGF receptor activation, generation of profibrotic ROS, and consequent collagen levels in mesangial cells in vitro. 3,6 More recently, we showed that integrin a1b1 also exerts its antifibrotic role by regulating both the level and phosphorylation state of caveolin-1, 7,8 a scaffolding protein that alters EGF receptor activation. Taken together, we have shown that integrin a1b1 protects mice from glomerular injury by controlling many cell signaling pathways that regulate collagen synthesis.…”

mentioning

confidence: 99%

See 3 more Smart Citations

Inhibition of Integrin α2β1 Ameliorates Glomerular Injury

Borza

Su²,

Chen³

et al. 2012

Journal of the American Society of Nephrology

Self Cite

View full text Add to dashboard Cite

Mesangial cells and podocytes express integrins a1b1 and a2b1, which are the two major collagen receptors that regulate multiple cellular functions, including extracellular matrix homeostasis. Integrin a1b1 protects from glomerular injury by negatively regulating collagen production, but the role of integrin a2b1 in renal injury is unclear. Here, we subjected wild-type and integrin a2-null mice to injury with adriamycin or partial renal ablation. In both of these models, integrin a2-null mice developed significantly less proteinuria and glomerulosclerosis. In addition, selective pharmacological inhibition of integrin a2b1 significantly reduced adriamycin-induced proteinuria, glomerular injury, and collagen deposition in wildtype mice. This inhibitor significantly reduced collagen synthesis in wild-type, but not integrin a2-null, mesangial cells in vitro, demonstrating that its effects are integrin a2b1-dependent. Taken together, these results indicate that integrin a2b1 contributes to glomerular injury by positively regulating collagen synthesis and suggest that its inhibition may be a promising strategy to reduce glomerular injury and proteinuria. The most common cause of end stage kidney disease is glomerulosclerosis, which is characterized by excessive collagen deposition in the glomerulus. Although numerous disease processes can initiate glomerular injury, they all result in abnormal glomerular collagen homeostasis with progression. Glomerular collagen turnover is regulated by multiple factors, including growth factors and profibrotic reactive oxygen species (ROSs) as well as cell extracellular matrix interactions mediated by the matrix receptors integrins (reviewed in ref. 1). Of these factors, the mechanisms by which integrins regulate glomerulosclerosis are the most poorly understood.Integrins consist of two noncovalently associated a-and b-subunits that combine to form 24 different heterodimers in mammals (reviewed in ref.2). The integrin extracellular domains contain the ligand binding site and confer ligand specificity, whereas the cytoplasmic domain interacts with the cytoskeleton and regulates cell signaling. Integrins control critical cell functions, including proliferation, survival, migration, and matrix homeostasis (reviewed in refs. 1 and 2). Thus, it is not surprising that integrins regulate tissue responses to injury in whole organisms.The best-studied integrin in the context of glomerular injury is the major collagen IV receptor, integrin a1b1, which is expressed by mesangial cells 3 and podocytes. 4 We have shown that integrin

show abstract

Section: Discussionmentioning

confidence: 88%

Section: Ros Evaluationmentioning

confidence: 99%

Section: Cell Culture and Transfectionmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Inhibition of Integrin α2β1 Ameliorates Glomerular Injury

Borza

Su²,

Chen³

et al. 2012

Journal of the American Society of Nephrology

Self Cite

View full text Add to dashboard Cite

show abstract

“…Conversely, integrin α1 is expressed at low levels in human breast cancer cell lines (18) and is downregulated in breast and ovarian cancer (19), suggesting that its loss might be associated with malignancy. Furthermore, integrin α1 can negatively regulate EGFR signaling in prostate and cervical cancer cells (20) as well as in mesangial cells (21). In the present study, a cell adhesion blocking assay showed that anti-CD49a (integrin α1 subunit) mAb significantly reduced the adhesiveness of the clones compared to the controls.…”

Section: Discussionmentioning

confidence: 63%

Role of integrin α1 subunits in gastric cancer patients with peritoneal dissemination

et al. 2011

View full text Add to dashboard Cite

Abstract. The interaction between gastric cancer (GC) cells and the peritoneum is a critical event in peritoneal dissemination. The molecular mechanisms of this dissemination, however, remain unclear. Integrins are heterodimeric cell adhesion molecules consisting of α and β subunits that serve as adhesion receptors for extracellular matrix proteins and cellular ligands, and may participate in GC peritoneal dissemination. In this study, we isolated fresh GC cells from a patient with peritoneal metastasis and examined them for integrin expression and investigated the role of integrin α1 subunit molecules in GC. Five clones (KGC1C2, KGC1F3, KGC1H3, KGC1E8, KGC1G10) were established from the clinical GC sample and used in an in vitro adhesion model using a single cell culture method. Each clone was transplanted into the peritoneal cavity of SCID mice, where each clone formed tumors and caused conglutination of organs in the abdominal cavity. We analyzed the expression of integrin subunits for each clone by flow cytometry and found that the expression ratio of α1 subunits paired with β1 subunits was detected at higher levels than other subunits. To verify that anti-integrin α1 subunit (CD49a) antibody inhibits cell adhesion in an in vitro adhesion assay, each clone was treated with anti-CD49a antibody, which significantly inhibited cell adhesion compared to the untreated group. Characterization of α1 subunit expression in GC may be useful in optimizing treatments for different individuals. Having high metastatic abilities, these 5 new GC clones may be beneficial for analyzing integrin function in tumor metastasis.

show abstract

Type IV collagen induces expression of thrombospondin‐1 that is mediated by integrin α1β1 in astrocytes

Yonezawa

Hattori

Inagaki

et al. 2010

Glia

View full text Add to dashboard Cite

Following brain injury, thrombospondin-1 (TSP-1) is involved in angiogenesis and synaptic recovery. In this study, we used a cold injury-model and found that TSP-1 mRNA was markedly upregulated after brain injury. Immunohistochemistry showed that TSP-1 was upregulated in both the core of the lesion and in the perilesional area of injured brain tissue. Numerous astrocytes immunopositive for glial fibrillary acidic protein (GFAP) were found in the perilesional area, and TSP-1 was also expressed in almost all astrocytes surrounding blood vessels at 4 days after injury. Next, we examined the influence of vascular basement membrane components on TSP-1 expression. When astrocytes were cultured on type IV collagen, TSP-1 was significantly upregulated compared with the expression when cells were grown on laminin, fibronectin, or poly-L-lysine. This increase occurred exclusively when astrocytes were grown on the native form of type IV collagen but not on the heat-denatured form or the non-collagenous 1 domain. Further, integrin alpha1 and beta1 mRNAs were upregulated concomitantly with GFAP mRNA, and integrin alpha1 protein was localized to the endfeet of astrocytes that surrounded blood vessels in the injured brain. Using function-blocking antibodies, we found that the effect of type IV collagen was attributed to integrin alpha1beta1 in primary astrocytes. Collectively, our results suggest that vascular basement membrane components substantially impact gene expression in astrocytes during brain tissue repair.

show abstract

Integrin α1β1 Controls Reactive Oxygen Species Synthesis by Negatively Regulating Epidermal Growth Factor Receptor-Mediated Rac Activation

Cited by 99 publications

References 60 publications

Inhibition of Integrin α2β1 Ameliorates Glomerular Injury

Inhibition of Integrin α2β1 Ameliorates Glomerular Injury

Role of integrin α1 subunits in gastric cancer patients with peritoneal dissemination

Type IV collagen induces expression of thrombospondin‐1 that is mediated by integrin α1β1 in astrocytes

Contact Info

Product

Resources

About