Integrin α1β1 Regulates Epidermal Growth Factor Receptor Activation by Controlling Peroxisome Proliferator-Activated Receptor γ-Dependent Caveolin-1 Expression

Chen, Xiwu; Whiting, Carrie; Borza, Corina M.; Hu, Wen Yang; Mont, Stacey; Bulus, Nada; Zhang, Mingzhi; Harris, Raymond C.; Zent, Roy; Pozzi, Ambra

doi:10.1128/mcb.00892-09

Cited by 40 publications

(35 citation statements)

References 75 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: 91%

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: 91%

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

“…Integrin α1β1 reduces the production of reactive oxygen species by downregulating the activation state of the profibrotic epidermal growth factor (EGF) receptor. This is achieved by controlling the level and phosphorylation state of caveolin-1, a scaffolding protein involved in receptor signaling and localization Chen et al, 2007Chen et al, , 2010. In a mouse model for Alport syndrome (COL4A3 −/− mice), α1β1-mediated transmigration of monocytes on collagen XIII that is produced by vascular endothelial cells has been described (Dennis et al, 2010).…”

Section: Integrin α1β1mentioning

confidence: 99%

The integrin–collagen connection – a glue for tissue repair?

Zeltz

Gullberg

2016

Journal of Cell Science

173

121

View full text Add to dashboard Cite

There was an error published in J. Cell Sci. 129, 653-664.In Fig. 2A, the fibroblasts were incorrectly labelled. The correct annotation should have been α11 −/− fibroblast (left) and α11 +/+ fibroblast (right). The correct Fig. 2 is shown below. We apologise to the readers for any confusion that this error might have caused. Journal of Cell Science COMMENTARYThe integrin-collagen connection -a glue for tissue repair?Cedric Zeltz and Donald Gullberg* ABSTRACTThe α1β1, α2β1, α10β1 and α11β1 integrins constitute a subset of the integrin family with affinity for GFOGER-like sequences in collagens.Integrins α1β1 and α2β1 were originally identified on a subset of activated T-cells, and have since been found to be expressed on a number of cell types including platelets (α2β1), vascular cells (α1β1, α2β1), epithelial cells (α1β1, α2β1) and fibroblasts (α1β1, α2β1).Integrin α10β1 shows a distribution that is restricted to mesenchymal stem cells and chondrocytes, whereas integrin α11β1 appears restricted to mesenchymal stem cells and subsets of fibroblasts. The bulk of the current literature suggests that collagen-binding integrins only have a limited role in adult connective tissue homeostasis, partly due to a limited availability of cell-binding sites in the mature fibrillar collagen matrices. However, some recent data suggest that, instead, they are more crucial for dynamic connective tissue remodeling events -such as wound healing -where they might act specifically to remodel and restore the tissue architecture. This Commentary discusses the recent development in the field of collagen-binding integrins, their roles in physiological and pathological settings with special emphasis on wound healing, fibrosis and tumor-stroma interactions, and include a discussion of the most recently identified newcomers to this subfamilyintegrins α10β1 and α11β1.

show abstract

“…We have recently shown that loss of integrin ␣1␤1 leads to decreased basal levels of Cav-1, via a PPAR␥/ERK pathway, with consequent up-regulation of EGF receptor-mediated ROS production (35). Altogether, these data indicate that integrin ␣1␤1 might negatively regulate oxidative stress by positively regulating the total Cav-1 levels and, at the same time, negatively regulating the levels of pCav-1.…”

Section: Discussionmentioning

confidence: 56%

“…In conclusion, because integrin ␣1␤1 is required for 1) down-regulation of pCav-1 levels (present study), 2) downregulation of the profibrotic EGF receptor signaling (30,35), and 3) TCPTP recruitment and activation (26), we propose that TCPTP might act as an anti-ROS phosphatase by negatively regulating both EGF receptor activation and pCav-1.…”

Section: Discussionmentioning

confidence: 99%

Integrin α1β1 Promotes Caveolin-1 Dephosphorylation by Activating T Cell Protein-tyrosine Phosphatase

Borza

Chen

Mathew

et al. 2010

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Integrin ␣1␤1 is a collagen receptor that down-regulates collagen and reactive oxygen species (ROS) production, and mice lacking this receptor show increased ROS levels and exacerbated glomerular sclerosis following injury. Caveolin-1 (Cav-1) is a multifunctional protein that is tyrosine-phosphorylated in response to injury and has been implicated in ROSmediated injury. Cav-1 interacts with integrins, and integrin ␣1␤1 binds/activates T cell protein-tyrosine phosphatase (TCPTP), which is homologous to the tyrosine phosphatase PTP1B known to dephosphorylate Cav-1. In this study, we analyzed whether phosphorylated Cav-1 (pCav-1) is a substrate of TCPTP and if integrin ␣1␤1 is essential for promoting TCPTP-mediated Cav-1 dephosphorylation. We found that Cav-1 phosphorylation is significantly higher in cells lacking integrin ␣1␤1 at base line and following oxidative stress. Overexpression of TCPTP leads to reduced pCav-1 levels only in cells expressing integrin ␣1␤1. Using solid phase binding assays, we demonstrated that 1) purified Cav-1 directly interacts with TCPTP and the integrin ␣1 subunit, 2) pCav-1 is a substrate of TCPTP, and 3) TCPTP-mediated Cav-1 dephosphorylation is highly increased by the addition of purified integrin ␣1␤1 or an integrin ␣1 cytoplasmic peptide to which TCPTP has been shown to bind. Thus, our results demonstrate that pCav-1 is a new substrate of TCPTP and that integrin ␣1␤1 acts as a negative regulator of Cav-1 phosphorylation by activating TCPTP. This could explain the protective function of integrin ␣1␤1 in oxidative stress-mediated damage and why integrin ␣1-null mice are more susceptible to fibrosis following injury.Caveolin-1 (Cav-1) is a key component of caveolae, plasma membrane invaginations enriched in sphingolipids and cholesterol, which function in lipid metabolism, transcytosis, and receptor trafficking (1). Cav-1 interacts with and regulates the localization and function of various transmembrane proteins (1, 2). For instance, Cav-1 negatively regulates TGF-␤ signaling (3) as well as EGF receptor expression and activation (4). In addition, Cav-1 participates in integrin-mediated signaling, as demonstrated by the finding that Cav-1-mediated integrin ␤1 endocytosis is critical for regulation of fibronectin turnover (5).Cav-1 is phosphorylated at tyrosine 14 by the Src family kinases in response to various stimuli, including growth factor-mediated signaling, mechanical stretch, and hyperosmolarity (6 -10). Cav-1 is also phosphorylated in response to oxidative stress, since hydrogen peroxide induces Cav-1 phosphorylation in endothelial cells (11-13), fibroblasts (7,10,14) and renal cells (15). Finally, Cav-1 phosphorylation increases in vivo in brain injury (16) and in the spinal cord following experimental autoimmune encephalomyelitis (17). However, whether increased pCav-1 contributes to or protects from injury is controversial at present. In this context, increased expression of pCav-1 is associated with cell survival after oxidative stress (15); however, in contrast to these...

show abstract

Integrin α1β1 Regulates Epidermal Growth Factor Receptor Activation by Controlling Peroxisome Proliferator-Activated Receptor γ-Dependent Caveolin-1 Expression

Cited by 40 publications

References 75 publications

Inhibition of Integrin α2β1 Ameliorates Glomerular Injury

Inhibition of Integrin α2β1 Ameliorates Glomerular Injury

The integrin–collagen connection – a glue for tissue repair?

Integrin α1β1 Promotes Caveolin-1 Dephosphorylation by Activating T Cell Protein-tyrosine Phosphatase

Contact Info

Product

Resources

About