The alpha 5 beta 1 integrin fibronectin receptor, but not the alpha 5 cytoplasmic domain, functions in an early and essential step in fibronectin matrix assembly.

Wu, Chuanyue; Bauer, Jeffrey S.; Juliano, Rudolph L.; McDonald, John A.

doi:10.1016/s0021-9258(20)80623-1

Cited by 149 publications

(34 citation statements)

References 37 publications

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“…The integrin a v subunit has been explicitly characterized to heterodimerize with integrin b subunits to form integrins a v b 3 , a v b 5 , a v b 6 , and a v b 8 , all of which have been reported to modulate TGFb activation (52). Integrin a 5 b 1 is the major receptor for fibronectin (53); fibronectin is required for TGFb activation (54) and fibronectin matrix assembly (55), suggesting the unique possibility that integrin a 5 may also play a role in the liberation and activation of TGFb. In endothelial cells, it was shown that fibronectin and its receptor (e.g., integrin a 5 b 1 ) mediated SMAD phosphorylation following exogenous application of TGFb1 and BMP-9 (56).…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-92 Expression in CD133+ Melanoma Stem Cells Regulates Immunosuppression in the Tumor Microenvironment via Integrin-Dependent Activation of TGFβ

2019

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In addition to being refractory to treatment, melanoma cancer stem cells (CSC) are known to suppress host antitumor immunity, the underlying mechanisms of which need further elucidation. In this study, we established a novel role for miR-92 and its associated gene networks in immunosuppression. CSCs were isolated from the B16-F10 murine melanoma cell line based on expression of the putative CSC marker CD133 (Prominin-1). CD133 þ cells were functionally distinct from CD133 À cells and showed increased proliferation in vitro and enhanced tumorigenesis in vivo. CD133 þ CSCs also exhibited a greater capacity to recruit immunosuppressive cell types during tumor formation, including FoxP3 þ Tregs, myeloid-derived suppressor cells (MDSC), and M2 macrophages. Using microarray technology, we identified several miRs that were significantly downregulated in CD133 þ cells compared with CD133 À cells, including miR-92. Decreased expression of miR-92 in CSCs led to higher expression of target molecules integrin a V and a 5 subunits, which, in turn, enhanced TGFb activation, as evidenced by increased phosphorylation of SMAD2. CD133 þ cells transfected with miR-92a mimic and injected in vivo showed significantly decreased tumor burden, which was associated with reduced immunosuppressive phenotype intratumorally. Using The Cancer Genome Atlas database of patients with melanoma, we also noted a positive correlation between integrin a 5 and TGFb1 expression levels and an inverse association between miR-92 expression and integrin alpha subunit expression. Collectively, this study suggests that a miR-92-driven signaling axis involving integrin activation of TGFb in CSCs promotes enhanced tumorigenesis through induction of intratumoral immunosuppression.Significance: CD133 þ cells play an active role in suppressing melanoma antitumor immunity by modulating miR-92, which increases influx of immunosuppressive cells and TGFb1 expression.

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Section: Discussionmentioning

confidence: 99%

MicroRNA-92 Expression in CD133+ Melanoma Stem Cells Regulates Immunosuppression in the Tumor Microenvironment via Integrin-Dependent Activation of TGFβ

2019

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“…Cells are well known to communicate with ECM proteins such as fibronectin through integrin receptors. ␤1-Integrin is one of the major fibronectin receptors; thus, integrin-fibronectin interactions are important in regulating cell behavior including cell adhesion and wound healing (78,85). It has been reported that the loss of ␤1-integrin leads to loss of cell-to-cell and cell-to-ECM contact and cell death (65,67,68).…”

Section: Discussionmentioning

confidence: 99%

Deletion of β1-integrin in collecting duct principal cells leads to tubular injury and renal medullary fibrosis

Mamuya

Xie

Lei

et al. 2017

American Journal of Physiology-Renal Physiology

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The renal collecting duct (CD) contains two major cell types, intercalated (ICs) and principal cells (PCs). A previous report showed that deletion of β1-integrin in the entire renal CD causes defective CD morphogenesis resulting in kidney dysfunction. However, subsequent deletion of β1-integrin specifically in ICs and PCs, respectively, did not cause any morphological defects in the CDs. The discrepancy between these studies prompts us to reinvestigate the role of β1-integrin in CD cells, specifically in the PCs. We conditionally deleted β1-integrin in mouse CD PCs using a specific aquaporin-2 (AQP2) promoter Cre-LoxP system. The resulting mutant mice, β-1AQP2-Cre+, had lower body weight, failed to thrive, and died around 8-12 wk. Their CD tubules were dilated, and some of them contained cellular debris. Increased apoptosis and proliferation of PCs were observed in the dilated CDs. Trichrome staining and electron microscopy revealed the presence of peritubular and interstitial fibrosis that is associated with increased production of extracellular matrix proteins including collagen type IV and fibronectin, as detected by immunoblotting. Further analysis revealed a significantly increased expression of transforming growth factor-β (TGF-β)-induced protein, fibronectin, and TGF-β receptor-1 mRNAs and concomitantly increased phosphorylation of SMAD-2 that indicates the activation of the TGF-β signaling pathway. Therefore, our data reveal that normal expression of β1-integrin in PCs is a critical determinant of CD structural and functional integrity and further support the previously reported critical role of β1-integrin in the development and/or maintenance of the CD structure and function.

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“…28 It is also known that fibronectin polymerization is dependent on interaction with cell-surface receptors. 29 Therefore, to determine whether there was a relationship between the assembly of collagen on SMCs and assembly of fibronectin, we co-incubated SMC cultures with Texas Red-labeled soluble collagen and Oregon Green-labeled soluble fibronectin. As shown in Fig- ure 4A, newly assembled collagen fibrils co-localized with newly assembled fibronectin fibrils.…”

Section: Smc-mediated Collagen Assembly Is Integrated With Fibronectin Assemblymentioning

confidence: 99%

Vascular Smooth Muscle Cells Orchestrate the Assembly of Type I Collagen via α2β1 Integrin, RhoA, and Fibronectin Polymerization

Diepstraten

D’Souza

et al. 2003

The American Journal of Pathology

151

143

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Assembly of collagen into fibrils is widely studied as a spontaneous and entropy-driven process. To determine whether vascular smooth muscle cells (SMCs) impact the formation of collagen fibrils, we microscopically tracked the conversion of soluble to insoluble collagen in human SMC cultures, using fluorescent type I collagen at concentrations less than that which supported self-assembly. Collagen microaggregates were found to form on the cell surface, initially as punctate collections and then as an increasingly intricate network of fibrils. These fibrils displayed 67-nm periodicity and were found in membrane-delimited cellular invaginations. Fibril assembly was inhibited by an anti-alpha2beta1 integrin antibody and accelerated by an alpha2beta1 integrin antibody that stimulates a high-affinity binding state. Newly assembled collagen fibrils were also found to co-localize with newly assembled fibronectin fibrils. Moreover, inhibition of fibronectin assembly with an anti-alpha5beta1 integrin antibody completely inhibited collagen assembly. Collagen fibril formation was also linked to the cytoskeleton. Fibrils formed on the stretched tails of SMCs, ran parallel to actin microfilament bundles, and formed poorly on SMCs transduced with retrovirus containing cDNA for dominant-negative RhoA and robustly on SMCs expressing constitutively active RhoA. Lysophosphatidic acid, which activates RhoA and stimulates fibronectin assembly, stimulated collagen fibril formation, establishing for the first time that collagen polymerization can be regulated by soluble agonists of cell function. Thus, collagen fibril formation is under close cellular control and is dynamically integrated with fibronectin assembly, opening new possibilities for modifying collagen deposition.

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The alpha 5 beta 1 integrin fibronectin receptor, but not the alpha 5 cytoplasmic domain, functions in an early and essential step in fibronectin matrix assembly.

Cited by 149 publications

References 37 publications

MicroRNA-92 Expression in CD133+ Melanoma Stem Cells Regulates Immunosuppression in the Tumor Microenvironment via Integrin-Dependent Activation of TGFβ

MicroRNA-92 Expression in CD133+ Melanoma Stem Cells Regulates Immunosuppression in the Tumor Microenvironment via Integrin-Dependent Activation of TGFβ

Deletion of β1-integrin in collecting duct principal cells leads to tubular injury and renal medullary fibrosis

Vascular Smooth Muscle Cells Orchestrate the Assembly of Type I Collagen via α2β1 Integrin, RhoA, and Fibronectin Polymerization

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