Redox Control of Integrin Adhesion Receptors

Smith, Jeffrey W.; Yan, Boxu; Lombardo, Christian R.

doi:10.1016/s0076-6879(02)53045-7

Cited by 11 publications

(8 citation statements)

References 9 publications

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“…There are increasing numbers of examples of biologic phenomena that may be controlled by thiol-disulfide exchange, including some involving proteins released from, and on, platelets. [48][49][50][51] Moreover, mechanical force has been implicated in model systems as contributing to or controlling exposure of thiol groups in proteins and thioredoxin-catalyzed thiol-disulfide exchange. 23,32,33 Finally, our data may have implications for interpreting previous studies in which cells were subjected to shear in the presence of serum or under conditions in which the cells may have released latent TGF-␤, because some of the observed effects may have been due to activation of latent TGF-␤1 rather than a direct effect of the shear.…”

Section: Discussionmentioning

confidence: 99%

In vitro and in vivo evidence for shear-induced activation of latent transforming growth factor-β1

Ahamed

Burg

Yoshinaga

et al. 2008

Blood

134

159

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Transforming growth factor-␤1 (TGF-␤1) has potent physiologic and pathologic effects on a variety of cell types at subnanomolar concentrations. Platelets contain 40 times as much TGF-␤1 as other cells and secrete it as an inactive (latent) form in complex with latency-associated peptide (LAP), which is disulfide bonded via Cys33 to latent TGF-␤ binding protein 1 (LTBP-1). Little is known about how latent TGF-␤1 becomes activated in vivo.Here we show that TGF-␤1 released from platelets or fibroblasts undergoes dramatic activation when subjected to stirring or shear forces, providing a potential mechanism for physiologic control. Thioldisulfide exchange appears to contribute to the process based on the effects of thiol-reactive reagents and differences in thiol labeling of TGF-␤1 before and after stirring or shear. Activation required the presence of LTBP, as TGF-␤1 contained in complex with only LAP could not be activated by stirring when studied as either a recombinant purified protein complex or in the platelet releasates or sera of mice engineered to contain an LAP C33S mutation. Release IntroductionTransforming growth factor-␤1 (TGF-␤1) has potent physiologic and pathologic effects on a variety of cell types at subnanomolar concentrations, including cells of the immune and hematopoietic systems, as well as malignant cells and fibroblasts, 1 with the latter responding with increased collagen production leading to tissue fibrosis. 2 Nearly all cellular TGF-␤1 exists, however, in a biologically inactive (latent) form in a noncovalent complex with the remaining portion of its precursor molecule, latency-associated peptide (LAP), which is disulfide bonded to a latent TGF-␤ binding protein 3,or 4), forming the large latent complex (LLC). 3 Although much is known about the signaling mechanisms and downstream effects of TGF-␤1, 4 and several latent TGF-␤1 activating mechanisms have been identified in vitro (reviewed in Annes et al 3 ), little is known about the physiologic mechanisms that control latent TGF-␤1 activation in vivo. Recent data support activation of LLC TGF-␤1 via a traction mechanism, 3,[5][6][7][8][9][10][11] with LAP binding to integrins ␣V␤5, ␣V␤6, and ␣V␤8, and LTBP-1 binding to extracellular matrix.Blood platelets are a rich source of TGF-␤1, containing 40 to 100 times as much as other cells, 12 and releasing it when activated by a variety of agents, including thrombin, which is produced during blood clotting. [13][14][15][16][17][18][19] Virtually all of the TGF-␤1 released from platelets is in the LLC. 3,16 Because platelet latent TGF-␤1 is released into the circulation, and because traction on the molecule has been proposed as a mechanism of latent TGF-␤1 activation, 5,6 we hypothesized that intravascular shear force may serve as an analog of traction mediated by cellular contraction and contribute to the activation of latent TGF-␤1 released from platelets. We therefore tested this hypothesis by both in vitro and in vivo experiments. Methods Antibodies and reagentsAnti-TGF-␤1 (polyclonal chi...

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Section: Discussionmentioning

confidence: 99%

In vitro and in vivo evidence for shear-induced activation of latent transforming growth factor-β1

Ahamed

Burg

Yoshinaga

et al. 2008

Blood

134

159

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“…26 Moreover, it has been reported that integrin activities are regulated by extracellular redox state. 27,28 As such, it is tempting to speculate that ecSOD, a potent superoxide scavenger in the extracellular space, may participate in regulating function of integrins via binding to fibulin-5.…”

Section: Discussionmentioning

confidence: 99%

Fibulin-5 Is a Novel Binding Protein for Extracellular Superoxide Dismutase

Nguyen

Itoh

Jeney

et al. 2004

Circulation Research

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Abstract-The extracellular superoxide dismutase (ecSOD) plays an important role in atherosclerosis and endothelial function by modulating levels of the superoxide anion (O 2 ⅐Ϫ ) in the extracellular space. Although heparan sulfate proteoglycan is an important ligand for ecSOD, little is known about other biological binding partners of ecSOD. The goal of this study was to identify novel proteins that interact with ecSOD. A yeast two-hybrid screening of a human aorta cDNA library using ecSOD as bait identified fibulin-5 as a predominant binding protein for ecSOD. Further analysis showed that the binding domain of ecSOD within fibulin-5 mapped to its C-terminal domain. In vitro pulldown assays and coimmunoprecipitation analysis further confirmed that ecSOD interacts with fibulin-5 in vitro and in vivo. Studies using fibulin-5 Ϫ/Ϫ mice indicated that fibulin-5 is required for binding of ecSOD to vascular tissue. Importantly, the decrease in tissue-bound ecSOD levels in aortas from fibulin-5 Ϫ/Ϫ mice was associated with an increase in vascular O 2 ⅐Ϫ levels. Furthermore, immunohistochemical analysis using ApoE Ϫ/Ϫ mice suggested a codistribution of ecSOD and fibulin-5 in atherosclerotic vessels. In summary, we provide in this study the first evidence that the ecSOD-fibulin-5 interaction is required for ecSOD binding to vascular tissues, thereby regulating vascular O 2 ⅐Ϫ levels. This interaction may represent a novel mechanism for controlling vascular redox state in the extracellular space in various cardiovascular diseases such as atherosclerosis and hypertension in which oxidative stress is increased. ⅐Ϫ ) is increased in many common cardiovascular diseases including atherosclerosis, hypercholesterolemia, hypertension, ischemic heart disease, diabetic cardiomyopathy, and heart failure. 1 One of the major cellular defenses against O 2 ⅐Ϫ and formation of peroxynitrite is the superoxide dismutases (SODs). 2 In mammalian tissue, three isoforms of superoxide dismutase have been identified: Cu/ZnSOD, MnSOD, and extracellular superoxide dismutase (ecSOD). These isozymes differ in their location: Cu/ZnSOD is localized in the cytosol, MnSOD in the mitochondria, and ecSOD in the extracellular space. In the vessel wall, one-third to one-half of the total vascular SOD is ecSOD. 3 In healthy vessels, ecSOD is produced predominately by vascular smooth muscle cells, but in atherosclerotic vessels, ecSOD is also generated by lipid-laden macrophages. 4,5 Because of its extracellular location, ecSOD plays an important role in modulating nitric oxide bioactivity by protecting nitric oxide from O 2 ⅐Ϫ in the vascular extracellular space, especially in pathological states, such as atherosclerosis and hypertension where O 2 ⅐Ϫ is increased. 2,6 The ecSOD is a secretory tetrameric glycoprotein with a heparin-binding domain. 7 The protein is composed of an N-terminal signal peptide, which permits secretion from cell, an N-linked glycosylation site at Asn-89, which contributes to the solubility of the enzyme, an active site that binds...

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“…91 Compared with Mn 2ϩ , DTT is a more potent integrin activator and is normally irreversible. 92 This too has become widely used as a positive control for the highest level of integrin activation and as a way of rescuing integrin activation exogenously.…”

Section: Re-creation Of Integrin Activation With Rgd Peptides or Redumentioning

confidence: 99%

Reconstruction of integrin activation

Kim

Ginsberg

2012

Blood

104

108

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IntroductionWhat I cannot create, I do not understand. Richard Feynman Regulation of cell adhesion through cell-matrix or cell-cell interaction is a critical step in various physiologic processes, such as cell migration and anchoring during development of the blood-forming organs, recruitment of cells into sites of inflammation, and aggregation and adhesion of platelets. Integrins are cell surface receptors composed of type I heterodimeric transmembrane proteins, formed by a combination of 18 ␣-subunits and 8 ␤-subunits. Twenty-four integrins have been identified so far. 1 In blood cells, integrins are usually in a resting (inactive) state with low affinity for their ligands; they can quickly switch to an activated, high-affinity state in response to agonists, such as proteases or adenine nucleotides, a process often referred to as inside-out activation or inside-out signaling. [1][2][3][4][5] Disruption of integrin function causes several hematologic diseases. For example, loss of integrin-␣IIb␤3 (GPIIb-IIIa), the most abundant platelet integrin, causes Glanzmann thrombasthenia, a hereditary hemorrhagic disorder. [6][7][8][9] In the early 1990s, investigators also identified Glanzmann thrombasthenia patients whose platelet ␣IIb␤3, although expressed in normal amount, cannot be activated by agonists because of mutations in the ␤3 cytoplasmic domain. 10,11 These mutations, although not fully explained until the recent understanding of talin and kindlin function in integrin regulation, provided important early insight indicating that integrins were regulated from inside-out (reviewed in the last section).Similarly, a subset of integrins, such as ␤2-integrins and ␣4-integrins, are expressed in leukocytes and mediate their adhesion to endothelium during various stages of extravasation during inflammatory responses. Loss of integrin-␤2 (CD18) expression causes leukocyte adhesion deficiency I (LAD I), a disease characterized by recurrent infections. 12 Certain patients with LAD symptoms have normal levels of ␤2-integrins combined with a bleeding diathesis. These patients' leukocytes are defective in ␤2-and ␤1-integrin activation, whereas their platelets also exhibit defects in activation of ␣IIb␤3; this variant is termed LAD III, or Lad1v. [13][14][15][16] The defective integrin activation in these LAD patients is caused by kindlin-3 mutations. [13][14][15]17 Some groups have also suggested the name of integrin activation deficiency disease for these conditions. 14 Furthermore, Kindler syndrome, a skin blistering disease, is the result of defective ␤1-integrin activation caused by kindlin-1 mutations. 18,19 As proteins involved in multiple biologic processes and located at the cell surface, integrins are also readily accessible therapeutic targets. For example, inhibitors of integrin-␣IIb␤3 are currently used in the prevention and treatment of arterial thrombosis in the acute settings of percutaneous coronary intervention. 20 Other integrin-blocking agents against ␣4 are currently used for multiple sclerosis and Croh...

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Redox Control of Integrin Adhesion Receptors

Cited by 11 publications

References 9 publications

In vitro and in vivo evidence for shear-induced activation of latent transforming growth factor-β1

In vitro and in vivo evidence for shear-induced activation of latent transforming growth factor-β1

Fibulin-5 Is a Novel Binding Protein for Extracellular Superoxide Dismutase

Reconstruction of integrin activation

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