scholarly journals Novel Linear Peptides with High Affinity to αvβ3 Integrin for Precise Tumor Identification

Theranostics ◽  
2017 ◽  
Vol 7 (6) ◽  
pp. 1511-1523 ◽  
Author(s):  
Yi Ma ◽  
Guanhua Ai ◽  
Congying Zhang ◽  
Menglu Zhao ◽  
Xue Dong ◽  
...  
Keyword(s):  
Αvβ3 Integrin ◽  
High Affinity ◽  
Tumor Identification

GSH-Activated Light-Up Near-Infrared Fluorescent Probe with High Affinity to αvβ3 Integrin for Precise Early Tumor Identification

2018 ◽  
Vol 10 (37) ◽  
pp. 30994-31007 ◽  
Author(s):  
Zhenwei Yuan ◽  
Lijuan Gui ◽  
Jinrong Zheng ◽  
Yisha Chen ◽  
Sisi Qu ◽  
...  
Keyword(s):  
Fluorescent Probe ◽  
Near Infrared ◽  
Αvβ3 Integrin ◽  
High Affinity ◽  
Tumor Identification ◽  
Early Tumor

scholarly journals Transmembrane-truncated αvβ3 integrin retains high affinity for ligand binding: evidence for an ‘inside-out’ suppressor?

1998 ◽  
Vol 330 (2) ◽  
pp. 861-869 ◽  
Author(s):  
J. Raj MEHTA ◽  
Beate DIEFENBACH ◽  
Alex BROWN ◽  
Eilish CULLEN ◽  
Alfred JONCZYK ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Wound Repair ◽  
Molecular Mechanisms ◽  
Full Length ◽  
Αvβ3 Integrin ◽  
Cytoplasmic Domains ◽  
Bivalent Cation ◽  
High Affinity ◽  
Cellular Environment

The molecular mechanisms of αvβ3 integrin affinity regulation have important biological implications in tumour development, wound repair and angiogenesis. We expressed, purified and characterized recombinant forms of human αvβ3 (r-αvβ3) and compared the activation state of these with αvβ3 in its cellular environment. The ligand specificity and selectivity of recombinant full-length and double transmembrane truncations of r-αvβ3 cloned in BacPAK6 vectors and expressed in Sf9 and High Five insect cells were compared with those of native placental αvβ3 and the receptor in situ on the cell surface. r-αvβ3 integrins were purified by affinity chromatography from detergent extracts of cells (full-length), and from the culture medium of cells expressing double-truncated r-αvβ3. r-αvβ3 had the same epitopes, ligand-binding specificities, bivalent cation requirements and susceptibility to RGD-containing peptides as native αvβ3. On M21-L4 melanoma cells, αvβ3 mediated binding to vitronectin, but not to fibrinogen unless activated with Mn2+. Non-activated αIIbβ3 integrin as control in M21-L-IIb cells had the opposite profile, mediating binding to fibrinogen, but not to vitronectin unless activated with Mn2+. Thus these receptors had moderate to low ligand affinity. In marked contrast, purified αvβ3 receptors, with or without transmembrane and cytoplasmic domains, were constitutively of high affinity and able to bind strongly to vitronectin, fibronectin and fibrinogen under physiological conditions. Our data suggest that, in contrast with the positive regulation of αIIbβ3 in situ, intracellular controls lower the affinity of αvβ3, and the cytoplasmic domains may act as a target for negative regulators of αvβ3 activity.

scholarly journals Adhesion Molecules in Melanoma—More than Just Superglue?

1996 ◽  
Vol 89 (7) ◽  
pp. 393-395 ◽  
Author(s):  
MD Mason ◽  
R Allman ◽  
M Quibell
Keyword(s):  
Signal Transduction ◽  
Cyclic Peptide ◽  
Αvβ3 Integrin ◽  
Cell Surface Molecules ◽  
Malignant Cells ◽  
Cell Behaviour ◽  
Surface Molecules ◽  
High Affinity ◽  
Natural Ligands ◽  
Integrin Family

Malignant melanoma is increasing in incidence, and, though early lesions are readily treatable, systemic therapy for metastatic disease remains disappointing. Integrins are a family of cell-surface molecules that mediate adhesion between the cell and the extracellular matrix. One member of the integrin family, the αvβ3 integrin, is associated with progression of melanomas, in that the most malignant cells express the highest levels of αvβ3. Like many members of the integrin family, αvβ3 recognizes the sequence Arg-Gly-Asp (RGD) in its ligands, and other molecules that contain this sequence will compete with the natural ligands (such as vitronectin) for binding. There is growing evidence that integrins function as receptors for signal transduction, and that integrin-mediated signalling can affect cell behaviour and even cell survival. Under certain circumstances, loss of integrin-mediated signalling will induce apoptosis, or programmed cell death, and we have demonstrated that melanoma cells treated with a cyclic peptide with high affinity for the αvβ3 integrin will undergo apoptosis within three days. This mechanism might be exploited therapeutically.

scholarly journals How the headpiece hinge angle is opened: new insights into the dynamics of integrin activation

2006 ◽  
Vol 175 (2) ◽  
pp. 349-360 ◽  
Author(s):  
Eileen Puklin-Faucher ◽  
Mu Gao ◽  
Klaus Schulten ◽  
Viola Vogel
Keyword(s):  
Crystal Structure ◽  
Peptide Ligand ◽  
Αvβ3 Integrin ◽  
Integrin Activation ◽  
Structural Variations ◽  
High Affinity ◽  
Hybrid Domain ◽  
Conformational Constraints ◽  
Allosteric Pathway ◽  
Hinge Angle

How the integrin head transitions to the high-affinity conformation is debated. Although experiments link activation with the opening of the hinge angle between the βA and hybrid domains in the ligand-binding headpiece, this hinge is closed in the liganded αvβ3 integrin crystal structure. We replaced the RGD peptide ligand of this structure with the 10th type III fibronectin module (FnIII10) and discovered through molecular dynamics (MD) equilibrations that when the conformational constraints of the leg domains are lifted, the βA/hybrid hinge opens spontaneously. Together with additional equilibrations on the same nanosecond timescale in which small structural variations impeded hinge-angle opening, these simulations allowed us to identify the allosteric pathway along which ligand-induced strain propagates via elastic distortions of the α1 helix to the βA/hybrid domain hinge. Finally, we show with steered MD how force accelerates hinge-angle opening along the same allosteric pathway. Together with available experimental data, these predictions provide a novel framework for understanding integrin activation.

Manganese-induced integrin affinity maturation promotes recruitment of αVβ3 integrin to focal adhesions in endothelial cells: evidence for a role of phosphatidylinositol 3-kinase and Src

2004 ◽  
Vol 92 (07) ◽  
pp. 151-161 ◽  
Author(s):  
Olivier Dormond ◽  
Lionel Ponsonnet ◽  
Meriem Hasmim ◽  
Alessandro Foletti ◽  
Curzio Rüegg
Keyword(s):  
Focal Adhesions ◽  
Affinity Maturation ◽  
Stress Fiber ◽  
Fiber Formation ◽  
Αvβ3 Integrin ◽  
Actin Stress Fiber ◽  
Phosphatidylinositol 3 Kinase ◽  
High Affinity ◽  
Stress Fiber Formation ◽  
Actin Stress Fiber Formation

SummaryIntegrin activity is controlled by changes in affinity (i.e. ligand binding) and avidity (i.e. receptor clustering). Little is known, however, about the effect of affinity maturation on integrin avidity and on the associated signaling pathways. To study the effect of affinity maturation on integrin avidity, we stimulated human umbilical vein endothelial cells (HUVEC) with MnCl2 to increase integrin affinity and monitored clustering of β1 and β3 integrins. In unstimulated HUVEC, β1 integrins were present in fibrillar adhesions, while αVβ3 was detected in peripheral focal adhesions. Clustered β1 and β3 integrins expressed high affinity/ligand-induced binding site (LIBS) epitopes. MnCl2-stimulation promoted focal adhesion and actin stress fiber formation at the basal surface of the cells, and strongly enhanced mAb LM609 staining and expression of β3 high affinity/LIBS epitopes at focal adhesions. MnCl2-induced αVβ3 clustering was blocked by a soluble RGD peptide, by wortmannin and LY294002, two parmacological inhibitors of phosphatidylinositol 3-kinase (PI 3-K), and by over-expressing a dominant negative PI 3-K mutant protein. Conversely, over-expression of active PI 3-K and pharmacological inhibiton of Src with PP2 and CGP77675, enhanced basal and manganese-induced αVβ3 clustering. Transient increased phosphorylation of protein kinase B/Akt, a direct target of PI 3K, occurred upon manganese stimulation. MnCl2 did not alter β1 integrin distribution or β1 high-affinity/LIBS epitope expression. Based on these results, we conclude that MnCl2-induced αVβ3 integrin affinity maturation stimulates focal adhesion and actin stress fiber formation, and promotes recruitment of high affinity αVβ3 to focal adhesions. Affinity-modulated αVβ3 clustering requires PI3-K signaling and is negatively regulate by Src.

scholarly journals High-Affinity αvβ3 Integrin Targeted Optical Probe as a New Imaging Biomarker for Early Atherosclerosis: Initial Studies in Watanabe Rabbits

2009 ◽  
Vol 12 (1) ◽  
pp. 2-8 ◽  
Author(s):  
Julie Heroux ◽  
Ahmed M. Gharib ◽  
Narasimhan S. Danthi ◽  
Sylvain Cecchini ◽  
Jacques Ohayon ◽  
...  
Keyword(s):  
Optical Probe ◽  
Imaging Biomarker ◽  
Αvβ3 Integrin ◽  
High Affinity ◽  
Early Atherosclerosis
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