Integrin activation by talin

Ratnikov, Boris I.; Partridge, Anthony W.; Ginsberg, Mark H.

doi:10.1111/j.1538-7836.2005.01362.x

Cited by 65 publications

(49 citation statements)

References 96 publications

(134 reference statements)

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“…This interaction is further supported by the fact that Talin1 contains LIM and actin binding domains. 42,43 Talin is a major cytoskeletal protein that colocalizes with activated cytoplasmic domains of ␤-integrins 44 and links them to the intracellular actin cytoskeleton. Several binding partners for Talin have been described; these include integrins, focal adhesion kinase, and F-actin.…”

Section: Discussionmentioning

confidence: 99%

Fhl-1, a New Key Protein in Pulmonary Hypertension

et al. 2008

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Background-Pulmonary hypertension (PH) is a severe disease with a poor prognosis. Different forms of PH are characterized by pronounced vascular remodeling, resulting in increased vascular resistance and subsequent right heart failure. The molecular pathways triggering the remodeling process are poorly understood. We hypothesized that underlying key factors can be identified at the onset of the disease. Thus, we screened for alterations to protein expression in lung tissue at the onset of PH in a mouse model of hypoxia-induced PH. Methods and Results-Using 2-dimensional polyacrylamide gel electrophoresis in combination with matrix-assisted laser desorption/ionization time-of-flight analysis, we identified 36 proteins that exhibited significantly altered expression after short-term hypoxic exposure. Among these, Fhl-1, which is known to be involved in muscle development, was one of the most prominently upregulated proteins. Further analysis by immunohistochemistry, Western blot, and laser-assisted microdissection followed by quantitative polymerase chain reaction confirmed the upregulation of Fhl-1, particularly in the pulmonary vasculature. Comparable upregulation was confirmed (1) after full establishment of hypoxia-induced PH, (2) in 2 rat models of PH (monocrotaline-treated and hypoxic rats treated with the vascular endothelial growth factor receptor antagonist SU5416), and (3) in lungs from patients with idiopathic pulmonary arterial hypertension. Furthermore, we demonstrated that regulation of Fhl-1 was hypoxia-inducible transcription factor dependent. Abrogation of Fhl-1 expression in primary human pulmonary artery smooth muscle cells by small-interfering RNA suppressed, whereas Fhl-1 overexpression increased, migration and proliferation. Coimmunoprecipitation experiments identified Talin1 as a new interacting partner of Fhl-1. Conclusions-Protein screening identified Fhl-1 as a novel protein regulated in various forms of PH, including idiopathic pulmonary arterial hypertension.

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Section: Discussionmentioning

confidence: 99%

Fhl-1, a New Key Protein in Pulmonary Hypertension

et al. 2008

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“…Previous studies showed that talin is also crucial in regulating integrin signaling. The NH 2 -terminal globular head domain of talin is responsible for promoting integrin activation and clustering (4,10,44,56). Since force-induced exposure of vinculin-binding sites on talin through a conformational change leads to the reinforcement of the focal adhesions, talin is also considered as a key mechanotransduced molecule in focal adhesions (5,20,28,35).…”

Section: Discussionmentioning

confidence: 99%

“…Among numerous focal adhesion complex proteins, FAK is a key regulator (26). It transmits information from integrin to the various signaling pathways, including those that regulate cellular events such as cell shape, migration, growth, differentiation, and apoptosis (22,23,44,52). FAK is a 125-kDa cytoplasmic tyrosine kinase and is autophosphorylated at Tyr397 immediately after integrin clustering.…”

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confidence: 99%

Mechanosensing machinery for cells under low substratum rigidity

Wei¹,

Lin²,

Shen³

et al. 2008

American Journal of Physiology-Cell Physiology

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Wei WC, Lin HH, Shen MR, Tang MJ. Mechanosensing machinery for cells under low substratum rigidity. Am J Physiol Cell Physiol 295: C1579 -C1589, 2008. First published October 15, 2008 doi:10.1152/ajpcell.00223.2008.-Mechanical stimuli are essential during development and tumorigenesis. However, how cells sense their physical environment under low rigidity is still unknown. Here we show that low rigidity of collagen gel downregulates ␤ 1 -integrin activation, clustering, and focal adhesion kinase (FAK) Y397 phosphorylation, which is mediated by delayed raft formation. Moreover, overexpression of autoclustered ␤ 1-integrin (V737N), but not constitutively active ␤ 1-integrin (G429N), rescues FAKY397 phosphorylation level suppressed by low substratum rigidity. Using fluorescence resonance energy transfer to assess ␤ 1-integrin clustering, we have found that substratum rigidity between 58 and 386 Pa triggers ␤ 1-integrin clustering in a dose-dependent manner, which is highly dependent on actin filaments but not microtubules. Furthermore, augmentation of ␤ 1-integrin clustering enhances the interaction between ␤ 1-integrin, FAK, and talin. Our results indicate that contact with collagen fibrils is not sufficient for integrin activation. However, substratum rigidity is required for integrin clustering and activation. Together, our findings provide new insight into the mechanosensing machinery and the mode of action for epithelial cells in response to their physical environment under low rigidity.focal adhesion kinase; ␤ 1-integrin activation; ␤1-integrin clustering; lipid raft; actin cytoskeleton EXTRACELLULAR MATRIX (ECM) has an active and complex role in regulating the behavior of the cells that contact it, influencing their survival, adhesion, spreading, migration, proliferation, apoptosis, and differentiation (32). The major receptors of ECM are integrins, which are transmembrane receptors composed of two subunits, ␣ and ␤, that form connections between the cytoskeleton and ECM. Each ␣␤ heterodimer has its own binding and signal specificity (25). The initiation of integrinmediated activities involves two steps, namely, integrin activation and clustering. Integrins are locked in the inactive form without stimulation of extracellular ligands. After binding to its ligand with the extracellular domain (outside-in) (19) or stimulation by intracellular signals (inside-out) (38), an integrin is activated and its extracellular domain undergoes conformational changes, which lead to exposure of several ligandinduced binding sites (LIBS) (49). In addition to conformation changes, ligand binding also induces elevation of lateral mobility and clustering of integrins in the plasma membrane (31). Both ligand binding and clustering of integrins are critically important to activate intracellular signals. However, the regulatory mechanisms of controlling integrin activation and clustering are still unclear.Activation of integrin leads to the recruitment and organization of a number of different cytoskeletal proteins (␣-actinin, tal...

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“…For instance, the binding of the cytoskeletal protein talin-1 to the cytoplasmic domain of ␤ 3 -integrin was shown to be required for activation of the ␣ IIb ␤ 3 integrin. 21 Moreover, changing a single amino acid in the cytoplasmic domain of ␤ 3 -integrin selectively disrupted talin-1 binding and reduced arterial thrombosis in an animal model 22 showing that blockade of this interaction could be a new antithrombotic strategy. Interestingly, most of the proteins identified in the present study are interconnected in a common network that primarily involves cytoskeletal and signaling proteins, processes closely related to platelet activation.…”

Section: Signaling Pathways As Possible Future Targets For Antiplatelmentioning

confidence: 99%

Variations in Platelet Proteins Associated With ST-Elevation Myocardial Infarction

Parguiña

Grigorian-Shamagian

Agra

et al. 2011

ATVB

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Objective-Our aim in this study was to provide novel information on the molecular mechanisms playing a major role in the unwanted platelet activation associated with ST-elevation myocardial infarction (STEMI). Methods and Results-We compared the platelet proteome of 11 STEMI patients to a matched control group of 15 stable chronic ischemic cardiopathy patients. In addition, we did a prospective study to follow the STEMI patients over time.Proteins were separated by high-resolution 2D gel electrophoresis, identified by mass spectrometry, and validated by Western blotting. Platelets from STEMI patients on admission displayed 56 protein spot differences (corresponding to 42 unique genes) compared with the control group. The number of differences decreased with time during the patients' follow-up. Interestingly, the adapter protein CrkL and the active form of Src (phosphorylated in Tyr418) were found to be upregulated in platelets from STEMI patients. Major signaling pathways related to the proteins identified include integrin, integrin-linked kinase, and glycoprotein VI (GPVI) signaling. Interestingly, a study on an independent cohort of patients showed a higher degree of activation of GPVI signaling in STEMI patients. Conclusion-CrkL, the active form of Src, and GPVI signaling are upregulated in platelets from STEMI patients. Key Words: acute coronary syndromes Ⅲ platelets Ⅲ GPVI signaling Ⅲ proteomics A cute coronary syndromes (ACSs) encompass unstable angina, non-ST segment elevation (NSTE) myocardial infarction, and ST-segment elevation myocardial infarction (STEMI). The latter usually occurs when thrombus forms on a ruptured atheromatous plaque and causes a prolonged occlusion of an epicardial coronary artery. 1 There is no doubt platelets play a fundamental role in the pathogenesis of an ACS, being implicated in the thrombus formation that follows the atheroma plaque rupture. 2 Activated platelets release proteins in the coronary circulation of ACS patients, such as matrix metalloproteinases, that contribute to sustained intracoronary platelet activation. 3 Following an ACS, antiplatelet therapy is recommended to reduce the growth of a thrombus. Primary targets of such therapy are molecules involved in platelet activation and aggregation. Nevertheless, there is a need for the development of a new generation of safer and more effective antithrombotic drugs with larger therapeutic windows and for a better understanding of the pathogenic processes that lead to thrombotic occlusion of blood vessels linked to an acute event. 2 Proteomics has emerged as a promising tool in cardiovascular research, and more precisely in the study of ACSs. 4 Studies have included plasma, monocytes, and, very recently, platelets. [5][6][7][8] The objective of these studies was the identification of novel screening and diagnostic biomarkers that might help to predict the disease and provide novel information on the molecular events associated with it, hopefully leading to the identification of novel drug targets. We have been inv...

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Integrin activation by talin

Cited by 65 publications

References 96 publications

Fhl-1, a New Key Protein in Pulmonary Hypertension

Fhl-1, a New Key Protein in Pulmonary Hypertension

Mechanosensing machinery for cells under low substratum rigidity

Variations in Platelet Proteins Associated With ST-Elevation Myocardial Infarction

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