Integrin activation

Banno, Asoka; Ginsberg, Mark H.

doi:10.1042/bst0360229

Cited by 126 publications

(120 citation statements)

References 63 publications

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“…PMA was used to stimulate integrin activation, which mimics the physiological integrin inside-out activation cascade (Banno and Ginsberg, 2008). We did not detect PMAinduced PAC-1 binding to WT a IIb b 3 (data not shown).…”

Section: The A-integrin Ct MD Region Is Required For Kindlin-induced mentioning

confidence: 88%

The dual structural roles of the membrane distal region of α integrin cytoplasmic tail in integrin inside-out activation

Liu¹,

Wang²,

Thinn³

et al. 2015

Journal of Cell Science

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BSTRACTStudies on the mechanism of integrin inside-out activation have been focused on the role of b-integrin cytoplasmic tails, which are relatively conserved and bear binding sites for the intracellular activators including talin and kindlin. Cytoplasmic tails for a-integrins share a conserved GFFKR motif at the membrane-proximal region and this forms a specific interface with the b-integrin membraneproximal region to keep the integrin inactive. The a-integrin membrane-distal regions, after the GFFKR motif, are diverse both in length and sequence and their roles in integrin activation have not been well-defined. In this study, we report that the a-integrin cytoplasmic membrane-distal region contributes to maintaining integrin in the resting state and to integrin inside-out activation.Complete deletion of the a-integrin membrane-distal region diminished talin-and kindlin-mediated integrin ligand binding and conformational change. A proper length and suitable amino acids in a-integrin membrane-distal region was found to be important for integrin inside-out activation. Our data establish an essential role for the a-integrin cytoplasmic membrane-distal region in integrin activation and provide new insights into how talin and kindlin induce the high-affinity integrin conformation that is required for fully functional integrins.

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Section: The A-integrin Ct MD Region Is Required For Kindlin-induced mentioning

confidence: 88%

The dual structural roles of the membrane distal region of α integrin cytoplasmic tail in integrin inside-out activation

Liu¹,

Wang²,

Thinn³

et al. 2015

Journal of Cell Science

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“…Many integrins are expressed in a low-affinity binding state, which can be transformed to a high-affinity form upon cellular activation. 21 We hypothesized that inside-out regulation could contribute to immune complex binding to Fc␥R occupied by IgG. Indeed, several studies support intracellular proteins interacting with Fc␥RI and possibly affecting ligand binding.…”

Section: Introductionmentioning

confidence: 99%

Cytokine-induced immune complex binding to the high-affinity IgG receptor, FcγRI, in the presence of monomeric IgG

Poel

Karssemeijer

Boross

et al. 2010

Blood

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IntroductionFc receptors are receptors for immunoglobulins that play a central role in immunity. On human leukocytes, a myriad of Fc␥ receptors are expressed; among these receptors, Fc␥RI is the only known high-affinity receptor for immunoglobulin G (IgG). 1 Fc␥RI is constitutively expressed on monocytes, macrophages, and myeloid dendritic cells. Interferon␥ (IFN␥) can enhance surface expression of Fc␥RI on these cells, and Fc␥RI expression can be induced on granulocytes by IFN␥ or granulocyte colony-stimulating factor (G-CSF) stimulation. In contrast, cytokines such as interleukin-4 (IL-4), IL-10, and transforming growth factor-␤ (TGF-␤) downregulate activating Fc receptors, including Fc␥RI, and enhance expression of the inhibitory receptor Fc␥RIIb. 2,3 In vitro, IFN␥ treatment leads to increased Fc␥ receptor-induced cytokine production. 4 In vivo, the role of Fc␥RI in immunity remains unclear, as due to its high affinity Fc␥RI is believed to be saturated with monomeric IgG. This has led to the concept that prebound monomeric IgG prevents participation of Fc␥RI in clearing immune complexes by extravasated effector cells. 5 Nevertheless, several in vivo studies documented a role for Fc␥RI, varying from a contribution during inflammation and autoimmune reactions, 6-8 or, during monoclonal antibody (mAb)-based immunotherapy in melanoma and B-cell lymphoma models, 9,10 to a malaria model in which transgenic expression of human Fc␥RI was central for effective mAb treatment. 11 Furthermore, Fc␥RI can induce potent proinflammatory signaling compared with Fc␥RIIa, 12 and can efficiently mediate both major histocompatibility complex class II (MHC-II) antigen presentation and cross-presentation. [13][14][15][16] It remains unclear how Fc␥RI contributes to immune complex clearance in the presence of high IgG levels. For Fc␣RI 17,18 and Fc␥RIIa 19,20 it has been shown that cytokine stimulation can increase ligand binding of these receptors. This appears analogous to inside-out regulation described for integrins. Many integrins are expressed in a low-affinity binding state, which can be transformed to a high-affinity form upon cellular activation. 21 We hypothesized that inside-out regulation could contribute to immune complex binding to Fc␥R occupied by IgG. Indeed, several studies support intracellular proteins interacting with Fc␥RI and possibly affecting ligand binding. 22,23 In this study, we investigated the effect of cytokine stimulation on Fc␥RI ligand binding. Stimulation of Fc␥RI-expressing Ba/F3 cells and primary monocytes resulted in increased binding of immune complexes, whereas binding of monomeric IgG was only moderately enhanced. Upon cellular activation, Fc␥RI could readily bind immune complexes despite pre-engaged monomeric IgG. Taken together, these data might explain how Fc␥RI supports leukocyte interaction with immune complexes. Methods Antibodies and reagentsAnti-Fc␥RI-A647 was from BioLegend (clone 10.1). Unlabeled 10.1 mAb and mouse IgG1/IgG2a isotype were from eBioscience and BD Pharmingen, respect...

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“…The ability of talin to interact with integrins is itself regulated as the FERM domain is autoinhibited by binding to its C-terminal tail in an intra-or intermolecular manner (2,3,7,8). Autoinhibition of talin can be removed by the Rap1 effector Rap1-GTP-interacting adaptor molecule in response to extracellular cues (9). Experimentally, the autoinhibition can be removed by expressing the talin head (or FERM) domain in the absence of the inhibitory tail.…”

mentioning

confidence: 99%

Integrin αIIbβ3 Activation in Chinese Hamster Ovary Cells and Platelets Increases Clustering Rather than Affinity

Bunch¹

2010

Journal of Biological Chemistry

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Integrin ␣IIb␤3 affinity regulation by talin binding to the cytoplasmic tail of ␤3 is a generally accepted model for explaining activation of this integrin in Chinese hamster ovary cells and human platelets. Most of the evidence for this model comes from the use of multivalent ligands. This raises the possibility that the activation being measured is that of increased clustering of the integrin rather than affinity. Using a newly developed assay that probes integrins on the surface of cells with only monovalent ligands prior to fixation, I do not find increases in affinity of ␣IIb␤3 integrins by talin head fragments in Chinese hamster ovary cells, nor do I observe affinity increases in human platelets stimulated with thrombin. Binding to a multivalent ligand does increase in both of these cases. This assay does report affinity increases induced by either Mn 2؉ , a cytoplasmic domain mutant (D723R) in the cytoplasmic domain of ␤3, or preincubation with a peptide ligand. These results reconcile the previously observed differences between talin effects on integrin activation in Drosophila and vertebrate systems and suggest new models for talin regulation of integrin activity in human platelets.Integrins are adhesive heterodimeric transmembrane proteins that bind to extracellular matrix ligands or to cell surface proteins on adjacent cells. The cytoplasmic tails of the integrins are linked directly, or via adaptors, to numerous cytoskeletal and signaling proteins and transmit signals from the outside of the cell to the inside. The adhesive properties of integrins are dynamically regulated as these receptors shift between different conformations upon binding to extracellular ligands or cytoplasmic proteins. Thus, integrins are present in high or low affinity states on the surface of cells depending on the cellular environment. Regulation of integrin activation is critical in controlling cell adhesion, migration, and extracellular matrix assembly. This regulation is therefore important in normal development, hemostasis, inflammation, angiogenesis, tumor cell metastasis, and immune responses (1-4).Talin is one of the most intensively studied cytoplasmic activators of integrin activity (5, 6). The N-terminal globular head region of talin contains a FERM 2 (band four-point-one, ezrin, radixin, moesin homology) domain that has the ability to bind to ␤3 integrin cytoplasmic tails, and this results in the activation of ␣IIb␤3 integrins. The ability of talin to interact with integrins is itself regulated as the FERM domain is autoinhibited by binding to its C-terminal tail in an intra-or intermolecular manner (2,3,7,8). Autoinhibition of talin can be removed by the Rap1 effector Rap1-GTP-interacting adaptor molecule in response to extracellular cues (9). Experimentally, the autoinhibition can be removed by expressing the talin head (or FERM) domain in the absence of the inhibitory tail. Overexpression of the talin head or FERM domain activates the ␤3 and ␤1 integrins, and inhibition of talin expression reduces integrin activ...

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Integrin activation

Cited by 126 publications

References 63 publications

The dual structural roles of the membrane distal region of α integrin cytoplasmic tail in integrin inside-out activation

The dual structural roles of the membrane distal region of α integrin cytoplasmic tail in integrin inside-out activation

Cytokine-induced immune complex binding to the high-affinity IgG receptor, FcγRI, in the presence of monomeric IgG

Integrin αIIbβ3 Activation in Chinese Hamster Ovary Cells and Platelets Increases Clustering Rather than Affinity

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