Suppression of integrin activation by the membrane-distal sequence of the integrin alphaIIb cytoplasmic tail

Yamanouchi, Jun; Hato, Takaaki; Tamura, T.; Fujita, Shigeru

doi:10.1042/bj20031753

Cited by 10 publications

(11 citation statements)

References 44 publications

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“…The latter results are consistent with NMR studies that showed minimal effects of the PP mutations on the membrane proximal clasp [30]. However, other mutational studies [41], as well as independent approaches, do suggest a role of the C‐terminus of α IIb CT in α IIb β 3 activation [30,42]. Clearly, further investigation is needed.…”

Section: Changes In the Cytoplasmic Tail (Ct) Domainsupporting

confidence: 82%

Platelet integrin αIIbβ3: activation mechanisms

Qin

Plow

2007

Journal of Thrombosis and Haemostasis

177

160

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Summary. Integrin αIIbβ3 plays a critical role in platelet aggregation, a central response in hemostasis and thrombosis. This function of αIIbβ3 depends upon a transition from a resting to an activated state such that it acquires the capacity to bind soluble ligands. Diverse platelet agonists alter the cytoplasmic domain of αIIbβ3 and initiate a conformational change that traverses the transmembrane region and ultimately triggers rearrangements in the extracellular domain to permit ligand binding. The membrane‐proximal regions of αIIb and β3 cytoplasmic tails, together with the transmembrane segments of the subunits, contact each other to form a complex which restrains the integrin in the resting state. It is unclasping of this complex that induces integrin activation. This clasping/unclasping process is influenced by multiple cytoplasmic tail binding partners. Among them, talin appears to be a critical trigger of αIIbβ3 activation, but other binding partners, which function as activators or suppressors, are likely to act as co‐regulators of integrin activation.

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Section: Changes In the Cytoplasmic Tail (Ct) Domainsupporting

confidence: 82%

Platelet integrin αIIbβ3: activation mechanisms

Qin

Plow

2007

Journal of Thrombosis and Haemostasis

177

160

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“…Monoclonal Antibodies and Plasmids-PAC1, a monoclonal antibody specifically recognizing the active conformation of ␣IIb␤3, was a generous gift from Dr. S. J. Shattil (University of California, San Diego). 4 B10 is a non-function-blocking anti-␣IIb␤3 complex-specific monoclonal antibody produced in our laboratory (15,25). AP3, a non-function-blocking anti-␤3 monoclonal antibody, was obtained from GTI, Brookfield, WI.…”

Section: Methodsmentioning

confidence: 99%

“…A lipid-modified peptide containing the membrane-distal sequence (RPPLEED) inhibits agonist-induced ␣IIb␤3 activation (13). Mutation of the ␣IIb RPP distal sequence activates ␣IIb␤3 in a metabolic energy-dependent manner (14,15). These findings suggest that the membrane-distal region of the ␣IIb tail suppresses energy-dependent ␣IIb␤3 activation, although the mechanism responsible for activation of the ␣IIb␤3 mutants remains unclear.…”

mentioning

confidence: 99%

Cooperative Role of the Membrane-proximal and -distal Residues of the Integrin β3 Cytoplasmic Domain in Regulation of Talin-mediated αIIbβ3 Activation

Hato

Yamanouchi

Tamura

et al. 2008

Journal of Biological Chemistry

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Integrin cytoplasmic tails regulate integrin activation that is required for high affinity binding with ligands. The interaction of the integrin beta subunit tail with a cytoplasmic protein, talin, largely contributes to integrin activation. Here we report the cooperative interaction of the beta3 membrane-proximal and -distal residues in regulation of talin-mediated alpha IIb beta3 activation. Because a chimeric integrin, alpha IIb beta3/beta1, in which the beta3 tail was replaced with the beta1 tail was constitutively active, we searched for the residues responsible for integrin activation among the residues that differed between the beta3 and beta1 tails. Single amino acid substitutions of Ile-719 and Glu-749 in the beta3 membrane-proximal and -distal regions, respectively, with the corresponding beta1 residues or alanine rendered alphaIIbbeta3 constitutively active. The I719M/E749S double mutant had the same ligand binding activity as alpha IIb beta3/beta1. These beta3 mutations also induced alphaVbeta3 activation. Conversely, substitution of Met-719 or Ser-749 in the beta1 tail with the corresponding beta3 tail residue (M719I or S749E) inhibited alpha IIb beta3/beta1 activation, and the M719I/S749E double mutant inhibited ligand binding to a level comparable with that of the wild-type alpha IIb beta3. Knock down of talin by short hairpin RNA inhibited the I719M- and E749S-induced alpha IIb beta3 activation. These results suggest that the beta3 membrane-proximal and -distal residues cooperatively regulate talin-mediated alpha IIb beta3 activation.

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“…However, the molecular mechanisms of integrin αvβ3 affinity regulation have been hampered by the lack of a suitable model in cultured cells convenient for adhesion assay. It has been reported that the binding of αvβ3 to VN is regulated [27,28] ; however, the measurement of the alternation of the adhesion affinity of the αvβ3 expressing cells to VN has proven to be difficult.…”

Section: Introductionmentioning

confidence: 99%

Fibrinogen interaction of CHO cells expressing chimeric αIIb/αvβ3 integrin

Chen

et al. 2008

Acta Pharmacologica Sinica

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Aim: The molecular mechanisms of the affinity regulation of αvβ3 integrin are important in tumor development, wound repairing, and angiogenesis. It has been established that the cytoplasmic domains of αvβ3 integrin play an important role in integrin‐ligand affinity regulation. However, the relationship of structure‐function within these domains remains unclear. Methods: The extracellular and transmembrane domain of αIIb was fused to the αv integrin cytoplasmic domain, and the chimeric α subunit was coexpressed in Chinese hamster ovary (CHO) cells with the wild‐type β3 subunit or with 3 mutant β3 sequences bearing truncations at the positions of T741, Y747, and F754, respectively. The CHO cells expressing these recombinant integrins were tested for soluble fibrinogen binding and the cell adhesion and spreading on immobilized fibrinogen. Results: All 4 types of integrins bound soluble fibrinogen in the absence of agonist stimulation, and only the cells expressing the chimeric α subunit with the wild‐type β3 subunit, but not those with truncated β3, could adhere to and spread on immobilized fibrinogen. Conclusion: The substitution αIIb at the cytoplasmic domain with the αv cyto‐plasmic sequence rendered the extracellular αIIbβ3 a constitutively activated conformation for ligands without the need of “inside‐out” signals. Our results also indicated that the COOH‐terminal sequence of β3 might play a key role in integrin αIIb/αvβ3‐mediated cell adhesion and spreading on immobilized fibrinogen. The cells expressing αIIb/αvβ3 have enormous potential for facilitating drug screening for antagonists either to αvβ3 intracellular interactions or to αIIbβ3 receptor functions.

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Suppression of integrin activation by the membrane-distal sequence of the integrin alphaIIb cytoplasmic tail

Cited by 10 publications

References 44 publications

Platelet integrin αIIbβ3: activation mechanisms

Platelet integrin αIIbβ3: activation mechanisms

Cooperative Role of the Membrane-proximal and -distal Residues of the Integrin β3 Cytoplasmic Domain in Regulation of Talin-mediated αIIbβ3 Activation

Fibrinogen interaction of CHO cells expressing chimeric αIIb/αvβ3 integrin

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