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Directly Activating the Integrin ?IIb?3 Initiates Outside-In Signaling by Causing ?IIb?3 Clustering.

ABSTRACT: ?IIb?3 activation in platelets is followed by activation of the tyrosine kinase c-Src associated with the carboxyl terminus of the ?3 cytosolic tail. Exogenous peptides designed to interact with the ?IIb transmembrane (TM) domain activate single ?IIb?3 molecules in platelets by binding to the ?IIb TM domain and causing separation of the ?IIb?3 TM domain heterodimer. Here we asked whether directly activating single ?IIb?3 molecules in platelets using the designed peptide anti-?IIb TM also initiates ?IIb?3-mediated outside-in signaling by causing activation of ?3-associated c-Src. Anti-?IIb TM caused activation of ?3-associated c-Src and the kinase Syk, but not the kinase FAK, under conditions that precluded extracellular ligand binding to ?IIb?3. c-Src and Syk are activated by trans-autophosphorylation, suggesting that activation of individual ?IIb?3 molecules can initiate ?IIb?3 clustering in the absence of ligand binding. Consistent with this possibility, incubating platelets with anti-?IIb TM resulted in the redistribution of ?IIb?3 from a homogenous ring located at the periphery of discoid platelets into nodular densities consistent with clustered ?IIb?3. Thus, these studies indicate that not only is resting ?IIb?3 poised to undergo a conformational change that exposes its ligand-binding site, but it is poised to rapidly assemble into intracellular signal-generating complexes as well.

SUBMITTER: Fong KP

PROVIDER: S-EPMC4882439 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Directly Activating the Integrin αIIbβ3 Initiates Outside-In Signaling by Causing αIIbβ3 Clustering.

Fong Karen P KP Zhu Hua H Span Lisa M LM Moore David T DT Yoon Kyungchul K Tamura Ryo R Yin Hang H DeGrado William F WF Bennett Joel S JS

The Journal of biological chemistry 20160407 22

αIIbβ3 activation in platelets is followed by activation of the tyrosine kinase c-Src associated with the carboxyl terminus of the β3 cytosolic tail. Exogenous peptides designed to interact with the αIIb transmembrane (TM) domain activate single αIIbβ3 molecules in platelets by binding to the αIIb TM domain and causing separation of the αIIbβ3 TM domain heterodimer. Here we asked whether directly activating single αIIbβ3 molecules in platelets using the designed peptide anti-αIIb TM also initiat ...[more]

PMID: 27056329

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Directly Activating the Integrin ?IIb?3 Initiates Outside-In Signaling by Causing ?IIb?3 Clustering.

Publications

Directly Activating the Integrin αIIbβ3 Initiates Outside-In Signaling by Causing αIIbβ3 Clustering.

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