Pro-inflammatory sPLA-IIA induces integrin activation through direct binding to a newly identified binding-site (site 2) in integrins {alpha}v{beta}3, {alpha}4{beta}1, and {alpha}5{beta}1. [Cell Biology]

November 14th, 2014 by Fujita, M., Zhu, K., Fujita, C. K., Zhao, M., Lam, K. S., Kurth, M. J., Takada, Y. K., Takada, Y.

Integrins are activated by signaling from inside the cell (inside-out signaling) through global conformational changes of integrins. We recently discovered that fractalkine activates integrins in the absence of CX3CR1 through the direct binding of fractalkine to a ligand-binding site in the integrin headpiece (site 2) that is distinct from the classical RGD-binding site (site 1). We propose that fractalkine binding to the newly identified site 2 induces activation of site 1 though conformational changes (in an allosteric mechanism). We reasoned that site 2-mediated activation of integrins is not limited to fractalkine. Human secreted phospholipase A2 type IIA (sPLA2-IIA), a pro-inflammatory protein, binds to integrins αvβ3 and α4β1 (site 1) and this interaction initiates a signaling pathway that leads to cell proliferation and inflammation. Human sPLA2-IIA does not bind to M-type receptor very well. Here we describe that sPLA2-IIA directly activated purified soluble integrin αvβ3 and transmembrane αvβ3 on the cell surface. This activation did not require catalytic activity or M-type receptor. Docking simulation predicted that sPLA2-IIA binds to site 2 in the closed-headpiece of αvβ3. A peptide from site 2 of integrin β1 specifically bound to sPLA2-IIA and suppressed sPLA2-IIA-induced integrin activation. This suggests that sPLA2-IIA activates αvβ3 through binding to site 2. sPLA2-IIA also activated integrins α4β1 and α5β1 in a site 2-mediated manner. We recently identified small compounds that bind to sPLA2-IIA and suppress integrin-sPLA2-IIA interaction (e.g., Cmpd21). Cmpd21 effectively suppressed sPLA2-IIA-induced integrin activation. These results define a novel mechanism of pro-inflammatory action of sPLA2-IIA through integrin activation.
  • Posted in Journal of Biological Chemistry, Publications
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