251. Pro-inflammatory Secretory Phospholipase A2 Type IIA Binds to Integrins αvβ3 and α4β1 and Induces Proliferation of Monocytic Cells in an Integrin-dependent Manner.
- Author
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Jun Saegusa, kakura, Nobuaki, Chun-Yi Wu, Hoogland, Case, Zi Ma, Lam, Kit S., Fu-Tong Liu, Takada, Yoko K., and Takada, Yoshikazu
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PHOSPHOLIPASES , *CARCINOGENESIS , *ARACHIDONIC acid , *MUTAGENESIS , *INTEGRINS , *NODULAR fasciitis - Abstract
Secretory phospholipase A2 group IIA (sPLA2-IIA) plays an important role in the pathogenesis of inflammatory diseases. Catalytic activity of this enzyme that generates arachidonic acid is a major target for development of anti-inflammatory agents. Independent of its catalytic activity, sPLA2-IIA induces pro-inflammatory signals in a receptor-mediated mechanism (e.g. through the M-type receptor). However, the M-type receptor is species-specific: sPLA2-IIA binds to the M-type receptor in rodents and rabbits, but not in human. Thus sPLA2-IIA receptors in human have not been established. Here we demonstrated that sPLA2-IIA bound to integrin αvβ3 at a high affinity (KD = 2 × 10-7 M). We identified amino acid residues in sPLA2-IIA (Arg-74 and Arg-100) that are critical for integrin binding using docking simulation and mutagenesis. The integrin-binding site did not include the catalytic center or the M-type receptor-binding site. sPLA2-IIA also bound to α4β1. We showed that sPLA2- IIA competed with VCAM-1 for binding to α4β1, and bound to a site close to those for VCAM-1 and CS-1 in the α4 subunit. Wild type and the catalytically inactive H47Q mutant of sPLA2- IIA induced cell proliferation and ERK1/2 activation in monocytic cells, but the integrin binding-defective R74E/R100E mutant did not. This indicates that integrin binding is required, but catalytic activity is not required, for sPLA2-IIA-induced proliferative signaling. These results suggest that integrins αvβ3 and α4β1 may serve as receptors for sPLA2-IIA and mediate pro-inflammatory action of sPLA2-IIA, and that integrin-sPLA2- IIA interaction is a novel therapeutic target. [ABSTRACT FROM AUTHOR]
- Published
- 2008
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