Pro-inflammatory secretory phospholipase A2 type IIA binds to integrins αvβ3 and α4β1 and induces proliferation of monocytic cells in an integrin-dependent manner

Jun Saegusa, Nobuaki Akakura, Chun Yi Wu, Case Hoogland, Zi Ma, Kit Lam, Fu-Tong Liu, Yoko K. Takada, Yoshikazu Takada

Research output: Contribution to journalArticle

64 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)26107-26115
Number of pages9
JournalJournal of Biological Chemistry
Volume283
Issue number38
DOIs
StatePublished - Sep 19 2008

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ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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