Binding of autotaxin to integrins localizes lysophosphatidic acid production to platelets and mammalian cells

Zachary Fulkerson, Tao Wu, Manjula Sunkara, Craig Vander Kooi, Andrew J. Morris, Susan S. Smyth

Research output: Contribution to journalArticlepeer-review

123 Scopus citations

Abstract

Autotaxin (ATX) is a secreted lysophospholipase D that generates the bioactive lipid mediator lysophosphatidic acid (LPA). We and others have reported that ATX binds to integrins, but the function of ATX-integrin interactions is unknown. The recently reported crystal structure ofATXsuggests a role for the solvent-exposed surface of the N-terminal tandem somatomedin B-like domains in binding to platelet integrin αIIbβ3. The opposite face of the somatomedin B-like domain interacts with the catalytic phosphodiesterase (PDE) domain to form a hydrophobic channel through which lysophospholipid substrates enter and leave the active site. Based on this structure, we hypothesize that integrin-bound ATX can access cell surface substrates and deliver LPA to cell surface receptors. To test this hypothesis, we investigated the integrin selectivity and signaling pathways that promoteATXbinding to platelets.Wereport that both platelet β1 and β3 integrins interact in an activation-dependent manner with ATX via the SMB2 domain. ATX increases thrombin-stimulated LPA production by washed platelets ~10-fold. When incubated under conditions to promote integrin activation, ATX generates LPA from CHO cells primed with bee venom phospholipase A2, and ATX-mediated LPAproduction is enhanced more than 2-fold byCHOcell overexpression of integrin β3. The effects of ATX on platelet and cell-associatedLPAproduction, but not hydrolysis of small molecule or detergent-solubilized substrates, are attenuated by point mutations in the SMB2 that impair integrin binding. Integrin binding therefore localizes ATX activity to the cell surface, providing a mechanism to generate LPA in the vicinity of its receptors.

Original languageEnglish
Pages (from-to)34654-34663
Number of pages10
JournalJournal of Biological Chemistry
Volume286
Issue number40
DOIs
StatePublished - Oct 7 2011

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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