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Antiphospholipid antibodies induce thrombosis by PP2A activation via apoER2-Dab2-SHC1 complex formation in endothelium

Anastasia Sacharidou, Ken L. Chambliss, Victoria Ulrich, Jane E. Salmon, Yu-Min Shen, Joachim Herz, David Y. Hui, Lance S. Terada, Philip W. Shaul and Chieko Mineo

Key points

  • The activation of PP2A in endothelium underlies thrombus formation induced by aPL in mice.

  • Endothelial apoER2 serves as a scaffold for aPL-induced assembly of a Dab2 and SHC1- containing protein complex that assembles and activates PP2A.

Abstract

In the antiphospholipid syndrome (APS), antiphospholipid antibody (aPL) recognition of β2 glycoprotein (β2GPI) promotes thrombosis, and preclinical studies indicate that this is due to endothelial NO synthase (eNOS) antagonism via apoER2-dependent processes. How apoER2 molecularly links these events is unknown. Here we show that in endothelial cells the apoER2 cytoplasmic tail serves as a scaffold for aPL-induced assembly and activation of the heterotrimeric protein phosphatase PP2A. Dab2 recruitment to the apoER2 NPXY motif promotes the activating L309 methylation of the PP2A catalytic subunit by leucine methyl transferase-1. Concurrently SHC1 recruits the PP2A scaffolding subunit to the proline-rich apoER2 C-terminus along with two distinct regulatory PP2A subunits that mediate inhibitory dephosphorylation of Akt and eNOS. In mice the coupling of these processes in endothelium is demonstrated to underlie aPL-invoked thrombosis. By elucidating these intricacies in the pathogenesis of APS-related thrombosis, numerous potential new therapeutic targets have been identified.

  • Submitted November 6, 2017.
  • Accepted February 23, 2018.