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, Chieko Mineo

Research output: Contribution to journalArticle

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Abstract

In the antiphospholipid syndrome (APS), antiphospholipid antibody (aPL) recognition of b2 glycoprotein I promotes thrombosis, and preclinical studies indicate that this is due to endothelial nitric oxide synthase (eNOS) antagonism via apolipoprotein E receptor 2 (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 2A (PP2A). Disabled-2 (Dab2) recruitment to the apoER2 NPXY motif promotes the activating L309 methylation of the PP2A catalytic subunit by leucine methyl transferase-1. Concurrently, Src homology domain-containing transforming protein 1 (SHC1) recruits the PP2A scaffolding subunit to the proline-rich apoER2 C terminus along with 2 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.

Original languageEnglish (US)
Pages (from-to)2097-2110
Number of pages14
JournalBlood
Volume131
Issue number19
DOIs
StatePublished - May 10 2018

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Protein Phosphatase 2
Antiphospholipid Antibodies
Endothelium
Thrombosis
Chemical activation
Antiphospholipid Syndrome
Nitric Oxide Synthase Type III
Methylation
src Homology Domains
Endothelial cells
Transferases
Proline
Scaffolds
Tail
Catalytic Domain
Glycoproteins
Endothelial Cells
low density lipoprotein receptor-related protein 8
Proteins

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Antiphospholipid antibodies induce thrombosis by PP2A activation via apoER2-Dab2-SHC1 complex formation in endothelium. / Sacharidou, Anastasia; Chambliss, Ken L.; Ulrich, Victoria; Salmon, Jane E.; Shen, Yu Min; Herz, Joachim; Hui, David Y.; Terada, Lance S.; Shaul, Philip W.; Mineo, Chieko.

In: Blood, Vol. 131, No. 19, 10.05.2018, p. 2097-2110.

Research output: Contribution to journalArticle

Sacharidou, Anastasia ; Chambliss, Ken L. ; Ulrich, Victoria ; Salmon, Jane E. ; Shen, Yu Min ; Herz, Joachim ; Hui, David Y. ; Terada, Lance S. ; Shaul, Philip W. ; Mineo, Chieko. / Antiphospholipid antibodies induce thrombosis by PP2A activation via apoER2-Dab2-SHC1 complex formation in endothelium. In: Blood. 2018 ; Vol. 131, No. 19. pp. 2097-2110.
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