A motif in LILRB2 critical for Angptl2 binding and activation

Mi Deng Ph.D., Zhigang Lu, Junke Zheng, Xuan Wan, Xiaoli Chen, Kouyuki Hirayasu, Hanzi Sun, Yeeling Lam, Liping Chen, Qihui Wang, Chun Song, Niu Huang, George F. Gao, Youxing Jiang, Hisashi Arase, Chengcheng Zhang

Research output: Contribution to journalArticle

36 Scopus citations

Abstract

A better understanding of the interaction between extrinsic factors and surface receptors on stem cells will greatly benefit stemcell research and applications. Recently, we showed that several angiopoietin-like proteins (Angptls) bind and activate the immune inhibitory receptor human leukocyte immunoglobulin (Ig)-like receptor B2 (LILRB2) to support ex vivo expansion of hematopoietic stem cells (HSCs) and leukemia development. However, the molecular basis for the interaction between Angptls and LILRB2 was unclear. Here, we demonstrate that Angptl2 expressed in mammalian cells forms high-molecular- weight species and that ligand multimerization is required for activation of LILRB2 for downstream signaling. A novel motif in the first and fourth Ig domains of LILRB2 was identified that is necessary for the receptor to be bound and activated by Angptl2. The binding ofAngptl2 to LILRB2 is more potent than and not completely overlapped with the binding of another ligand, HLA-G. Immobilized anti-LILRB2 antibodies induce a more potent activation of LILRB2 than Angptl2, and we developed a serum-free culture containing defined cytokines and immobilized anti-LILRB2 that supports a net expansion of repopulating human cord blood HSCs. Our elucidation of the mode of Angptl binding to LILRB2 enabled the development of a new approach for ex vivo expansion of human HSCs.

Original languageEnglish (US)
Pages (from-to)924-935
Number of pages12
JournalBlood
Volume124
Issue number6
DOIs
Publication statusPublished - Aug 7 2014

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ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

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