Format

Send to

Choose Destination
See comment in PubMed Commons below
Blood. 2014 Aug 7;124(6):924-35. doi: 10.1182/blood-2014-01-549162. Epub 2014 Jun 4.

A motif in LILRB2 critical for Angptl2 binding and activation.

Author information

1
Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX;
2
Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX; Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School of Peking University, Shenzhen, China;
3
Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX; Department of Pathophysiology, Shanghai Universities E-Institute for Chemical Biology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China;
4
Department of Immunochemistry, Research Institute for Microbial Diseases and Laboratory of Immunochemistry, World Premier International Immunology Frontier Research Center, Osaka University, and Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Osaka, Japan;
5
National Institute of Biological Sciences, Beijing, China;
6
Chinese Academy of Sciences Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China;
7
Shandong University and National New Drug R&D Center in Shandong, Jinan, China; and.
8
Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX; Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, TX.

Abstract

A better understanding of the interaction between extrinsic factors and surface receptors on stem cells will greatly benefit stem cell 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 of Angptl2 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.

PMID:
24899623
PMCID:
PMC4126332
DOI:
10.1182/blood-2014-01-549162
[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire Icon for PubMed Central
    Loading ...
    Support Center