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Inhibitory receptors bind ANGPTLs and support blood stem cells and leukaemia development.

Zheng J, Umikawa M, Cui C, Li J, Chen X, Zhang C, Huynh H, Hyunh H, Kang X, Silvany R, Wan X, Ye J, Cantó AP, Chen SH, Wang HY, Ward ES, Zhang CC - Nature (2012)

Bottom Line: Angiopoietin-like proteins (ANGPTLs), a family of seven secreted glycoproteins, are known to support the activity of haematopoietic stem cells (HSCs) in vitro and in vivo.ANGPTLs also have important roles in lipid metabolism, angiogenesis and inflammation, but were considered 'orphan ligands' because no receptors were identified.In mouse transplantation acute myeloid leukaemia models, a deficiency in intracellular signalling of PIRB resulted in increased differentiation of leukaemia cells, revealing that PIRB supports leukaemia development.

View Article: PubMed Central - PubMed

Affiliation: Departments of Physiology and Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.

ABSTRACT
How environmental cues regulate adult stem cell and cancer cell activity through surface receptors is poorly understood. Angiopoietin-like proteins (ANGPTLs), a family of seven secreted glycoproteins, are known to support the activity of haematopoietic stem cells (HSCs) in vitro and in vivo. ANGPTLs also have important roles in lipid metabolism, angiogenesis and inflammation, but were considered 'orphan ligands' because no receptors were identified. Here we show that the immune-inhibitory receptor human leukocyte immunoglobulin-like receptor B2 (LILRB2) and its mouse orthologue paired immunoglobulin-like receptor (PIRB) are receptors for several ANGPTLs. LILRB2 and PIRB are expressed on human and mouse HSCs, respectively, and the binding of ANGPTLs to these receptors supported ex vivo expansion of HSCs. In mouse transplantation acute myeloid leukaemia models, a deficiency in intracellular signalling of PIRB resulted in increased differentiation of leukaemia cells, revealing that PIRB supports leukaemia development. Our study indicates an unexpected functional significance of classical immune-inhibitory receptors in maintenance of stemness of normal adult stem cells and in support of cancer development.

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Angptls bind PirB and support the repopulation of mouse HSCsa, Flow cytometry analysis of FLAG-Angptl2 or GST-Angptl5-FLAG binding to PirB transfected 293T cells. b, Angptl2 binds to the extracellular domain of PirB but not Tie-2 in the conditioned medium of co-transfected 293T cells. c, PirB is expressed on mouse BM Lin−Sca-1+Kit+ cells. Isotype control on left. d, Competitive reconstitution of 8-day cultured progenies of input equivalent 250 Lin−Sca-1+Kit+CD34−Flk2− BM HSCs from WT or PirBTM donors (n = 5). SCF, TPO, and FGF-1, with or without Angptl2, were used in culture. * p < 0.05. Error bars, s.e.m.
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Figure 3: Angptls bind PirB and support the repopulation of mouse HSCsa, Flow cytometry analysis of FLAG-Angptl2 or GST-Angptl5-FLAG binding to PirB transfected 293T cells. b, Angptl2 binds to the extracellular domain of PirB but not Tie-2 in the conditioned medium of co-transfected 293T cells. c, PirB is expressed on mouse BM Lin−Sca-1+Kit+ cells. Isotype control on left. d, Competitive reconstitution of 8-day cultured progenies of input equivalent 250 Lin−Sca-1+Kit+CD34−Flk2− BM HSCs from WT or PirBTM donors (n = 5). SCF, TPO, and FGF-1, with or without Angptl2, were used in culture. * p < 0.05. Error bars, s.e.m.

Mentions: The paired immunoglobulin-like receptor B (PirB) is the only mouse membrane ortholog of human LILRBs 16,17. Angptl2, Angptl3, and GST-Angptl5 bound to PirB as determined by flow cytometry (Fig. 3a, Supplementary Fig. 9) and by Co-IP (Fig. 3b, Supplementary Fig. 10). As were human cord blood HSCs, mouse HSCs were also enriched for PirB expression (Fig. 3c, Supplementary Fig. 11).


Inhibitory receptors bind ANGPTLs and support blood stem cells and leukaemia development.

Zheng J, Umikawa M, Cui C, Li J, Chen X, Zhang C, Huynh H, Hyunh H, Kang X, Silvany R, Wan X, Ye J, Cantó AP, Chen SH, Wang HY, Ward ES, Zhang CC - Nature (2012)

Angptls bind PirB and support the repopulation of mouse HSCsa, Flow cytometry analysis of FLAG-Angptl2 or GST-Angptl5-FLAG binding to PirB transfected 293T cells. b, Angptl2 binds to the extracellular domain of PirB but not Tie-2 in the conditioned medium of co-transfected 293T cells. c, PirB is expressed on mouse BM Lin−Sca-1+Kit+ cells. Isotype control on left. d, Competitive reconstitution of 8-day cultured progenies of input equivalent 250 Lin−Sca-1+Kit+CD34−Flk2− BM HSCs from WT or PirBTM donors (n = 5). SCF, TPO, and FGF-1, with or without Angptl2, were used in culture. * p < 0.05. Error bars, s.e.m.
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Related In: Results  -  Collection

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Figure 3: Angptls bind PirB and support the repopulation of mouse HSCsa, Flow cytometry analysis of FLAG-Angptl2 or GST-Angptl5-FLAG binding to PirB transfected 293T cells. b, Angptl2 binds to the extracellular domain of PirB but not Tie-2 in the conditioned medium of co-transfected 293T cells. c, PirB is expressed on mouse BM Lin−Sca-1+Kit+ cells. Isotype control on left. d, Competitive reconstitution of 8-day cultured progenies of input equivalent 250 Lin−Sca-1+Kit+CD34−Flk2− BM HSCs from WT or PirBTM donors (n = 5). SCF, TPO, and FGF-1, with or without Angptl2, were used in culture. * p < 0.05. Error bars, s.e.m.
Mentions: The paired immunoglobulin-like receptor B (PirB) is the only mouse membrane ortholog of human LILRBs 16,17. Angptl2, Angptl3, and GST-Angptl5 bound to PirB as determined by flow cytometry (Fig. 3a, Supplementary Fig. 9) and by Co-IP (Fig. 3b, Supplementary Fig. 10). As were human cord blood HSCs, mouse HSCs were also enriched for PirB expression (Fig. 3c, Supplementary Fig. 11).

Bottom Line: Angiopoietin-like proteins (ANGPTLs), a family of seven secreted glycoproteins, are known to support the activity of haematopoietic stem cells (HSCs) in vitro and in vivo.ANGPTLs also have important roles in lipid metabolism, angiogenesis and inflammation, but were considered 'orphan ligands' because no receptors were identified.In mouse transplantation acute myeloid leukaemia models, a deficiency in intracellular signalling of PIRB resulted in increased differentiation of leukaemia cells, revealing that PIRB supports leukaemia development.

View Article: PubMed Central - PubMed

Affiliation: Departments of Physiology and Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.

ABSTRACT
How environmental cues regulate adult stem cell and cancer cell activity through surface receptors is poorly understood. Angiopoietin-like proteins (ANGPTLs), a family of seven secreted glycoproteins, are known to support the activity of haematopoietic stem cells (HSCs) in vitro and in vivo. ANGPTLs also have important roles in lipid metabolism, angiogenesis and inflammation, but were considered 'orphan ligands' because no receptors were identified. Here we show that the immune-inhibitory receptor human leukocyte immunoglobulin-like receptor B2 (LILRB2) and its mouse orthologue paired immunoglobulin-like receptor (PIRB) are receptors for several ANGPTLs. LILRB2 and PIRB are expressed on human and mouse HSCs, respectively, and the binding of ANGPTLs to these receptors supported ex vivo expansion of HSCs. In mouse transplantation acute myeloid leukaemia models, a deficiency in intracellular signalling of PIRB resulted in increased differentiation of leukaemia cells, revealing that PIRB supports leukaemia development. Our study indicates an unexpected functional significance of classical immune-inhibitory receptors in maintenance of stemness of normal adult stem cells and in support of cancer development.

Show MeSH
Related in: MedlinePlus