Efnb1 and Efnb2 Proteins Regulate Thymocyte Development, Peripheral T Cell Differentiation, and Antiviral Immune Responses and Are Essential for Interleukin-6 (IL-6) Signaling

Luo, Hongyu; Charpentier, Tania; Wang, Xuehai; Qi, Shijie; Han, Bing; Wu, Tao; Terra, Rafik; Lamarre, Alain; Wu, Jiangping

doi:10.1074/jbc.m111.302596

Cited by 54 publications

(68 citation statements)

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“…The scheme, procedures, and verification of the generation of Efnb1 floxed mice have been reported recently by us (18). Efnb1 is an X-linked gene.…”

Section: Generation Of Smooth Muscle Cell-specific Efnb1 Ko Mice-mentioning

confidence: 99%

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Possible Role of Efnb1 Protein, a Ligand of Eph Receptor Tyrosine Kinases, in Modulating Blood Pressure

Luo

Thorin

et al. 2012

Journal of Biological Chemistry

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Background: Currently, there is no knowledge about the function of ephrins in vascular smooth muscle contraction and blood pressure regulation. Results: Stimulating Efnb1 reduces vascular smooth muscle cell contraction. Efnb1 null mutation increases RhoA activation and heightens blood pressure in mice. Conclusion: Efnb1 can regulate vessel tone and blood pressure. Significance: We identified a new group of molecules capable of regulating blood pressure.

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“…The scheme, procedures, and verification of the generation of Efnb1 floxed mice have been reported recently by us (18). Efnb1 is an X-linked gene.…”

Section: Generation Of Smooth Muscle Cell-specific Efnb1 Ko Mice-mentioning

confidence: 99%

“…To study the function of Efnb1 in VMSCs, we generated conditional KO mice (18). These mice (Efnb1 f/f for females and Efnb1 f for males as Efnb1 is an X-linked gene) were crossed with smMHC-Cre-IRES-eGFP transgenic mice (19).…”

Section: Generation Of Smc-specific Efnb1mentioning

confidence: 99%

Possible Role of Efnb1 Protein, a Ligand of Eph Receptor Tyrosine Kinases, in Modulating Blood Pressure

Luo

Thorin

et al. 2012

Journal of Biological Chemistry

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“…14 They were backcrossed with C57BL/6J for 10 generations and then mated with smooth muscle myosin heavy chain promoter-driven Cre transgenic mice (smMHC-Cre-IRES-eGFP) in the C57BL/6J background 12 to obtain SMC cellspecific Efnb2 gene KO mice. The ages of the KO and WT mice for the in vivo study were described in given experiments.…”

Section: Generation Of Smc-specific Efnb2 and Ephb4 Gene Knockout (Komentioning

confidence: 99%

“…The floxed Efnb2 mice 14 in the C57BL/6J background were crossed with transgenic mice expressing smooth muscle myosin heavy chain promoter-driven Cre recombinase (also in the C57BL/6J background 12 to achieve SMC-specific deletion of EFNB2. The deletion of Efnb2 at the mRNA level in vascular smooth muscles, but not in the spleen, heart, brain or liver, was confirmed by RT-qPCR (Figure 1a; Supplementary Figure 1).…”

Section: Smc-specific Deletion Of Efnb2 In Micementioning

confidence: 99%

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Reduced blood pressure after smooth muscle EFNB2 deletion and the potential association of EFNB2 mutation with human hypertension risk

et al. 2016

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Ephrin B2 (EFNB2) is a ligand for erythropoietin-producing hepatocellular kinases (EPH), the largest family of receptor tyrosine kinases. It has critical functions in many biological systems, but is not known to regulate blood pressure. We generated mice with a smooth muscle cell (SMC)-specific deletion of EFNB2 and investigated its roles in blood pressure regulation and vascular SMC (VSMC) contractility. Male Efnb2 knockout (KO) mice presented reduced blood pressure, whereas female KO mice had no such reduction. Both forward signaling from EFNB2 to EPHs and reverse signaling from EPHs to EFNB2 were involved in regulating VSMC contractility, with EPHB4 serving as a critical molecule for forward signaling, based on crosslinking studies. We also found that a region from aa 313 to aa 331 in the intracellular tail of EFNB2 was essential for reverse signaling regulating VSMC contractility, based on deletion mutation studies. In a human genetic study, we identified five SNPs in the 3′ region of the EFNB2 gene, which were in linkage disequilibrium and were significantly associated with hypertension for male but not female subjects, consistent with our findings in mice. The coding (minor) alleles of these five SNPs were protective in males. We have thus discovered a previously unknown blood pressure-lowering mechanism mediated by EFNB2 and identified EFNB2 as a gene associated with hypertension risk in humans. European Journal of Human Genetics (2016) 24, 1817-1825; doi:10.1038/ejhg.2016.105; published online 17 August 2016 INTRODUCTION Erythropoietin-producing hepatocellular kinases (EPH) are the largest family of receptor tyrosine kinases. In the basis of sequence homology, they are divided into A and B subfamilies. 1 Their ligands, called ephrins (EFNs), are also cell surface molecules. 2 EFNs are also divided into A and B subfamilies, based on the way they anchor on the cell surface: the A subfamily anchors on the cell surface through glycophosphatidylinositol, and the B subfamily, through a transmembrane domain. 2 The interactions between EPH kinases and EFNs are promiscuous, but EPHA kinases preferably interact with EFNA ligands, and EPHB kinases with EFNB ligands, which have three members, EFNB1, EFNB2 and EFNB3. 2 Although EPH members and EFN members share homology with their respective members, each member has its distinct function in different cellular processes. [3][4][5][6][7] In general, the EPH kinases interact with their EFN ligands on neighboring cells, because EPHs and EFNs are all cell surface molecules. 2 These molecules could be cleaved from the cell surface by enzymes such as ADAM10, 8,9 an unspecified matrix metalloproteinase, 10 or γ-secretase; 11 therefore, it is possible that the shed soluble fragments of EPH and EFN might be able to influence cells and tissues at a distance by blocking the interaction of EPHs and EFNs there.

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Role of EFNB1 and EFNB2 in Mouse Collagen‐Induced Arthritis and Human Rheumatoid Arthritis

Wang

et al. 2015

Arthritis & Rheumatology

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Objective EFNB1 and EFNB2 are ligands for Eph receptor tyrosine kinases. This study was undertaken to investigate how the expression of Efnb1 and Efnb2 on murine T cells influences the pathogenesis of collagen‐induced arthritis (CIA) and to assess correlations between the T cell expression of these 2 molecules and measures of disease activity in patients with rheumatoid arthritis (RA). Methods CIA was studied in mice with T cell–specific deletion (double gene knockout [dKO]) of both Efnb1 and Efnb2. Expression of EFNB1 and EFNB2 messenger RNA (mRNA) in peripheral blood T cells from patients with RA was determined by quantitative reverse transcription– polymerase chain reaction. Results In dKO mice, clinical scores of arthritis were reduced compared to those in wild‐type (WT) control mice. Serum collagen‐specific antibody titers in dKO mice were lower than those in WT mice. In analyses based on equal cell numbers, dKO mouse T cells, as compared to WT mouse T cells, provided vastly inferior help to B cells in the production of collagen‐specific antibodies in vitro. T cells from dKO mice were compromised in their ability to migrate to the arthritic paws in vivo and in their ability to undergo chemotaxis toward CXCL12 in vitro. Deletion mutation of Efnb1 and Efnb2 intracellular tails revealed critical regions in controlling T cell chemotaxis. T cells from RA patients expressed higher EFNB1 mRNA levels, which correlated with RA symptoms and laboratory findings. Conclusion Efnb1 and Efnb2 in T cells are essential for pathogenic antibody production and for T cell migration to the inflamed paws in mice with CIA. These findings suggest that the expression of EFNB1 in T cells might be a useful parameter for monitoring RA disease activity and treatment responses.

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Efnb1 and Efnb2 Proteins Regulate Thymocyte Development, Peripheral T Cell Differentiation, and Antiviral Immune Responses and Are Essential for Interleukin-6 (IL-6) Signaling

Cited by 54 publications

References 54 publications

Possible Role of Efnb1 Protein, a Ligand of Eph Receptor Tyrosine Kinases, in Modulating Blood Pressure

Possible Role of Efnb1 Protein, a Ligand of Eph Receptor Tyrosine Kinases, in Modulating Blood Pressure

Reduced blood pressure after smooth muscle EFNB2 deletion and the potential association of EFNB2 mutation with human hypertension risk

Role of EFNB1 and EFNB2 in Mouse Collagen‐Induced Arthritis and Human Rheumatoid Arthritis

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