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Molecular interactions of EphA4, growth hormone receptor, Janus kinase 2, and signal transducer and activator of transcription 5B.

ABSTRACT: We previously reported that EphA4, a member of the Eph family of receptor tyrosine kinases, is an important modulator of growth hormone (GH) signaling, leading to augmented synthesis of insulin-like growth factor 1 (IGF1) for postnatal body growth. In the present study, we report the molecular interactions of EphA4, GH receptor (GHR), Janus kinase 2 (JAK2), and signal transducer and activator of transcription 5B (STAT5B). EphA4 binds to GHR at both its extracellular and intracellular domains and phosphorylates GHR when stimulated with a ligand. The cytoplasmic domain of EphA4 binds to the carboxy-terminus of JAK2 in contrast to the known binding of GHR to the amino-terminus. STAT5B binds to the amino-terminal kinase domain of EphA4. Ligand-activated EphA4 and JAK2 phosphorylate each other and STAT5B, but JAK2 does not appear to phosphorylate EphA4-bound STAT5B. Ligand-activated EphA4 induces the nuclear translocation of STAT5B in a JAK2-independent manner. GHR expression is required for the activation of STAT5B signaling, even via the JAK2-independent pathway. Various ephrins that have affinity for EphA4 induce STAT5B phosphorylation. These findings suggest the molecular mechanisms by which ephrin/EphA4 signaling enhances the canonical GH-IGF1 axis.

SUBMITTER: Sawada T

PROVIDER: S-EPMC5501605 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Molecular interactions of EphA4, growth hormone receptor, Janus kinase 2, and signal transducer and activator of transcription 5B.

Sawada Takahiro T Arai Daiki D Jing Xuefeng X Miyajima Masayasu M Frank Stuart J SJ Sakaguchi Kazushige K

PloS one 20170707 7

We previously reported that EphA4, a member of the Eph family of receptor tyrosine kinases, is an important modulator of growth hormone (GH) signaling, leading to augmented synthesis of insulin-like growth factor 1 (IGF1) for postnatal body growth. In the present study, we report the molecular interactions of EphA4, GH receptor (GHR), Janus kinase 2 (JAK2), and signal transducer and activator of transcription 5B (STAT5B). EphA4 binds to GHR at both its extracellular and intracellular domains and ...[more]

PMID: 28686668

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Project description:OBJECTIVE:Glomerular mesangial expansion and podocyte loss are important early features of diabetic nephropathy, whereas tubulointerstitial injury and fibrosis are critical for progression of diabetic nephropathy to kidney failure. Therefore, we analyzed the expression of genes in glomeruli and tubulointerstitium in kidney biopsies from diabetic nephropathy patients to identify pathways that may be activated in humans but not in murine models of diabetic nephropathy that fail to progress to glomerulosclerosis, tubulointerstitial fibrosis, and kidney failure. RESEARCH DESIGN AND METHODS:Kidney biopsies were obtained from 74 patients (control subjects, early and progressive type 2 diabetic nephropathy). Glomerular and tubulointerstitial mRNAs were microarrayed, followed by bioinformatics analyses. Gene expression changes were confirmed by real-time RT-PCR and immunohistological staining. Samples from db/db C57BLKS and streptozotocin-induced DBA/2J mice, commonly studied murine models of diabetic nephropathy, were analyzed. RESULTS:In human glomeruli and tubulointerstitial samples, the Janus kinase (Jak)-signal transducer and activator of transcription (Stat) pathway was highly and significantly regulated. Jak-1, -2, and -3 as well as Stat-1 and -3 were expressed at higher levels in patients with diabetic nephropathy than in control subjects. The estimated glomerular filtration rate significantly correlated with tubulointerstitial Jak-1, -2, and -3 and Stat-1 expression (R(2) = 0.30-0.44). Immunohistochemistry found strong Jak-2 staining in glomerular and tubulointerstitial compartments in diabetic nephropathy compared with control subjects. In contrast, there was little or no increase in expression of Jak/Stat genes in the db/db C57BLKS or diabetic DBA/2J mice. CONCLUSIONS:These data suggest a direct relationship between tubulointerstitial Jak/Stat expression and progression of kidney failure in patients with type 2 diabetic nephropathy and distinguish progressive human diabetic nephropathy from nonprogressive murine diabetic nephropathy.

Project description:BACKGROUND Rheumatoid arthritis is an autoimmune disease that causes chronic joint inflammation and there is no cure. Baicalin, as an ingredient in the roots of Scutellaria baicalensis, is supposed to possess an anti-inflammatory effect. However, the protective effect of baicalin on collagen-induced arthritis requires further investigation. MATERIAL AND METHODS A model of rheumatoid arthritis was established in 20 mice (8- to 10-weeks old). The mice were randomly divided into 2 groups after modeling and then injected with saline or baicalin, respectively. The synovial fluids and tissues were collected, and the pressure pain threshold and clinical arthritis score were measured. The levels of tumor necrosis factor (TNF)-?, interlukin-1? (IL-1?), IL-6, matrix metalloproteinases (MMP)-2, MMP-9, nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and their downstream inflammatory mediators Janus kinase 1 (JAK1)/signal transducer and activator of transcription 3 (STAT3), extracellular signal-regulated kinases 1/2 (ERK1/2), p38, Jun N-terminal kinases (JNK) activation were detected using enzyme-linked immunosorbent assay (ELISA), and western blotting analyses. The mononuclear cells apoptosis ratio was calculated by flowcytometry analyses. RESULTS Baicalin significantly reduced disease activities in a rheumatoid arthritis mouse model, which were reflected by pressure pain thresholds and clinical arthritis scores. Relevant proinflammatory cytokines such as TNF-?, IL-1?, IL-6, gelatinases (MMP-2, MMP-9) and inducible enzymes (iNOS, COX-2) were generally suppressed. Moreover, baicalin treatment induced cells apoptosis in synovial fluid monocytes and markedly down regulated JAK1/STAT3 but not mitogen-activated protein kinases (MAPKs) expressions in synovium of arthritis. CONCLUSIONS These observations confirm the relief of rheumatoid arthritis by baicalin. Our results indicate the effect is related with the modulation of decreased proinflammatory cytokines and inflammatory markers. And the apoptosis promotion of monocytes in synovial fluid were also inhibited. Moreover, the molecular mechanism implies suppressed JAK1/STAT3 signaling with baicalin treatment.

Dataset Information

Molecular interactions of EphA4, growth hormone receptor, Janus kinase 2, and signal transducer and activator of transcription 5B.

Publications

Molecular interactions of EphA4, growth hormone receptor, Janus kinase 2, and signal transducer and activator of transcription 5B.

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