The Src non-receptor tyrosine kinase paradigm: New insights into mammalian Sertoli cell biology

Chojnacka, Katarzyna; Mruk, Dolores D.

doi:10.1016/j.mce.2015.08.012

Cited by 24 publications

(14 citation statements)

References 146 publications

(167 reference statements)

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“…The SRC tyrosine kinases present several functional domains. When the Tyr 530 in the C-terminus is dephosphorylated, the kinase activity is triggered, and the protein interacts with target proteins (Chojnacka & Mruk 2015). ESR1-Tyr537 phosphorylation induces its molecular interaction with SRC protein (Nieto et al 2015), leading to SRC activation (Barletta et al 2004); on the other hand, ESR1-Tyr537 phosphorylation has been Insulin stimulation did not alter redistribution of ESR1.…”

Section: Discussionmentioning

confidence: 96%

Estradiol-induced regulation of GLUT4 in 3T3-L1 cells: involvement of ESR1 and AKT activation

Campello

Fátima

Barreto-Andrade

et al. 2017

Journal of Molecular Endocrinology

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Impaired insulin-stimulated glucose uptake involves reduced expression of the GLUT4 (solute carrier family 2 facilitated glucose transporter member 4, gene). 17β-estradiol (E) modulates /GLUT4 expression, but the involved mechanisms are unclear. Although E exerts biological effects by binding to estrogen receptors 1/2 (ESR1/2), which are nuclear transcriptional factors; extranuclear effects have also been proposed. We hypothesize that E regulates GLUT4 through an extranuclear ESR1 mechanism. Thus, we investigated the effects of E upon (1) subcellular distribution of ESRs and the proto-oncogene tyrosine-protein kinases (SRC) involvement; (2) serine/threonine-protein kinase (AKT) activation; (3) /GLUT4 expression and (4) GLUT4 subcellular distribution and glucose uptake in 3T3-L1 adipocytes. Differentiated 3T3-L1 adipocytes were cultivated or not with E for 24 h, and additionally treated or not with ESR1-selective agonist (PPT), ESR1-selective antagonist (MPP) or selective SRC inhibitor (PP2). Subcellular distribution of ESR1, ESR2 and GLUT4 was analyzed by immunocytochemistry; mRNA and GLUT4 were quantified by qPCR and Western blotting, respectively; plasma membrane GLUT4 translocation and glucose uptake were analyzed under insulin stimulus for 20 min or not. E induced (1) translocation of ESR1, but not of ESR2, from nucleus to plasma membrane and AKT phosphorylation, effects mimicked by PPT and blocked by MPP and PP2; (2) increased /GLUT4 expression and (3) increased insulin-stimulated GLUT4 translocation and glucose uptake. In conclusion, E treatment promoted a SRC-mediated nucleus-plasma membrane shuttle of ESR1, and increased AKT phosphorylation, /GLUT4 expression and plasma membrane GLUT4 translocation; consequently, improving insulin-stimulated glucose uptake. These results unravel mechanisms through which estrogen improves insulin sensitivity.

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Section: Discussionmentioning

confidence: 96%

Estradiol-induced regulation of GLUT4 in 3T3-L1 cells: involvement of ESR1 and AKT activation

Campello

Fátima

Barreto-Andrade

et al. 2017

Journal of Molecular Endocrinology

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“…Indeed, the reduction of ZO-1 signal and its delocalization from the membrane to the cytoplasmic compartment was reported as related to degradation of the Cx43 gap junction [ 35 ]. Interestingly, a role of kinase Src in the interaction of Cx43 with ZO-1 and in the internalization of the BTB proteins was demonstrated [ 33 , 36 , 37 ]. In accord, we have recently found that flutamide-induced disassembly of adherens junctions at the BTB is related to altered Src distribution at this region [ 20 ].…”

Section: Discussionmentioning

confidence: 99%

Flutamide induces alterations in the cell-cell junction ultrastructure and reduces the expression of Cx43 at the blood-testis barrier with no disturbance in the rat seminiferous tubule morphology

Chojnacka

Hejmej

Zarzycka

et al. 2016

Reprod Biol Endocrinol

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BackgroundPresent study was designed to establish a causal connection between changes in the cell-cell junction protein expression at the blood-testis barrier and alterations in the adult rat testis histology following an anti-androgen flutamide exposure. Particular emphasis was placed on the basal ectoplasmic specialization (ES) in the seminiferous epithelium and expression of gap junction protein, connexin 43 (Cx43).MethodsFlutamide (50 mg/kg body weight) was administered to male rats daily from 82 to 88 postnatal day. Testes from 90-day-old control and flutamide-exposed rats were used for all analyses. Testis morphology was analyzed using light and electron microscopy. Gene and protein expressions were analyzed by real-time RT-PCR and Western blotting, respectively, protein distribution by immunohistochemistry, and steroid hormone concentrations by radioimmunoassay.ResultsSeminiferous epithelium of both groups of rats displayed normal histology without any loss of germ cells. In accord, no difference in the apoptosis and proliferation level was found between control and treated groups. As shown by examination of semi-thin and ultrathin sections, cell surface occupied by the basal ES connecting neighboring Sertoli cells and the number of gap and tight junctions coexisting with the basal ES were apparently reduced in flutamide-treated rats. Moreover, the appearance of unconventional circular ES suggests enhanced internalization and degradation of the basal ES. These changes were accompanied by decreased Cx43 and ZO-1 expression (p < 0.01) and a loss of linear distribution of these proteins at the region of the blood-testis barrier. On the other hand, Cx43 expression in the interstitial tissue of flutamide-treated rats increased (p < 0.01), which could be associated with Leydig cell hypertrophy. Concomitantly, both intratesticular testosterone and estradiol concentrations were elevated (p < 0.01), but testosterone to estradiol ratio decreased significantly (p < 0.05) in flutamide-treated rats compared to the controls.ConclusionsShort-term treatment with flutamide applied to adult rats exerts its primary effect on the basal ES, coexisting junctional complexes and their constituent proteins Cx43 and ZO-1, without any apparent morphological alterations in the seminiferous epithelium. In the interstitial compartment, however, short-term exposure leads to both histological and functional changes of the Leydig cells.

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“…The physiological Src proto-oncogene is a non-receptor tyrosine kinase that phosphorylates diverse substrates, including ezrin and caveolin-1 [ 25 , 32 , 33 ]. Phosphorylated caveolin-1 (p-caveolin-1) was reported to in turn initiate the formation of endocytic carriers during JEV infection [ 21 ].…”

Section: Resultsmentioning

confidence: 99%

Ezrin is essential for the entry of Japanese encephalitis virus into the human brain microvascular endothelial cells

Liu

Yang

Wang

et al. 2020

Emerging Microbes & Infections

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Japanese encephalitis virus (JEV) remains the predominant cause of viral encephalitis worldwide. It reaches the central nervous system upon crossing the blood-brain barrier through pathogenic mechanisms that are not completely understood. Here, using a high-throughput siRNA screening assay combined with verification experiments, we found that JEV enters the primary human brain microvascular endothelial cells (HBMEC) through a caveolae-mediated endocytic pathway. The role of ezrin, an essential host factor for JEV entry based on our screening, in caveolaemediated JEV internalization was investigated. We observed that JEV internalization in HBMEC is largely dependent on ezrin-mediated actin cytoskeleton polymerization. Moreover, Src, a protein predicted by a STRING database search, was found to be required in JEV entry. By a variety of pharmacological inhibition and immunoprecipitation assays, we found that Src, ezrin, and caveolin-1 were sequentially activated and formed a complex during JEV infection. A combination of in vitro kinase assay and subcellular analysis demonstrated that ezrin is essential for Src-caveolin-1 interactions. In vivo, both Src and ezrin inhibitors protected ICR suckling mice against JEV-induced mortality and diminished mouse brain viral load. Therefore, JEV entry into HBMEC requires the activation of the Src-ezrin-caveolin-1 signalling axis, which provides potential targets for restricting JEV infection.

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The Src non-receptor tyrosine kinase paradigm: New insights into mammalian Sertoli cell biology

Cited by 24 publications

References 146 publications

Estradiol-induced regulation of GLUT4 in 3T3-L1 cells: involvement of ESR1 and AKT activation

Estradiol-induced regulation of GLUT4 in 3T3-L1 cells: involvement of ESR1 and AKT activation

Flutamide induces alterations in the cell-cell junction ultrastructure and reduces the expression of Cx43 at the blood-testis barrier with no disturbance in the rat seminiferous tubule morphology

Ezrin is essential for the entry of Japanese encephalitis virus into the human brain microvascular endothelial cells

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