RESUMO
BACKGROUND: T cell migration is essential for immune responses and inflammation. Activation of the T-cell receptor (TCR) triggers a migration stop signal to facilitate interaction with antigen-presenting cells and cell retention at inflammatory sites, but the mechanisms responsible for this effect are not known. METHODOLOGY/PRINCIPAL FINDINGS: Migrating T cells are polarized with a lamellipodium at the front and uropod at the rear. Here we show that transient TCR activation induces prolonged inhibition of T-cell migration. TCR pre-activation leads to cells with multiple lamellipodia and lacking a uropod even after removal of the TCR signal. A similar phenotype is induced by expression of constitutively active Rac1, and TCR signaling activates Rac1. TCR signaling acts via Rac to reduce phosphorylation of ezrin/radixin/moesin proteins, which are required for uropod formation, and to increase stathmin phosphorylation, which regulates microtubule stability. T cell polarity and migration is partially restored by inhibiting Rac or by expressing constitutively active moesin. CONCLUSIONS/SIGNIFICANCE: We propose that transient TCR signaling induces sustained inhibition of T cell migration via Rac1, increased stathmin phosphorylation and reduced ERM phosphorylation which act together to inhibit T-cell migratory polarity.
Assuntos
Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T/citologia , Proteínas rac de Ligação ao GTP/metabolismo , Animais , Movimento Celular , Polaridade Celular , Proteínas do Citoesqueleto/metabolismo , Ativação Enzimática , Humanos , Molécula 1 de Adesão Intercelular/metabolismo , Proteínas de Membrana/metabolismo , Proteínas dos Microfilamentos/metabolismo , Fosforilação , Transporte Proteico , Pseudópodes/metabolismo , Estatmina/metabolismo , Linfócitos T/metabolismoRESUMO
Cell polarity plays a key role in the development of the central nervous system (CNS). Interestingly, disruption of cell polarity is seen in many cancers. ASPP2 is a haplo-insufficient tumor suppressor and an activator of the p53 family. In this study, we show that ASPP2 controls the polarity and proliferation of neural progenitors in vivo, leading to the formation of neuroblastic rosettes that resemble primitive neuroepithelial tumors. Consistent with its role in cell polarity, ASPP2 influences interkinetic nuclear migration and lamination during CNS development. Mechanistically, ASPP2 maintains the integrity of tight/adherens junctions. ASPP2 binds Par-3 and controls its apical/junctional localization without affecting its expression or Par-3/aPKC lambda binding. The junctional localization of ASPP2 and Par-3 is interdependent, suggesting that they are prime targets for each other. These results identify ASPP2 as a regulator of Par-3, which plays a key role in controlling cell proliferation, polarity, and tissue organization during CNS development.
Assuntos
Moléculas de Adesão Celular/fisiologia , Sistema Nervoso Central/embriologia , Proteínas Supressoras de Tumor/fisiologia , Proteínas Adaptadoras de Transdução de Sinal , Animais , Sequência de Bases , Proteínas de Ciclo Celular , Polaridade Celular/fisiologia , Proliferação de Células , Sistema Nervoso Central/anormalidades , Sistema Nervoso Central/citologia , Sistema Nervoso Central/metabolismo , Primers do DNA/genética , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neocórtex/anormalidades , Neocórtex/embriologia , Neurônios/citologia , Neurônios/metabolismo , Gravidez , Ligação Proteica , Retina/anormalidades , Retina/embriologia , Junções Íntimas/metabolismo , Junções Íntimas/ultraestrutura , Proteínas Supressoras de Tumor/deficiência , Proteínas Supressoras de Tumor/genéticaRESUMO
BACKGROUND: Two published case studies have reported SRI/SNRI-associated low testosterone levels. Apathy and low testosterone, observed during venlafaxine treatment in one report, both resolved upon venlafaxine discontinuation. No studies have investigated the effect of chronic SRI treatment on human testosterone levels. As decreased testosterone has several negative health effects, we conducted a pilot study investigating the effect of fluoxetine treatment on testosterone levels. METHODS: Fourteen depressive disorder patients in good health (BDI = 15) were studied. In addition, 4 non-depressed patients were studied. Testosterone levels were drawn, and an apathy questionnaire (under development, not yet validated) was administered at intake. Fluoxetine was provided (10 mg/day for 7 days then 20 mg/day). To measure outcome, a follow-up testosterone level was drawn after 1 month's treatment. RESULTS: Eleven depressed, and 3 non-depressed, patients completed the study. While there were large differences-both increases and decreases-in some individuals' testosterone levels after fluoxetine treatment, for the study population as a whole, there was no relationship (depressed patients, p = 0.4; non-depressed patients, p 0.3) between fluoxetine treatment and testosterone levels.In patients with BDI = 20, testosterone levels at intake were highly associated with intake apathy levels (p = 0.0033). CONCLUSIONS: Further, larger, studies correlating changes in testosterone levels during SRI treatment with treatment response, apathy levels and possibly sexual dysfunction seem indicated.