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1.
Gut ; 69(1): 146-157, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-30723104

RESUMO

OBJECTIVE: We explored the hypothesis that TGR5, the bile acid (BA) G-protein-coupled receptor highly expressed in biliary epithelial cells, protects the liver against BA overload through the regulation of biliary epithelium permeability. DESIGN: Experiments were performed under basal and TGR5 agonist treatment. In vitro transepithelial electric resistance (TER) and FITC-dextran diffusion were measured in different cell lines. In vivo FITC-dextran was injected in the gallbladder (GB) lumen and traced in plasma. Tight junction proteins and TGR5-induced signalling were investigated in vitro and in vivo (wild-type [WT] and TGR5-KO livers and GB). WT and TGR5-KO mice were submitted to bile duct ligation or alpha-naphtylisothiocyanate intoxication under vehicle or TGR5 agonist treatment, and liver injury was studied. RESULTS: In vitro TGR5 stimulation increased TER and reduced paracellular permeability for dextran. In vivo dextran diffusion after GB injection was increased in TGR5-knock-out (KO) as compared with WT mice and decreased on TGR5 stimulation. In TGR5-KO bile ducts and GB, junctional adhesion molecule A (JAM-A) was hypophosphorylated and selectively downregulated among TJP analysed. TGR5 stimulation induced JAM-A phosphorylation and stabilisation both in vitro and in vivo, associated with protein kinase C-ζ activation. TGR5 agonist-induced TER increase as well as JAM-A protein stabilisation was dependent on JAM-A Ser285 phosphorylation. TGR5 agonist-treated mice were protected from cholestasis-induced liver injury, and this protection was significantly impaired in JAM-A-KO mice. CONCLUSION: The BA receptor TGR5 regulates biliary epithelial barrier function in vitro and in vivo through an impact on JAM-A expression and phosphorylation, thereby protecting liver parenchyma against bile leakage.


Assuntos
Sistema Biliar/fisiopatologia , Colestase Intra-Hepática/prevenção & controle , Receptores Acoplados a Proteínas-G/fisiologia , Animais , Bile/metabolismo , Ácidos e Sais Biliares/metabolismo , Moléculas de Adesão Celular/metabolismo , Células Cultivadas , Colestase Intra-Hepática/metabolismo , Impedância Elétrica , Epitélio/fisiopatologia , Ácidos Isonipecóticos/farmacologia , Ácidos Isonipecóticos/uso terapêutico , Camundongos Endogâmicos C57BL , Camundongos Knockout , Oximas/farmacologia , Oximas/uso terapêutico , Permeabilidade , Fosforilação/fisiologia , Receptores de Superfície Celular/metabolismo , Receptores Acoplados a Proteínas-G/agonistas , Transdução de Sinais/fisiologia , Proteínas de Junções Íntimas/metabolismo
2.
Adv Exp Med Biol ; 1172: 1-19, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31628649

RESUMO

The common γ chain (γc) family of hematopoietic cytokines consists of six distinct four α-helix bundle soluble ligands that signal through receptors which include the shared γc subunit to coordinate a wide range of physiological processes, in particular, those related to innate and adaptive immune function. Since the first crystallographic structure of a γc family cytokine/receptor signaling complex (the active Interleukin-2 [IL-2] quaternary complex) was determined in 2005 [1], tremendous progress has been made in the structural characterization of this protein family, transforming our understanding of the molecular mechanisms underlying immune activity. Although many conserved features of γc family cytokine complex architecture have emerged, distinguishing details have been observed for individual cytokine complexes that rationalize their unique functional properties. Much work remains to be done in the molecular characterization of γc family signaling, particularly with regard to intracellular activation events, and looking forward, new technologies in structural biophysics will offer further insight into the biology of cytokine signaling to inform the design of targeted therapeutics for treatment of immune-linked diseases such as cancer, infection, and autoimmune disorders.


Assuntos
Subunidade gama Comum de Receptores de Interleucina , Transdução de Sinais , Animais , Humanos , Subunidade gama Comum de Receptores de Interleucina/química , Subunidade gama Comum de Receptores de Interleucina/fisiologia , Interleucina-2/química , Interleucina-2/fisiologia , Receptores de Citocinas/metabolismo , Transdução de Sinais/fisiologia
4.
Nat Cell Biol ; 21(9): 1102-1112, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31481792

RESUMO

The classical model of tissue renewal posits that small numbers of quiescent stem cells (SCs) give rise to proliferating transit-amplifying cells before terminal differentiation. However, many organs house pools of SCs with proliferative and differentiation potentials that diverge from this template. Resolving SC identity and organization is therefore central to understanding tissue renewal. Here, using a combination of single-cell RNA sequencing (scRNA-seq), mouse genetics and tissue injury approaches, we uncover cellular hierarchies and mechanisms that underlie the maintenance and repair of the continuously growing mouse incisor. Our results reveal that, during homeostasis, a group of actively cycling epithelial progenitors generates enamel-producing ameloblasts and adjacent layers of non-ameloblast cells. After injury, tissue repair was achieved through transient increases in progenitor-cell proliferation and through direct conversion of Notch1-expressing cells to ameloblasts. We elucidate epithelial SC identity, position and function, providing a mechanistic basis for the homeostasis and repair of a fast-turnover ectodermal appendage.


Assuntos
Ameloblastos/citologia , Diferenciação Celular/fisiologia , Proliferação de Células/fisiologia , Ectoderma/citologia , Incisivo/citologia , Animais , Divisão Celular/fisiologia , Células Epiteliais/citologia , Camundongos Transgênicos , Transdução de Sinais/fisiologia , Células-Tronco/citologia
5.
Clin Exp Rheumatol ; 37 Suppl 119(4): 141-146, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31498062

RESUMO

Systemic sclerosis (SSc) is a complex autoimmune disease characterised by fibrosis of the skin and multiple internal organs. Interleukin 33 (IL-33) has recently been investigated as a potential key player in the pathogenesis of SSc and other fibrotic diseases, owing to its effects on tissue fibrosis. Understanding how IL-33 is regulated and how it contributes to the development of fibrosis will be important to elucidate disease pathogenesis and may shed light on new areas for therapeutic development for patients. Here we discuss the recent research progress in our understanding of the role and the underlying mechanisms of IL-33/ST2 signaling pathway in SSc and other fibrotic diseases.


Assuntos
Interleucina-33 , Receptores de Superfície Celular/fisiologia , Escleroderma Sistêmico , Transdução de Sinais/fisiologia , Fibrose/metabolismo , Humanos , Interleucina-33/metabolismo , Receptores de Interleucina/metabolismo , Escleroderma Sistêmico/metabolismo , Pele
6.
Transplant Proc ; 51(6): 2124-2131, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31399188

RESUMO

BACKGROUND: Acute rejection of a kidney allograft results from adaptive immune responses and marked inflammation. The eicosanoid prostaglandin E2 (PGE2) modulates the inflammatory response, is generated by cyclooxygenase 2 (COX-2), and binds to 1 of the 4 G protein-coupled E prostanoid cell surface receptors (EP1-4). Receptor activation results in in proinflammatory (EP1 and EP3) or anti-inflammatory (EP2 and EP4) responses. We theorized that expression of the components of the COX-PGE2-EP signaling pathway correlates with acute rejection in a porcine model of allogeneic renal transplantation. METHOD: COX-2 enzyme and EP receptor protein expression were quantitated with western blotting and immunohistochemistry from allotransplants (n = 18) and autotransplants (n = 5). Linear regression analysis was used to correlate EP receptor expression with the Banff category of rejection. RESULTS: Pigs with advanced rejection demonstrated significant increases in serum PGE2 metabolites, while pigs with less rejection demonstrated higher tissue concentrations of PGE2 metabolites. A significant negative correlation between COX-2 expression and Banff category of rejection (R = -0.877) was shown. Rejection decreased expression of EP2 and EP4. For both receptors, there was a significant negative correlation with the extent of rejection (R = -0.760 and R = -0.891 for EP2 and EP4, respectively). Rejection had no effect on the proinflammatory receptors EP1 and EP3. CONCLUSION: Downregulation of COX-2 and the anti-inflammatory EP2 and EP4 receptors is associated with acute rejection in unmatched pig kidney transplants, suggesting that the COX-2-PGE2-EP pathway may modulate inflammation in this model. Enhancing EP2 and/or EP4 activity may offer novel therapeutic approaches to controlling the inflammation of acute allograft rejection.


Assuntos
Dinoprostona/biossíntese , Rejeição de Enxerto/metabolismo , Transplante de Rim , Receptores de Prostaglandina/biossíntese , Animais , Ciclo-Oxigenase 2/metabolismo , Regulação para Baixo , Transdução de Sinais/fisiologia , Suínos
7.
J Cancer Res Clin Oncol ; 145(9): 2169-2197, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31401674

RESUMO

BACKGROUND: Recent studies have shown that the short-chain fatty acids (SCFAs) produced by the gut microbiota play a positive role in the development of colorectal cancer (CRC). AIMS: This study aims to elucidate the "food-microorganism-SCFAs" axis and to provide guidance for prevention and intervention in CRC. METHODS: The PubMed, Embase and Cochrane databases were searched from their inceptions to August 2018, and 75 articles and 25 conference abstracts were included and analysed after identification and screening. RESULTS: The concentrations of SCFAs in CRC patients and individuals with a high risk of CRC were higher than those in healthy individuals. The protective mechanism of SCFAs against CRC has been described in three aspects: epigenetics, immunology and molecular signalling pathways. Many food and plant extracts that were fermented by microorganisms produced SCFAs that play positive roles with preventive and therapeutic effects on CRC. The "food-microorganism-SCFAs" axis was constructed by summarizing the pertinent literature. CONCLUSIONS: This study provides insight into the basic research and practical application of SCFAs by assessing the protective effect of SCFAs on CRC.


Assuntos
Neoplasias Colorretais/prevenção & controle , Ácidos Graxos Voláteis/fisiologia , Comportamento Alimentar/fisiologia , Microbioma Gastrointestinal/fisiologia , Pesquisa Biomédica/métodos , Pesquisa Biomédica/tendências , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/microbiologia , Ácidos Graxos Voláteis/uso terapêutico , Alimentos , Humanos , Padrões de Prática Médica/tendências , Probióticos/uso terapêutico , Fatores de Risco , Transdução de Sinais/fisiologia
8.
Biol Res ; 52(1): 41, 2019 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-31387634

RESUMO

BACKGROUND: Di-N-butyl-phthalate (DBP) is an endocrine disrupting substance. We investigated the adverse effect of DBP on testis of male rat and reveal its potential mechanism of MAPK signaling pathway involved this effect in vivo and in vitro. Gonadal hormone, sperm quality, morphological change and the activation status of JNK, ERK1/2 and p38 was determined in vivo. Primary Sertoli cell was established and cultivated with JNK, ERK1/2 inhibitors, then determine the cell viability, apoptosis and the expression of p-JNK, p-ERK1/2. Data in this study were presented as mean ± SD and determined by one-way analysis of variance (ANOVA) followed by Bonferroni's test. Difference was considered statistically significant at P < 0.05. RESULTS: In vivo experiment, DBP impaired the normal structure of testicular tissue, reduced testosterone levels in blood serum, decreased sperm count and increased sperm abnormality, p-ERK1/2 and p-JNK in rat testicular tissue increased in a dose-dependent manner. In vitro studies, DBP could decrease the viability of Sertoli cells and increase p-ERK1/2 and p-JNK. Cell apoptosis in SP600125 + DBP group was significantly lower than in DBP group (P < 0.05). p-JNK was not significantly decreased in SP600125 + DBP group, while p-ERK1/2 was significantly decreased in U0126 + DBP group. CONCLUSIONS: These results suggest that DBP can lead to testicular damage and the activation of ERK1/2 and JNK pathways, the JNK signaling pathway may be primarily associated with its effect.


Assuntos
Dibutilftalato/farmacologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Transdução de Sinais/fisiologia , Testículo/lesões , Testículo/metabolismo , Animais , Proteínas Quinases JNK Ativadas por Mitógeno/fisiologia , Masculino , Proteínas Quinases Ativadas por Mitógeno/fisiologia , Ratos , Ratos Sprague-Dawley , Testículo/efeitos dos fármacos
9.
J Cancer Res Clin Oncol ; 145(9): 2261-2271, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31367836

RESUMO

PURPOSE: To investigate the role of sonic hedgehog (Shh) signaling and epithelial-mesenchymal transition (EMT) in bladder cancer progression and invasion. METHODS: We cultured three bladder cancer cell lines, muscle-invasive T24 and 5637, and non-muscle-invasive KK47, in the presence of a recombinant-Shh (r-Shh) protein or cyclopamine, a Shh signaling inhibitor, to investigate proliferation and expression of EMT markers. Wound-healing assays and transwell assay were performed to evaluate cell invasion and migration. Mice were then inoculated with bladder cancer cells and treated with cyclopamine. Mouse tumor samples were stained for Shh signaling and EMT markers. RESULTS: R-Shh protein enhanced cell proliferation, whereas cyclopamine significantly suppressed cell proliferation, especially in invasive cancer (5637 and T24) (p < 0.05). R-Shh protein promoted EMT, suppressed E-cadherin and enhanced N-cadherin and vimentin and Gli1, an Shh downstream molecule, while cyclopamine blocked EMT, especially in 5637 and T24. Cyclopamine also inhibited cell invasion and migration in vitro. In the animal study, intraperitoneal injection of cyclopamine significantly suppressed tumor growth in 5637 and T24 in mice (p = 0.01 and p = 0.004, respectively) and slightly suppressing KK47 tumor growth (p = 0.298). Significant cyclopamine-induced suppression of Gli1 in 5637 and T24 mouse tumors (both p = 0.03) was seen, suggesting that muscle-invasive bladder cancer may be more dependent on Shh signaling than non-muscle-invasive bladder cancer. CONCLUSIONS: Shh signaling and EMT were especially enhanced in muscle-invasive bladder cancer progression and invasion, and suppressed by the inhibition of Shh signaling.


Assuntos
Transição Epitelial-Mesenquimal/fisiologia , Proteínas Hedgehog/fisiologia , Neoplasias Musculares/secundário , Neoplasias da Bexiga Urinária/patologia , Animais , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Progressão da Doença , Proteínas Hedgehog/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Musculares/metabolismo , Invasividade Neoplásica , Transdução de Sinais/fisiologia , Neoplasias da Bexiga Urinária/metabolismo
10.
Nat Cell Biol ; 21(8): 966-977, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31371827

RESUMO

Migrasomes are recently identified vesicular organelles that form on retraction fibres behind migrating cells. Whether migrasomes are present in vivo and, if so, the function of migrasomes in living organisms is unknown. Here, we show that migrasomes are formed during zebrafish gastrulation and signalling molecules, such as chemokines, are enriched in migrasomes. We further demonstrate that Tspan4 and Tspan7 are required for migrasome formation. Organ morphogenesis is impaired in zebrafish MZtspan4a and MZtspan7 mutants. Mechanistically, migrasomes are enriched on a cavity underneath the embryonic shield where they serve as chemoattractants to ensure the correct positioning of dorsal forerunner cells vegetally next to the embryonic shield, thereby affecting organ morphogenesis. Our study shows that migrasomes are signalling organelles that provide specific biochemical information to coordinate organ morphogenesis.


Assuntos
Embrião não Mamífero/metabolismo , Morfogênese/fisiologia , Organelas/metabolismo , Proteínas de Peixe-Zebra/genética , Animais , Padronização Corporal/fisiologia , Movimento Celular/genética , Movimento Celular/fisiologia , Desenvolvimento Embrionário/fisiologia , Gastrulação/fisiologia , Organelas/genética , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Peixe-Zebra/embriologia
11.
Hypertension ; 74(4): 936-946, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31378107

RESUMO

Endothelial cells regulate vascular tone by producing both relaxing and contracting factors to control the local blood flow. Hypertension is a common side effect of mTORC1 (mammalian target of rapamycin complex 1) inhibitors. However, the role of endothelial mTORC1 in hypertension remains elusive. The present study aimed to determine the role of endothelial mTORC1 in Ang II (angiotensin II)-induced hypertension and the underlying mechanism. Endothelial mTORC1 activity was increased by Ang II both in vitro and in vivo. Blood pressure was higher in Tie-2-Cre-mediated regulatory associated protein of mTOR (mammalian target of rapamycin; Raptor) heterozygous-deficient (Tie2Cre-RaptorKD) mice than control mice both before and after Ang II infusion. Acetylcholine-evoked endothelium-dependent relaxation of mesenteric arteries was impaired in Tie2Cre-RaptorKD mice. Treatment with indomethacin or a specific COX (cyclooxygenase)-2 inhibitor, NS-398, but not L-NG-nitroarginine methyl ester reduced endothelium-dependent relaxation in Raptorflox/- mice to a similar extent as in Tie2Cre-RaptorKD mice. Metabolomic profiling revealed that the plasma content of prostaglandin E2 was reduced in Tie2Cre-RaptorKD mice with or without Ang II infusion. In endothelial cells, reduction of the protein level of YAP (yes-associated protein) with siRNA-mediated RPTOR deficiency was autophagy dependent and transcriptionally regulated the expression of COX-2 and mPGES-1 (microsomal prostaglandin E synthase-1). Hence, overexpression of YAP in endothelial cells enhanced the mRNA and protein levels of COX-2 and mPGES-1 and reversed the endothelial dysfunction and hypertension in Tie2Cre-RaptorKD mice. The present results demonstrate that suppression of mTORC1 activity in endothelial cells reduces prostaglandin E2 production and causes hypertension by reducing YAP-mediated COX-2/mPGES-1 expression.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Pressão Sanguínea/fisiologia , Endotélio Vascular/metabolismo , Hipertensão/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Fosfoproteínas/metabolismo , Transdução de Sinais/fisiologia , Angiotensina II , Animais , Pressão Sanguínea/efeitos dos fármacos , Proteínas de Ciclo Celular , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase/farmacologia , Dinoprostona/metabolismo , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Endotélio Vascular/efeitos dos fármacos , Hipertensão/induzido quimicamente , Indometacina/farmacologia , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/metabolismo , Camundongos , Prostaglandina-E Sintases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologia
12.
Cell Mol Life Sci ; 76(22): 4461-4492, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31428838

RESUMO

GPCR-G protein signaling system recognizes a multitude of extracellular ligands and triggers a variety of intracellular signaling cascades in response. In humans, this system includes more than 800 various GPCRs and a large set of heterotrimeric G proteins. Complexity of this system goes far beyond a multitude of pair-wise ligand-GPCR and GPCR-G protein interactions. In fact, one GPCR can recognize more than one extracellular signal and interact with more than one G protein. Furthermore, one ligand can activate more than one GPCR, and multiple GPCRs can couple to the same G protein. This defines an intricate multifunctionality of this important signaling system. Here, we show that the multifunctionality of GPCR-G protein system represents an illustrative example of the protein structure-function continuum, where structures of the involved proteins represent a complex mosaic of differently folded regions (foldons, non-foldons, unfoldons, semi-foldons, and inducible foldons). The functionality of resulting highly dynamic conformational ensembles is fine-tuned by various post-translational modifications and alternative splicing, and such ensembles can undergo dramatic changes at interaction with their specific partners. In other words, GPCRs and G proteins exist as sets of conformational/basic, inducible/modified, and functioning proteoforms characterized by a broad spectrum of structural features and possessing various functional potentials.


Assuntos
Proteínas Heterotriméricas de Ligação ao GTP/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Transdução de Sinais/fisiologia , Animais , Humanos , Ligantes , Processamento de Proteína Pós-Traducional/fisiologia
13.
Cell Mol Life Sci ; 76(22): 4405-4406, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31422443

RESUMO

The five articles in this multi-author review in CMLS provide examples of multi-functionality of proteins belonging to several families. Distinct structural features of proteins suggesting multi-functionality are emphasized: intrinsically disordered elements that can "mold" themselves to fit various binding partners, as well as short linear motifs within larger proteins that perform particular functions. Although only a few protein families are discussed in detail, the conclusions apply to numerous, if not all, proteins. Multi-functionality of virtually every protein implies that the manipulation of its expression levels by over-expression, knockdown, or knockout affects every one of its functions, known and unknown, so that the results of these experiments must be interpreted with this complexity in mind. Particular functions in a multi-functional protein are often fulfilled by identifiable smaller elements that can be expressed separately. Identification of mono-functional elements of a multi-functional protein paves the way to the construction of novel precisely targeted molecular tools for selective manipulation of cellular signaling that can be used for mechanistic studies in cell biology, as well as for therapeutic purposes.


Assuntos
Proteínas Intrinsicamente Desordenadas/metabolismo , Humanos , Ligação Proteica , Conformação Proteica , Transdução de Sinais/fisiologia
14.
Cell Mol Life Sci ; 76(22): 4413-4421, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31422444

RESUMO

Mammalian arrestins are a family of four highly homologous relatively small ~ 45 kDa proteins with surprisingly diverse functions. The most striking feature is that each of the two non-visual subtypes can bind hundreds of diverse G protein-coupled receptors (GPCRs) and dozens of non-receptor partners. Through these interactions, arrestins regulate the G protein-dependent signaling by the desensitization mechanisms as well as control numerous signaling pathways in the G protein-dependent or independent manner via scaffolding. Some partners prefer receptor-bound arrestins, some bind better to the free arrestins in the cytoplasm, whereas several show no apparent preference for either conformation. Thus, arrestins are a perfect example of a multi-functional signaling regulator. The result of this multi-functionality is that reduction (by knockdown) or elimination (by knockout) of any of these two non-visual arrestins can affect so many pathways that the results are hard to interpret. The other difficulty is that the non-visual subtypes can in many cases compensate for each other, which explains relatively mild phenotypes of single knockouts, whereas double knockout is lethal in vivo, although cultured cells lacking both arrestins are viable. Thus, deciphering the role of arrestins in cell biology requires the identification of specific signaling function(s) of arrestins involved in a particular phenotype. This endeavor should be greatly assisted by identification of structural elements of the arrestin molecule critical for individual functions and by the creation of mutants where only one function is affected. Reintroduction of these biased mutants, or introduction of monofunctional stand-alone arrestin elements, which have been identified in some cases, into double arrestin-2/3 knockout cultured cells, is the most straightforward way to study arrestin functions. This is a laborious and technically challenging task, but the upside is that specific function of arrestins, their timing, subcellular specificity, and relations to one another could be investigated with precision.


Assuntos
Arrestinas/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Animais , Humanos , Transdução de Sinais/fisiologia
15.
Cell Mol Life Sci ; 76(22): 4447-4459, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31435698

RESUMO

G-protein ßγ subunits are key participants in G-protein signaling. These subunits facilitate interactions between receptors and G proteins that are critical for the G protein activation cycle at the plasma membrane. In addition, they play roles in directly transducing signals to an ever expanding range of downstream targets, including integral membrane and cytosolic proteins. Emerging data indicate that Gßγ may play additional roles at intracellular compartments including endosomes, the Golgi apparatus, and the nucleus. Here, we discuss the molecular and structural basis for their ability to coordinate this wide range of cellular activities.


Assuntos
Subunidades beta da Proteína de Ligação ao GTP/metabolismo , Subunidades gama da Proteína de Ligação ao GTP/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Transdução de Sinais/fisiologia , Animais , Membrana Celular/metabolismo , Membrana Celular/fisiologia , Núcleo Celular/metabolismo , Núcleo Celular/fisiologia , Endossomos/metabolismo , Endossomos/fisiologia , Complexo de Golgi/metabolismo , Complexo de Golgi/fisiologia , Humanos
16.
Neuron ; 103(4): 563-581, 2019 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-31437453

RESUMO

Spike-timing-dependent synaptic plasticity (STDP) is a leading cellular model for behavioral learning and memory with rich computational properties. However, the relationship between the millisecond-precision spike timing required for STDP and the much slower timescales of behavioral learning is not well understood. Neuromodulation offers an attractive mechanism to connect these different timescales, and there is now strong experimental evidence that STDP is under neuromodulatory control by acetylcholine, monoamines, and other signaling molecules. Here, we review neuromodulation of STDP, the underlying mechanisms, functional implications, and possible involvement in brain disorders.


Assuntos
Plasticidade Neuronal/fisiologia , Neurotransmissores/fisiologia , Potenciais de Ação , Animais , Astrócitos/fisiologia , Comportamento/fisiologia , Encefalopatias/tratamento farmacológico , Encefalopatias/fisiopatologia , Mapeamento Encefálico , Humanos , Aprendizagem/fisiologia , Consolidação da Memória/fisiologia , Modelos Neurológicos , Terapia de Alvo Molecular , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/fisiopatologia , Transtornos do Neurodesenvolvimento/tratamento farmacológico , Transtornos do Neurodesenvolvimento/fisiopatologia , Neurônios/fisiologia , Transtorno Obsessivo-Compulsivo/tratamento farmacológico , Transtorno Obsessivo-Compulsivo/fisiopatologia , Terminações Pré-Sinápticas/fisiologia , Receptores de Neurotransmissores/fisiologia , Transdução de Sinais/fisiologia , Especificidade da Espécie , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/fisiopatologia , Transtornos Relacionados ao Uso de Substâncias/tratamento farmacológico , Transtornos Relacionados ao Uso de Substâncias/fisiopatologia , Fatores de Tempo
17.
Cell Mol Life Sci ; 76(22): 4423-4446, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31432234

RESUMO

Accumulating evidence indicates that G protein-coupled receptor kinase 2 (GRK2) is a versatile protein that acts as a signaling hub by modulating G protein-coupled receptor (GPCR) signaling and also via phosphorylation or scaffolding interactions with an extensive number of non-GPCR cellular partners. GRK2 multifunctionality arises from its multidomain structure and from complex mechanisms of regulation of its expression levels, activity, and localization within the cell, what allows the precise spatio-temporal shaping of GRK2 targets. A better understanding of the GRK2 interactome and its modulation mechanisms is helping to identify the GRK2-interacting proteins and its substrates involved in the participation of this kinase in different cellular processes and pathophysiological contexts.


Assuntos
Quinase 2 de Receptor Acoplado a Proteína G/metabolismo , Transdução de Sinais/fisiologia , Animais , Humanos , Fosforilação/fisiologia
18.
Nat Cell Biol ; 21(9): 1093-1101, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31451768

RESUMO

Mechanistic target of rapamycin (mTOR) kinase functions in two multiprotein complexes: lysosomal mTOR complex 1 (mTORC1) and mTORC2 at the plasma membrane. mTORC1 modulates the cell response to growth factors and nutrients by increasing protein synthesis and cell growth, and repressing the autophagy-lysosomal pathway1-4; however, dysfunction in mTORC1 is implicated in various diseases3,5,6. mTORC1 activity is regulated by phosphoinositide lipids7-10. Class I phosphatidylinositol-3-kinase (PI3K)-mediated production of phosphatidylinositol-3,4,5-trisphosphate6,11 at the plasma membrane stimulates mTORC1 signalling, while local synthesis of phosphatidylinositol-3,4-bisphosphate by starvation-induced recruitment of class II PI3K-ß (PI3KC2-ß) to lysosomes represses mTORC1 activity12. How the localization and activity of PI3KC2-ß are regulated by mitogens is unknown. We demonstrate that protein kinase N (PKN) facilitates mTORC1 signalling by repressing PI3KC2-ß-mediated phosphatidylinositol-3,4-bisphosphate synthesis downstream of mTORC2. Active PKN2 phosphorylates PI3KC2-ß to trigger PI3KC2-ß complex formation with inhibitory 14-3-3 proteins. Conversely, loss of PKN2 or inactivation of its target phosphorylation site in PI3KC2-ß represses nutrient signalling via mTORC1. These results uncover a mechanism that couples mTORC2-dependent activation of PKN2 to the regulation of mTORC1-mediated nutrient signalling by local lipid signals.


Assuntos
Lipídeos , Lisossomos/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Transdução de Sinais/fisiologia , Proliferação de Células/fisiologia , Fibroblastos/metabolismo , Humanos , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Complexos Multiproteicos/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo
19.
Acta Clin Croat ; 58(1): 128-138, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31363335

RESUMO

All transforming growth factors beta (TGFß) are cytokines that regulate several cellular functions such as cell growth, differentiation and motility. They may also have a role in immunosuppression. Their role is important for normal prostate development. TGFß is active in the regulation of balance between epithelial cell proliferation and apoptosis through stromal epithelia via the androgen receptor action. TGFß protects and maintains prostate stem cells, an important population necessary for prostate tissue regeneration. However, TGFß is shown to have a contrasting role in prostate tumor genesis. In the early stages of tumor development, TGFß acts as a tumor suppressor, whereas in the later stages, TGFß becomes a tumor promoter by inducing proliferation, invasion and metastasis. In this review, we outline complex interactions that TGFß-mediated signaling has on prostate tumor genesis, focusing on the role of these interactions during the course of prostate cancer and, in particular, during disease progression.


Assuntos
Neoplasias da Próstata/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Transdução de Sinais/fisiologia , Fator de Crescimento Transformador beta/metabolismo , Proliferação de Células , Progressão da Doença , Humanos , Masculino , Neoplasias da Próstata/patologia
20.
Hematol Oncol ; 37(4): 474-482, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31325181

RESUMO

LncRNAs play critical roles in various pathophysiological and biological processes, such as protein translation, RNA splicing, and epigenetic modification. Indeed, abundant evidences demonstrated that lncRNA act as competing endogenous RNAs (ceRNAs) to participate in tumorigenesis. However, little is known about the underlying function of lncRNA in nonhomologous end joining (NHEJ) pathway 1 (LINP1) in pediatric and adolescent acute myeloid leukemia (AML). The expression of LINP1 was examined in AML patient samples by qRT-PCR. Cell proliferation was examined by CCK-8 and Edu assays. ß-Galactosidase senescence assay, mGlucose uptake assay, lactate production assay, and Gene Ontology (GO) analysis were performed for functional analysis. We found that LINP1 was significantly overexpressed in AML patients at diagnosis, whereas downregulated after complete remission (CR). Furthermore, knockdown of LINP1 expression remarkably suppressed glucose uptake and AML cell maintenance. Mechanistically, LINP1 was found to inhibit the glucose metabolism by suppressing the expression of HNF4a. Both LINP1 and HNF4a knockdown reduced the expression levels of AMPK phosphorylation and WNT5A, indicating for the first time that LINP1 strengthened the HNF4a-AMPK/WNT5A signaling pathway involved in cell glucose metabolism modulation and AML cell survival. Taken together, our results indicated that LINP1 promotes the malignant phenotype of AML cells and stimulates glucose metabolism, which can be regarded as a potential prognostic marker and therapeutic target for AML.


Assuntos
Adenilato Quinase/fisiologia , Fator 4 Nuclear de Hepatócito/fisiologia , Leucemia Mieloide Aguda/genética , RNA Longo não Codificante/fisiologia , RNA Neoplásico/fisiologia , Transdução de Sinais/fisiologia , Proteína Wnt-5a/fisiologia , Adolescente , Animais , Medula Óssea/patologia , Divisão Celular , Criança , Regulação Leucêmica da Expressão Gênica , Técnicas de Silenciamento de Genes , Ontologia Genética , Glucose/metabolismo , Fator 4 Nuclear de Hepatócito/biossíntese , Fator 4 Nuclear de Hepatócito/genética , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Transplante de Neoplasias , Púrpura Trombocitopênica Idiopática/metabolismo , Interferência de RNA , RNA Longo não Codificante/biossíntese , RNA Longo não Codificante/genética , RNA Neoplásico/biossíntese , RNA Neoplásico/genética , RNA Interferente Pequeno/genética , Distribuição Aleatória , Indução de Remissão , Transdução de Sinais/genética , Células THP-1
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