Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 65
Filtrar
Más filtros

Banco de datos
Tipo del documento
Intervalo de año de publicación
2.
Cell ; 163(4): 811-28, 2015 Nov 05.
Artículo en Inglés | MEDLINE | ID: mdl-26544935

RESUMEN

Two decades of studies in multiple model organisms have established the Hippo pathway as a key regulator of organ size and tissue homeostasis. By inhibiting YAP and TAZ transcription co-activators, the Hippo pathway regulates cell proliferation, apoptosis, and stemness in response to a wide range of extracellular and intracellular signals, including cell-cell contact, cell polarity, mechanical cues, ligands of G-protein-coupled receptors, and cellular energy status. Dysregulation of the Hippo pathway exerts a significant impact on cancer development. Further investigation of the functions and regulatory mechanisms of this pathway will help uncovering the mystery of organ size control and identify new targets for cancer treatment.


Asunto(s)
Neoplasias/metabolismo , Tamaño de los Órganos , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal , Animales , Fenómenos Fisiológicos Celulares , Homeostasis , Humanos
3.
Cell ; 162(4): 780-94, 2015 Aug 13.
Artículo en Inglés | MEDLINE | ID: mdl-26276632

RESUMEN

The transcriptional co-activators YAP and TAZ are key regulators of organ size and tissue homeostasis, and their dysregulation contributes to human cancer. Here, we discover YAP/TAZ as bona fide downstream effectors of the alternative Wnt signaling pathway. Wnt5a/b and Wnt3a induce YAP/TAZ activation independent of canonical Wnt/ß-catenin signaling. Mechanistically, we delineate the "alternative Wnt-YAP/TAZ signaling axis" that consists of Wnt-FZD/ROR-Gα12/13-Rho GTPases-Lats1/2 to promote YAP/TAZ activation and TEAD-mediated transcription. YAP/TAZ mediate the biological functions of alternative Wnt signaling, including gene expression, osteogenic differentiation, cell migration, and antagonism of Wnt/ß-catenin signaling. Together, our work establishes YAP/TAZ as critical mediators of alternative Wnt signaling.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Fosfoproteínas/metabolismo , Vía de Señalización Wnt , Animales , Proteínas de Ciclo Celular , Línea Celular , Receptores Frizzled/metabolismo , Humanos , Ratones , Ratones Transgénicos , Transactivadores , Factores de Transcripción , Proteínas Señalizadoras YAP , beta Catenina/metabolismo
4.
Mol Cell ; 82(10): 1850-1864.e7, 2022 05 19.
Artículo en Inglés | MEDLINE | ID: mdl-35429439

RESUMEN

YAP and TAZ (YAP/TAZ), two major effectors of the Hippo signaling pathway, are frequently activated in human cancers. The activity of YAP/TAZ is strictly repressed upon phosphorylation by LATS1/2 tumor suppressors. However, it is unclear how LATS1/2 are precisely regulated by upstream factors such as Hippo kinases MST1/2. Here, we show that WWC proteins (WWC1/2/3) directly interact with LATS1/2 and SAV1, and SAV1, in turn, brings in MST1/2 to phosphorylate and activate LATS1/2. Hence, WWC1/2/3 play an organizer role in a signaling module that mediates LATS1/2 activation by MST1/2. Moreover, we have defined a minimum protein interaction interface on WWC1/2/3 that is sufficient to activate LATS1/2 in a robust and specific manner. The corresponding minigene, dubbed as SuperHippo, can effectively suppress tumorigenesis in multiple tumor models. Our study has uncovered a molecular mechanism underlying LATS1/2 regulation and provides a strategy for treating diverse malignancies related to Hippo pathway dysregulation.


Asunto(s)
Proteínas Serina-Treonina Quinasas , Transducción de Señal , Carcinogénesis , Vía de Señalización Hippo , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Fosforilación , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal/fisiología , Proteínas Supresoras de Tumor/metabolismo
5.
EMBO J ; 42(15): e112900, 2023 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-37350545

RESUMEN

The scaffolding protein angiomotin (AMOT) is indispensable for vertebrate embryonic angiogenesis. Here, we report that AMOT undergoes cleavage in the presence of lysophosphatidic acid (LPA), a lipid growth factor also involved in angiogenesis. AMOT cleavage is mediated by aspartic protease DNA damage-inducible 1 homolog 2 (DDI2), and the process is tightly regulated by a signaling axis including neurofibromin 2 (NF2), tankyrase 1/2 (TNKS1/2), and RING finger protein 146 (RNF146), which induce AMOT membrane localization, poly ADP ribosylation, and ubiquitination, respectively. In both zebrafish and mice, the genetic inactivation of AMOT cleavage regulators leads to defective angiogenesis, and the phenotype is rescued by the overexpression of AMOT-CT, a C-terminal AMOT cleavage product. In either physiological or pathological angiogenesis, AMOT-CT is required for vascular expansion, whereas uncleavable AMOT represses this process. Thus, our work uncovers a signaling pathway that regulates angiogenesis by modulating a cleavage-dependent activation of AMOT.


Asunto(s)
Angiomotinas , Pez Cebra , Animales , Ratones , Pez Cebra/metabolismo , Proteínas de Microfilamentos/metabolismo , Péptido Hidrolasas , Péptidos y Proteínas de Señalización Intercelular/genética
6.
EMBO J ; 42(11): e112126, 2023 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-36919851

RESUMEN

The Hippo pathway is a central regulator of organ size and tumorigenesis and is commonly depicted as a kinase cascade, with an increasing number of regulatory and adaptor proteins linked to its regulation over recent years. Here, we propose that two Hippo signaling modules, MST1/2-SAV1-WWC1-3 (HPO1) and MAP4K1-7-NF2 (HPO2), together regulate the activity of LATS1/2 kinases and YAP/TAZ transcriptional co-activators. In mouse livers, the genetic inactivation of either HPO1 or HPO2 module results in partial activation of YAP/TAZ, bile duct hyperplasia, and hepatocellular carcinoma (HCC). On the contrary, inactivation of both HPO1 and HPO2 modules results in full activation of YAP/TAZ, rapid development of intrahepatic cholangiocarcinoma (iCCA), and early lethality. Interestingly, HPO1 has a predominant role in regulating organ size. HPO1 inactivation causes a homogenous YAP/TAZ activation and cell proliferation across the whole liver, resulting in a proportional and rapid increase in liver size. Thus, this study has reconstructed the order of the Hippo signaling network and suggests that LATS1/2 and YAP/TAZ activities are finetuned by HPO1 and HPO2 modules to cause different cell fates, organ size changes, and tumorigenesis trajectories.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Ratones , Animales , Vía de Señalización Hippo , Transducción de Señal , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Carcinoma Hepatocelular/genética , Proteínas Señalizadoras YAP , Neoplasias Hepáticas/genética , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Carcinogénesis/genética , Transformación Celular Neoplásica , Fosfoproteínas/genética , Fosfoproteínas/metabolismo
7.
Cell ; 150(4): 780-91, 2012 Aug 17.
Artículo en Inglés | MEDLINE | ID: mdl-22863277

RESUMEN

The Hippo pathway is crucial in organ size control, and its dysregulation contributes to tumorigenesis. However, upstream signals that regulate the mammalian Hippo pathway have remained elusive. Here, we report that the Hippo pathway is regulated by G-protein-coupled receptor (GPCR) signaling. Serum-borne lysophosphatidic acid (LPA) and sphingosine 1-phosphophate (S1P) act through G12/13-coupled receptors to inhibit the Hippo pathway kinases Lats1/2, thereby activating YAP and TAZ transcription coactivators, which are oncoproteins repressed by Lats1/2. YAP and TAZ are involved in LPA-induced gene expression, cell migration, and proliferation. In contrast, stimulation of Gs-coupled receptors by glucagon or epinephrine activates Lats1/2 kinase activity, thereby inhibiting YAP function. Thus, GPCR signaling can either activate or inhibit the Hippo-YAP pathway depending on the coupled G protein. Our study identifies extracellular diffusible signals that modulate the Hippo pathway and also establishes the Hippo-YAP pathway as a critical signaling branch downstream of GPCR.


Asunto(s)
Receptores Acoplados a Proteínas G/metabolismo , Transducción de Señal , Aciltransferasas , Animales , Proteínas de Ciclo Celular , Línea Celular , Movimiento Celular , Proliferación Celular , Humanos , Lisofosfolípidos/metabolismo , Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , Tamaño de los Órganos , Fosforilación , Proteínas Serina-Treonina Quinasas/metabolismo , Suero/química , Esfingosina/análogos & derivados , Esfingosina/metabolismo , Factores de Transcripción/metabolismo
8.
Bioessays ; : e2400076, 2024 May 17.
Artículo en Inglés | MEDLINE | ID: mdl-38760875

RESUMEN

The Motin family proteins (Motins) are a class of scaffolding proteins consisting of Angiomotin (AMOT), AMOT-like protein 1 (AMOTL1), and AMOT-like protein 2 (AMOTL2). Motins play a pivotal role in angiogenesis, tumorigenesis, and neurogenesis by modulating multiple cellular signaling pathways. Recent findings indicate that Motins are components of the Hippo pathway, a signaling cascade involved in development and cancer. This review discusses how Motins are integrated into the Hippo signaling network, as either upstream regulators or downstream effectors, to modulate cell proliferation and migration. The repression of YAP/TAZ by Motins contributes to growth inhibition, whereas subcellular localization of Motins and their interactions with actin fibers are critical in regulating cell migration. The net effect of Motins on cell proliferation and migration may contribute to their diverse biological functions.

9.
Nature ; 560(7720): 655-660, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-30135582

RESUMEN

Mammalian cells are surrounded by neighbouring cells and extracellular matrix (ECM), which provide cells with structural support and mechanical cues that influence diverse biological processes1. The Hippo pathway effectors YAP (also known as YAP1) and TAZ (also known as WWTR1) are regulated by mechanical cues and mediate cellular responses to ECM stiffness2,3. Here we identified the Ras-related GTPase RAP2 as a key intracellular signal transducer that relays ECM rigidity signals to control mechanosensitive cellular activities through YAP and TAZ. RAP2 is activated by low ECM stiffness, and deletion of RAP2 blocks the regulation of YAP and TAZ by stiffness signals and promotes aberrant cell growth. Mechanistically, matrix stiffness acts through phospholipase Cγ1 (PLCγ1) to influence levels of phosphatidylinositol 4,5-bisphosphate and phosphatidic acid, which activates RAP2 through PDZGEF1 and PDZGEF2 (also known as RAPGEF2 and RAPGEF6). At low stiffness, active RAP2 binds to and stimulates MAP4K4, MAP4K6, MAP4K7 and ARHGAP29, resulting in activation of LATS1 and LATS2 and inhibition of YAP and TAZ. RAP2, YAP and TAZ have pivotal roles in mechanoregulated transcription, as deletion of YAP and TAZ abolishes the ECM stiffness-responsive transcriptome. Our findings show that RAP2 is a molecular switch in mechanotransduction, thereby defining a mechanosignalling pathway from ECM stiffness to the nucleus.


Asunto(s)
Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal , Proteínas de Unión al GTP rap/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Transformación Celular Neoplásica , Matriz Extracelular/química , Matriz Extracelular/genética , Matriz Extracelular/metabolismo , Femenino , Proteínas Activadoras de GTPasa/metabolismo , Quinasas del Centro Germinal , Factores de Intercambio de Guanina Nucleótido/metabolismo , Células HEK293 , Vía de Señalización Hippo , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Ratones , Ratones Endogámicos NOD , Ratones Desnudos , Ratones SCID , Proteínas del Tejido Nervioso/metabolismo , Fosfolipasa C gamma/metabolismo , Fosfoproteínas/metabolismo , Transactivadores , Factores de Transcripción , Proteínas Coactivadoras Transcripcionales con Motivo de Unión a PDZ , Transcriptoma , Proteínas Señalizadoras YAP , Proteínas de Unión al GTP rap/genética
10.
Genes Dev ; 29(22): 2362-76, 2015 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-26588989

RESUMEN

The mechanistic target of rapamycin (mTOR) is a central cell growth controller and forms two distinct complexes: mTORC1 and mTORC2. mTORC1 integrates a wide range of upstream signals, both positive and negative, to regulate cell growth. Although mTORC1 activation by positive signals, such as growth factors and nutrients, has been extensively investigated, the mechanism of mTORC1 regulation by stress signals is less understood. In this study, we identified the Nemo-like kinase (NLK) as an mTORC1 regulator in mediating the osmotic and oxidative stress signals. NLK inhibits mTORC1 lysosomal localization and thereby suppresses mTORC1 activation. Mechanistically, NLK phosphorylates Raptor on S863 to disrupt its interaction with the Rag GTPase, which is important for mTORC1 lysosomal recruitment. Cells with Nlk deletion or knock-in of the Raptor S863 phosphorylation mutants are defective in the rapid mTORC1 inhibition upon osmotic stress. Our study reveals a function of NLK in stress-induced mTORC1 modulation and the underlying biochemical mechanism of NLK in mTORC1 inhibition in stress response.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Complejos Multiproteicos/metabolismo , Presión Osmótica/fisiología , Serina-Treonina Quinasas TOR/metabolismo , Activación Enzimática , Eliminación de Gen , Técnicas de Sustitución del Gen , Células HEK293 , Humanos , Diana Mecanicista del Complejo 1 de la Rapamicina , Proteínas Quinasas Activadas por Mitógenos/genética , Fosforilación , Proteína Reguladora Asociada a mTOR
11.
Genes Dev ; 29(12): 1271-84, 2015 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-26109050

RESUMEN

YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif) are major downstream effectors of the Hippo pathway that influences tissue homeostasis, organ size, and cancer development. Aberrant hyperactivation of YAP/TAZ causes tissue overgrowth and tumorigenesis, whereas their inactivation impairs tissue development and regeneration. Dynamic and precise control of YAP/TAZ activity is thus important to ensure proper physiological regulation and homeostasis of the cells. Here, we show that YAP/TAZ activation results in activation of their negative regulators, LATS1/2 (large tumor suppressor 1/2) kinases, to constitute a negative feedback loop of the Hippo pathway in both cultured cells and mouse tissues. YAP/TAZ in complex with the transcription factor TEAD (TEA domain family member) directly induce LATS2 expression. Furthermore, YAP/TAZ also stimulate the kinase activity of LATS1/2 through inducing NF2 (neurofibromin 2). This feedback regulation is responsible for the transient activation of YAP upon lysophosphatidic acid (LPA) stimulation and the inhibition of YAP-induced cell migration. Thus, this LATS-mediated feedback loop provides an efficient mechanism to establish the robustness and homeostasis of YAP/TAZ regulation.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Retroalimentación Fisiológica/fisiología , Homeostasis/fisiología , Neurofibromina 2/metabolismo , Fosfoproteínas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Factores de Transcripción/metabolismo , Aciltransferasas , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Proteínas de Ciclo Celular , Movimiento Celular , Células Cultivadas , Proteínas de Unión al ADN/metabolismo , Activación Enzimática/fisiología , Femenino , Regulación de la Expresión Génica , Células HEK293 , Vía de Señalización Hippo , Homeostasis/genética , Humanos , Hígado/metabolismo , Masculino , Ratones , Fosfoproteínas/genética , Proteínas Serina-Treonina Quinasas/genética , Factores de Transcripción/genética , Proteínas Supresoras de Tumor/genética , Proteínas Señalizadoras YAP
12.
J Hepatol ; 77(2): 453-466, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35292350

RESUMEN

BACKGROUND & AIMS: The liver is a metabolically active organ and is also 'tolerogenic', exhibiting sophisticated mechanisms of immune regulation that prevent pathogen attacks and tumorigenesis. How metabolism impacts the tumor microenvironment (TME) in hepatocellular carcinoma (HCC) remains understudied. METHODS: We investigated the role of the metabolic regulator SIRT5 in HCC development by conducting metabolomic analysis, gene expression profiling, flow cytometry and immunohistochemistry analyses in oncogene-induced HCC mouse models and human HCC samples. RESULTS: We show that SIRT5 is downregulated in human primary HCC samples and that Sirt5 deficiency in mice synergizes with oncogenes to increase bile acid (BA) production, via hypersuccinylation and increased BA biosynthesis in the peroxisomes of hepatocytes. BAs act as a signaling mediator to stimulate their nuclear receptor and promote M2-like macrophage polarization, creating an immunosuppressive TME that favors tumor-initiating cells (TICs). Accordingly, high serum levels of taurocholic acid correlate with low SIRT5 expression and increased M2-like tumor-associated macrophages (TAMs) in HCC patient samples. Finally, administration of cholestyramine, a BA sequestrant and FDA-approved medication for hyperlipemia, reverses the effect of Sirt5 deficiency in promoting M2-like polarized TAMs and liver tumor growth. CONCLUSIONS: This study uncovers a novel function of SIRT5 in orchestrating BA metabolism to prevent tumor immune evasion and suppress HCC development. Our results also suggest a potential strategy of using clinically proven BA sequestrants for the treatment of patients with HCC, especially those with decreased SIRT5 and abnormally high BAs. LAY SUMMARY: Hepatocellular caricinoma (HCC) development is closely linked to metabolic dysregulation and an altered tumor microenvironment. Herein, we show that loss of the metabolic regulator Sirt5 promotes hepatocarcinogenesis, which is associated with abnormally elevated bile acids and subsequently an immunosuppressive microenvironment that favors HCC development. Targeting this mechanism could be a promising clinical strategy for HCC.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Sirtuinas , Animales , Ácidos y Sales Biliares , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Transformación Celular Neoplásica , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Ratones , Sirtuinas/genética , Microambiente Tumoral
14.
PLoS Biol ; 17(4): e3000201, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30933975

RESUMEN

Cellular senescence is a driver of various aging-associated disorders, including osteoarthritis. Here, we identified a critical role for Yes-associated protein (YAP), a major effector of Hippo signaling, in maintaining a younger state of human mesenchymal stem cells (hMSCs) and ameliorating osteoarthritis in mice. Clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR associated protein 9 nuclease (Cas9)-mediated knockout (KO) of YAP in hMSCs resulted in premature cellular senescence. Mechanistically, YAP cooperated with TEA domain transcriptional factor (TEAD) to activate the expression of forkhead box D1 (FOXD1), a geroprotective protein. YAP deficiency led to the down-regulation of FOXD1. In turn, overexpression of YAP or FOXD1 rejuvenated aged hMSCs. Moreover, intra-articular administration of lentiviral vector encoding YAP or FOXD1 attenuated the development of osteoarthritis in mice. Collectively, our findings reveal YAP-FOXD1, a novel aging-associated regulatory axis, as a potential target for gene therapy to alleviate osteoarthritis.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Factores de Transcripción Forkhead/metabolismo , Osteoartritis/metabolismo , Osteoartritis/patología , Factores de Transcripción/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Proliferación Celular/genética , Senescencia Celular/fisiología , Factores de Transcripción Forkhead/genética , Xenoinjertos , Humanos , Masculino , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/patología , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Ratones SCID , Osteoartritis/genética , Transducción de Señal , Factores de Transcripción/genética , Activación Transcripcional , Regulación hacia Arriba , Proteínas Señalizadoras YAP
15.
EMBO Rep ; 20(6)2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-30979708

RESUMEN

Type I interferon (IFN)-induced Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling drives the expression of IFN-stimulated genes (ISGs) to mediate antiviral response. The strength and duration of JAK-STAT signaling are tightly regulated to ensure effective antiviral defense while avoiding pathological inflammation and autoimmunity. Here, we report that cTAZ, an isoform of the Hippo pathway effector TAZ, is transcribed by an alternative promoter. Although majority of C-terminal sequences of TAZ is retained, cTAZ is not regulated by the Hippo signaling and does not mediate its growth-inhibitory functions. Instead, cTAZ negatively regulates JAK-STAT signaling by inhibiting STAT1/2 nuclear localization and ISG expression, and its expression is induced by type I IFN Thus, cTAZ functions as a modulator of JAK-STAT signaling and may play a role in fine-tuning cellular antiviral response.


Asunto(s)
Quinasas Janus/metabolismo , Regiones Promotoras Genéticas , Factores de Transcripción STAT/metabolismo , Transducción de Señal , Transactivadores/genética , Transcripción Genética , Animales , Perfilación de la Expresión Génica , Vía de Señalización Hippo , Humanos , Ratones , Modelos Biológicos , Fosforilación , Unión Proteica , Multimerización de Proteína , Proteínas Serina-Treonina Quinasas/metabolismo , Transporte de Proteínas , Isoformas de ARN , Factores de Transcripción STAT/química , Proteínas Coactivadoras Transcripcionales con Motivo de Unión a PDZ
16.
Nature ; 519(7541): 57-62, 2015 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-25731159

RESUMEN

Inflammation promotes regeneration of injured tissues through poorly understood mechanisms, some of which involve interleukin (IL)-6 family members, the expression of which is elevated in many diseases including inflammatory bowel diseases and colorectal cancer. Here we show in mice and human cells that gp130, a co-receptor for IL-6 cytokines, triggers activation of YAP and Notch, transcriptional regulators that control tissue growth and regeneration, independently of the gp130 effector STAT3. Through YAP and Notch, intestinal gp130 signalling stimulates epithelial cell proliferation, causes aberrant differentiation and confers resistance to mucosal erosion. gp130 associates with the related tyrosine kinases Src and Yes, which are activated on receptor engagement to phosphorylate YAP and induce its stabilization and nuclear translocation. This signalling module is strongly activated upon mucosal injury to promote healing and maintain barrier function.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Receptor gp130 de Citocinas/metabolismo , Células Epiteliales/citología , Inflamación/metabolismo , Mucosa Intestinal/citología , Fosfoproteínas/metabolismo , Proteínas Proto-Oncogénicas pp60(c-src)/metabolismo , Regeneración , Animales , Peso Corporal , Proteínas de Ciclo Celular , Diferenciación Celular , Proliferación Celular , Modelos Animales de Enfermedad , Activación Enzimática , Células Epiteliales/metabolismo , Células Epiteliales/patología , Células HEK293 , Homeostasis , Humanos , Inflamación/patología , Enfermedades Inflamatorias del Intestino/metabolismo , Enfermedades Inflamatorias del Intestino/patología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Ratones , Proteínas Proto-Oncogénicas c-yes/metabolismo , Receptores Notch/metabolismo , Transducción de Señal , Regulación hacia Arriba , Proteínas Señalizadoras YAP
17.
Genes Dev ; 27(4): 355-71, 2013 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-23431053

RESUMEN

Control of cell number is crucial in animal development and tissue homeostasis, and its dysregulation may result in tumor formation or organ degeneration. The Hippo pathway in both Drosophila and mammals regulates cell number by modulating cell proliferation, cell death, and cell differentiation. Recently, numerous upstream components involved in the Hippo pathway have been identified, such as cell polarity, mechanotransduction, and G-protein-coupled receptor (GPCR) signaling. Actin cytoskeleton or cellular tension appears to be the master mediator that integrates and transmits upstream signals to the core Hippo signaling cascade. Here, we review regulatory mechanisms of the Hippo pathway and discuss potential implications involved in different physiological and pathological conditions.


Asunto(s)
Péptidos y Proteínas de Señalización Intracelular/metabolismo , Transducción de Señal , Animales , Polaridad Celular , Citoesqueleto/metabolismo , Matriz Extracelular/metabolismo , Regulación de la Expresión Génica , Péptidos y Proteínas de Señalización Intracelular/genética , Fosfotransferasas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo
18.
Genes Dev ; 27(11): 1223-32, 2013 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-23752589

RESUMEN

The Hippo tumor suppressor pathway plays an important role in tissue homeostasis that ensures development of functional organs at proper size. The YAP transcription coactivator is a major effector of the Hippo pathway and is phosphorylated and inactivated by the Hippo pathway kinases Lats1/2. It has recently been shown that YAP activity is regulated by G-protein-coupled receptor signaling. Here we demonstrate that cyclic adenosine monophosphate (cAMP), a second messenger downstream from Gαs-coupled receptors, acts through protein kinase A (PKA) and Rho GTPases to stimulate Lats kinases and YAP phosphorylation. We also show that inactivation of YAP is crucial for PKA-induced adipogenesis. In addition, PKA activation in Drosophila inhibits the expression of Yorki (Yki, a YAP ortholog) target genes involved in cell proliferation and death. Taken together, our study demonstrates that Hippo-YAP is a key signaling branch of cAMP and PKA and reveals new insight into mechanisms of PKA in regulating a broad range of cellular functions.


Asunto(s)
Diferenciación Celular , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Proteínas de Drosophila/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal , Aciltransferasas , Adipogénesis , Animales , Línea Celular , Proliferación Celular , AMP Cíclico/metabolismo , Proteínas de Drosophila/antagonistas & inhibidores , Drosophila melanogaster/enzimología , Drosophila melanogaster/metabolismo , Activación Enzimática , Humanos , Ratones , Proteínas Nucleares/antagonistas & inhibidores , Proteínas Nucleares/metabolismo , Fosforilación , Sistemas de Mensajero Secundario/fisiología , Serina-Treonina Quinasa 3 , Transactivadores/antagonistas & inhibidores , Transactivadores/metabolismo , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Proteínas Señalizadoras YAP , Proteínas de Unión al GTP rho/metabolismo
19.
Biochem Biophys Res Commun ; 531(2): 96-104, 2020 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-32773110

RESUMEN

Yes-associated protein (YAP) is a key downstream effector of the highly conserved Hippo signaling pathway, which regulates organ size, regeneration and tumorigenesis. Known classically to function as a transcriptional co-activator, YAP interacts with TEA domain transcription factors (TEAD1-4) to induce expression of target genes. However, a number of genes are repressed upon YAP activation, suggesting a transcriptional repressor role of YAP. Here, we report that TP73 is a direct target gene of YAP, and its transcription is repressed by YAP in a TEAD-independent manner. On the other hand, WW domains of YAP are indispensable for the regulation of TP73 expression, which may recruit YAP to TP73 gene though interaction with ZEB1 and/or RUNX2, two transcriptional repressors. Moreover, YAP-mediated repression of TP73 promotes cancer cell survival in the presence of chemotherapeutic agents, suggesting YAP-TP73 signaling as a mechanism for cancer cell resistance to chemotherapies.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal , Factores de Transcripción/metabolismo , Transcripción Genética , Proteína Tumoral p73/genética , Proteínas Adaptadoras Transductoras de Señales/química , Secuencia de Bases , Línea Celular Tumoral , Subunidad alfa 1 del Factor de Unión al Sitio Principal/metabolismo , Resistencia a Antineoplásicos , Vía de Señalización Hippo , Humanos , Dominios Proteicos , Proteínas Represoras/metabolismo , Factores de Transcripción/química , Proteína Tumoral p73/metabolismo , Proteínas Señalizadoras YAP , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/metabolismo
20.
Genes Dev ; 26(19): 2138-43, 2012 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-22972936

RESUMEN

The Hippo signaling pathway plays a crucial role in tissue growth and tumorigenesis. Core components of the Hippo pathway include the MST1/2 and Lats1/2 kinases. Acting downstream from the Hippo pathway are the YAP/TAZ transcription coactivators, which are inhibited through phosphorylation by Lats. However, upstream signals that regulate the Hippo pathway have not been well delineated. Here we report that stimulation of protease-activated receptors (PARs) activates YAP/TAZ by decreasing phosphorylation and increasing nuclear localization. PAR1 acts through G(12/13) and Rho GTPase to inhibit the Lats1/2 kinase. Our observations establish thrombin as a physiological signal for the Hippo pathway and implicate Hippo-YAP as a key downstream signaling branch of PAR activation.


Asunto(s)
Péptidos y Proteínas de Señalización Intracelular/metabolismo , Proteínas Nucleares/metabolismo , Receptores Proteinasa-Activados/metabolismo , Factores de Transcripción/metabolismo , Citoesqueleto de Actina , Aciltransferasas , Proteínas de Ciclo Celular , Línea Celular Tumoral , Núcleo Celular/enzimología , Activación Enzimática/fisiología , Regulación de la Expresión Génica , Técnicas de Silenciamiento del Gen , Células HEK293 , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Proteínas Nucleares/genética , Oligopéptidos/metabolismo , Fosforilación , Proteínas Serina-Treonina Quinasas/metabolismo , Transporte de Proteínas , ARN Interferente Pequeño/metabolismo , Receptores Proteinasa-Activados/agonistas , Factores de Transcripción/genética
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA