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1.
Nature ; 464(7291): 1052-7, 2010 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-20393564

RESUMEN

The four receptors of the Notch family are widely expressed transmembrane proteins that function as key conduits through which mammalian cells communicate to regulate cell fate and growth. Ligand binding triggers a conformational change in the receptor negative regulatory region (NRR) that enables ADAM protease cleavage at a juxtamembrane site that otherwise lies buried within the quiescent NRR. Subsequent intramembrane proteolysis catalysed by the gamma-secretase complex liberates the intracellular domain (ICD) to initiate the downstream Notch transcriptional program. Aberrant signalling through each receptor has been linked to numerous diseases, particularly cancer, making the Notch pathway a compelling target for new drugs. Although gamma-secretase inhibitors (GSIs) have progressed into the clinic, GSIs fail to distinguish individual Notch receptors, inhibit other signalling pathways and cause intestinal toxicity, attributed to dual inhibition of Notch1 and 2 (ref. 11). To elucidate the discrete functions of Notch1 and Notch2 and develop clinically relevant inhibitors that reduce intestinal toxicity, we used phage display technology to generate highly specialized antibodies that specifically antagonize each receptor paralogue and yet cross-react with the human and mouse sequences, enabling the discrimination of Notch1 versus Notch2 function in human patients and rodent models. Our co-crystal structure shows that the inhibitory mechanism relies on stabilizing NRR quiescence. Selective blocking of Notch1 inhibits tumour growth in pre-clinical models through two mechanisms: inhibition of cancer cell growth and deregulation of angiogenesis. Whereas inhibition of Notch1 plus Notch2 causes severe intestinal toxicity, inhibition of either receptor alone reduces or avoids this effect, demonstrating a clear advantage over pan-Notch inhibitors. Our studies emphasize the value of paralogue-specific antagonists in dissecting the contributions of distinct Notch receptors to differentiation and disease and reveal the therapeutic promise in targeting Notch1 and Notch2 independently.


Asunto(s)
Anticuerpos/farmacología , Anticuerpos/uso terapéutico , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Receptores Notch/antagonistas & inhibidores , Inhibidores de la Angiogénesis/inmunología , Inhibidores de la Angiogénesis/farmacología , Inhibidores de la Angiogénesis/uso terapéutico , Animales , Anticuerpos/efectos adversos , Anticuerpos/inmunología , Especificidad de Anticuerpos/inmunología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Células Caliciformes/efectos de los fármacos , Células Caliciformes/patología , Humanos , Ratones , Ratones Endogámicos BALB C , Células 3T3 NIH , Neoplasias/irrigación sanguínea , Neoplasias/patología , Neovascularización Patológica/tratamiento farmacológico , Biblioteca de Péptidos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patología , Receptor Notch1/antagonistas & inhibidores , Receptor Notch1/inmunología , Receptor Notch2/antagonistas & inhibidores , Receptor Notch2/inmunología , Receptores Notch/genética , Receptores Notch/inmunología , Receptores Notch/metabolismo , Transducción de Señal/efectos de los fármacos
2.
Neuron ; 40(3): 501-14, 2003 Oct 30.
Artículo en Inglés | MEDLINE | ID: mdl-14642275

RESUMEN

Targeted deletion of focal adhesion kinase (fak) in the developing dorsal forebrain resulted in local disruptions of the cortical basement membrane located between the neuroepithelium and pia-meninges. At disruption sites, clusters of neurons invaded the marginal zone. Retraction of radial glial endfeet, midline fusion of brain hemispheres, and gliosis also occurred, similar to type II cobblestone lissencephaly as seen in congenital muscular dystrophy. Interestingly, targeted deletion of fak in neurons alone did not result in cortical ectopias, indicating that fak deletion from glia is required for neuronal mislocalization. Unexpectedly, fak deletion specifically from meningeal fibroblasts elicited similar cortical ectopias in vivo and altered laminin organization in vitro. These observations provide compelling evidence that FAK plays a key signaling role in cortical basement membrane assembly and/or remodeling. In addition, FAK is required within neurons during development because neuron-specific fak deletion alters dendritic morphology in the absence of lamination defects.


Asunto(s)
Membrana Basal/metabolismo , Corteza Cerebral/anomalías , Distrofias Musculares/metabolismo , Neuronas/metabolismo , Proteínas Tirosina Quinasas/metabolismo , Animales , Astrocitos/metabolismo , Astrocitos/patología , Proteínas Bacterianas/metabolismo , Membrana Basal/patología , Western Blotting , Calbindina 2 , Calbindinas , Proteínas Portadoras/metabolismo , Moléculas de Adhesión Celular Neuronal/metabolismo , Células Cultivadas , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Corteza Cerebral/ultraestructura , Proteínas del Citoesqueleto/metabolismo , Proteínas de Unión al ADN/metabolismo , Modelos Animales de Enfermedad , Duramadre , Distroglicanos , Embrión de Mamíferos , Proteínas de la Matriz Extracelular/metabolismo , Fibroblastos/metabolismo , Fibroblastos/virología , Quinasa 1 de Adhesión Focal , Proteína-Tirosina Quinasas de Adhesión Focal , Proteína Ácida Fibrilar de la Glía/metabolismo , Heterocigoto , Proteínas de Homeodominio/metabolismo , Inmunohistoquímica , Infecciones , Péptidos y Proteínas de Señalización Intracelular , Laminas/metabolismo , Glicoproteínas de Membrana/metabolismo , Ratones , Ratones Noqueados , Microscopía Electrónica , Proteínas Asociadas a Microtúbulos/metabolismo , Distrofias Musculares/congénito , Distrofias Musculares/genética , Distrofias Musculares/patología , Mutación , Proteínas del Tejido Nervioso , Neuronas/patología , Factores de Transcripción Otx , Fosfopiruvato Hidratasa/metabolismo , Fosfotirosina/metabolismo , Pruebas de Precipitina , Proteínas Tirosina Quinasas/deficiencia , Proteínas Tirosina Quinasas/genética , Proteína Reelina
3.
Nat Neurosci ; 7(10): 1059-69, 2004 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-15378065

RESUMEN

The formation of neuronal networks in the central nervous system (CNS) requires precise control of axonal branch development and stabilization. Here we show that cell-specific ablation of the murine gene Ptk2 (more commonly known as fak), encoding focal adhesion kinase (FAK), increases the number of axonal terminals and synapses formed by neurons in vivo. Consistent with this, fak mutant neurons also form greater numbers of axonal branches in culture because they have increased branch formation and reduced branch retraction. Expression of wild-type FAK, but not that of several FAK variants that prevent interactions with regulators of Rho family GTPases including the p190 Rho guanine nuclear exchange factor (p190RhoGEF), rescues the axonal arborization phenotype observed in fak mutant neurons. In addition, expression of a mutant p190RhoGEF that cannot associate with FAK results in a phenotype very similar to that of neurons lacking FAK. Thus, FAK functions as a negative regulator of axonal branching and synapse formation, and it seems to exert its actions, in part, through Rho family GTPases.


Asunto(s)
Axones/metabolismo , Encéfalo/anomalías , Diferenciación Celular/genética , Proteínas Tirosina Quinasas/metabolismo , Sinapsis/metabolismo , Animales , Axones/ultraestructura , Encéfalo/metabolismo , Encéfalo/ultraestructura , Células Cultivadas , Corteza Cerebelosa/anomalías , Corteza Cerebelosa/metabolismo , Corteza Cerebelosa/ultraestructura , Proteínas de Unión al ADN , Regulación hacia Abajo/genética , Quinasa 1 de Adhesión Focal , Proteína-Tirosina Quinasas de Adhesión Focal , Proteínas Activadoras de GTPasa , Regulación del Desarrollo de la Expresión Génica/genética , Factores de Intercambio de Guanina Nucleótido/genética , Factores de Intercambio de Guanina Nucleótido/metabolismo , Hipocampo/anomalías , Hipocampo/metabolismo , Hipocampo/ultraestructura , Ratones , Ratones Transgénicos , Microscopía Electrónica de Transmisión , Mutación/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fenotipo , Regiones Promotoras Genéticas/genética , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteínas Tirosina Quinasas/genética , Ratas , Proteínas Represoras , Sinapsis/ultraestructura
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