Carabias, A., M. Gomez-Hernandez, S. de Cima, A. Rodriguez-Blazquez, A. Moran-Vaquero, P. Gonzalez-Saenz, C. Guerrero and J. M. de Pereda (2020). "Mechanisms of autoregulation of C3G, activator of the GTPase Rap1, and its catalytic deregulation in lymphomas." Sci Signal 13(647). DOI: 10.1126/scisignal.abb7075
Science Signaling


Arturo Carabias, María Gomez Hernandez, Sergio de Cima, Antonio Rodriguez Blazquez, Alba Moran Vaquero, Patricia Gonzalez Saenz, Carmen Guerrero y José María de Pereda (2020)


C3G is a guanine nucleotide exchange factor (GEF) that regulates cell adhesion and migration by activating the GTPase Rap1. The GEF activity of C3G is stimulated by the adaptor proteins Crk and CrkL and by tyrosine phosphorylation. Here, we uncovered mechanisms of C3G autoinhibition and activation. Specifically, we found that two intramolecular interactions regulate the activity of C3G. First, an autoinhibitory region (AIR) within the central domain of C3G binds to and blocks the catalytic Cdc25H domain. Second, the binding of the protein's N-terminal domain to its Ras exchanger motif (REM) is required for its GEF activity. CrkL activated C3G by displacing the AIR/Cdc25HD interaction. Two missense mutations in the AIR found in non-Hodgkin's lymphomas, Y554H and M555K, disrupted the autoinhibitory mechanism. Expression of C3G-Y554H or C3G-M555K in Ba/F3 pro-B cells caused constitutive activation of Rap1 and, consequently, the integrin LFA-1. Our findings suggest that sustained Rap1 activation by deregulated C3G might promote progression of lymphomas and that designing therapeutics to target C3G might treat these malignancies.


La GTPasa pequeña celular Rap1 promueve la migración e invasión de tumores hematológicos. C3G es un factor de intercambio de nucleótido de guanina (GEF) que activa Rap1. En este trabajo hemos desvelado los mecanismos de autoinhibición y activación de C3G. Adicionalmente, hemos identificado mutaciones en C3G en pacientes con linfoma no Hodgkin que causan la activación constitutiva de la vía de señalización C3G-Rap1. Nuestro trabajo sugiere que la activación constitutiva de C3G contribuye al desarrollo de tumores hematológicos, siendo de esta forma una potencial diana terapéutica. 

Foto grupo C3G La Gaceta


Los grupos del Dr José María de Pereda y de la Dra Carmen Guerrero, del Centro de Investigación del Cáncer de Salamanca (CSIC-USAL), colaboran para comprender mecanismos moleculares de procesos de señalización celular que regulan la adhesión celular y sus alteraciones en enfermedades. Para ello emplean aproximaciones multidisciplinares que abarcan desde la biofísica y la biología estructural, hasta modelos animales.

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