Mechanisms of autoregulation of C3G, activator of the GTPase Rap1, and its catalytic deregulation in lymphomas

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Mechanisms of autoregulation of C3G, activator of the GTPase Rap1, and its catalytic deregulation in lymphomas. / Carabias, Arturo; Gomez-Hernandez, Maria; de Cima, Sergio; Rodriguez-Blazquez, Antonio; Moran-Vaquero, Alba; Gonzalez-Saenz, Patricia; Guerrero, Carmen; de Pereda, Jose M.

In: Science Signaling, Vol. 13, No. 647, 7075, 2020.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Carabias, A, Gomez-Hernandez, M, de Cima, S, Rodriguez-Blazquez, A, Moran-Vaquero, A, Gonzalez-Saenz, P, Guerrero, C & de Pereda, JM 2020, 'Mechanisms of autoregulation of C3G, activator of the GTPase Rap1, and its catalytic deregulation in lymphomas', Science Signaling, vol. 13, no. 647, 7075. https://doi.org/10.1126/scisignal.abb7075

APA

Carabias, A., Gomez-Hernandez, M., de Cima, S., Rodriguez-Blazquez, A., Moran-Vaquero, A., Gonzalez-Saenz, P., Guerrero, C., & de Pereda, J. M. (2020). Mechanisms of autoregulation of C3G, activator of the GTPase Rap1, and its catalytic deregulation in lymphomas. Science Signaling, 13(647), [7075]. https://doi.org/10.1126/scisignal.abb7075

Vancouver

Carabias A, Gomez-Hernandez M, de Cima S, Rodriguez-Blazquez A, Moran-Vaquero A, Gonzalez-Saenz P et al. Mechanisms of autoregulation of C3G, activator of the GTPase Rap1, and its catalytic deregulation in lymphomas. Science Signaling. 2020;13(647). 7075. https://doi.org/10.1126/scisignal.abb7075

Author

Carabias, Arturo ; Gomez-Hernandez, Maria ; de Cima, Sergio ; Rodriguez-Blazquez, Antonio ; Moran-Vaquero, Alba ; Gonzalez-Saenz, Patricia ; Guerrero, Carmen ; de Pereda, Jose M. / Mechanisms of autoregulation of C3G, activator of the GTPase Rap1, and its catalytic deregulation in lymphomas. In: Science Signaling. 2020 ; Vol. 13, No. 647.

Bibtex

@article{594ecfb3f109473badb6708228bedb72,
title = "Mechanisms of autoregulation of C3G, activator of the GTPase Rap1, and its catalytic deregulation in lymphomas",
abstract = "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.",
keywords = "NUCLEOTIDE EXCHANGE FACTOR, PROTEIN SECONDARY STRUCTURE, SH3 DOMAIN, SIGNALING PATHWAYS, TYROSINE KINASE, CELL-ADHESION, C-ABL, CRK, BINDING, RAS",
author = "Arturo Carabias and Maria Gomez-Hernandez and {de Cima}, Sergio and Antonio Rodriguez-Blazquez and Alba Moran-Vaquero and Patricia Gonzalez-Saenz and Carmen Guerrero and {de Pereda}, {Jose M.}",
year = "2020",
doi = "10.1126/scisignal.abb7075",
language = "English",
volume = "13",
journal = "Science Signaling",
issn = "1945-0877",
publisher = "American Association for the Advancement of Science",
number = "647",

}

RIS

TY - JOUR

T1 - Mechanisms of autoregulation of C3G, activator of the GTPase Rap1, and its catalytic deregulation in lymphomas

AU - Carabias, Arturo

AU - Gomez-Hernandez, Maria

AU - de Cima, Sergio

AU - Rodriguez-Blazquez, Antonio

AU - Moran-Vaquero, Alba

AU - Gonzalez-Saenz, Patricia

AU - Guerrero, Carmen

AU - de Pereda, Jose M.

PY - 2020

Y1 - 2020

N2 - 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.

AB - 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.

KW - NUCLEOTIDE EXCHANGE FACTOR

KW - PROTEIN SECONDARY STRUCTURE

KW - SH3 DOMAIN

KW - SIGNALING PATHWAYS

KW - TYROSINE KINASE

KW - CELL-ADHESION

KW - C-ABL

KW - CRK

KW - BINDING

KW - RAS

U2 - 10.1126/scisignal.abb7075

DO - 10.1126/scisignal.abb7075

M3 - Journal article

C2 - 32873726

VL - 13

JO - Science Signaling

JF - Science Signaling

SN - 1945-0877

IS - 647

M1 - 7075

ER -

ID: 250122616