2026-04-13T16:51:31Zhttps://recercat.cat/oai/request

oai:recercat.cat:10230/344422025-12-20T16:43:11Zcom_2072_6col_2072_452952

00925njm 22002777a 4500 dc Robles-Valero, Javier author Lorenzo-Martín, L. Francisco author Menacho Márquez, Mauricio author Fernández-Pisonero, Isabel author Abad, Antonio author Camós, Mireia author Toribio, María Luisa author Espinosa Blay, Lluís author Bigas Salvans, Anna author Bustelo, Xose R. author 2018-04-25T07:22:32Z 2018-04-25T07:22:32Z 2017 Rho guanine exchange factors (GEFs), the enzymes that stimulate Rho GTPases, are deemed as potential therapeutic targets owing to their protumorigenic functions. However, the understanding of the spectrum of their pathobiological roles in tumors is still very limited. We report here that the GEF Vav1 unexpectedly possesses tumor-suppressor functions in immature T cells. This function entails the noncatalytic nucleation of complexes between the ubiquitin ligase Cbl-b and the intracellular domain of Notch1 (ICN1) that favors ICN1 ubiquitinylation and degradation. Ablation of Vav1 promotes ICN1 signaling and the development of T cell acute lymphoblastic leukemia (T-ALL). The downregulation of Vav1 is essential for the pathogenesis of human T-ALL of the TLX+ clinical subtype, further underscoring the suppressor role of this pathway X.R.B. is supported by grants from the Castilla-León Government (BIO/SA01/15, CSI049U16), Spanish Ministry of Economy and Competitiveness (MINECO) (SAF2015-64556-R, RD12/0036/0002), Worldwide Cancer Research (14-1248), Ramón Areces Foundation, and Spanish Society Against Cancer. L.E. (PI13/00448), A.B. (SAF2013-40922-R, RD12/0036/0054), and M.L.T. (SAF2013-44857-R, RD12/0036/0075) are supported by MINECO grants. Spanish funding is partially supported by the European Regional Development Fund. We thank M. Blázquez for laboratory work, R. Valiente for ChIP-seq analyses, M. Dosil for comments on the manuscript, and CIC facilities' personnel for technical assistance Limfomes Leucèmia Cbl-b Notch1 Rho GTPases TLX Animal models Gene expression profiling Lymphoma A Paradoxical Tumor-Suppressor Role for the Rac1 Exchange Factor Vav1 in T Cell Acute Lymphoblastic Leukemia