A Paradoxical Tumor-Suppressor Role for the Rac1 Exchange Factor Vav1 in T Cell Acute Lymphoblastic Leukemia
Robles-Valero, Javier (Centro de Investigación del Cáncer)
Lorenzo-Martín, L. Francisco (Centro de Investigación del Cáncer)
Menacho-Márquez, Mauricio (Centro de Investigación del Cáncer)
Fernández-Pisonero, Isabel (Centro de Investigación del Cáncer)
Abad, Antonio (Centro de Investigación del Cáncer)
Camós, Mireia (Hospital Sant Joan de Déu (Manresa))
Toribio, María L. (Centro de Biología Molecular Severo Ochoa)
Espinosa, Lluís (Institut Hospital del Mar d'Investigacions Mèdiques)
Bigas Salvans, Anna (Institut Hospital del Mar d'Investigacions Mèdiques)
Bustelo, Xosé R. (Centro de Investigación del Cáncer)
Universitat Autònoma de Barcelona

Date:	2017
Abstract:	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. Robles-Valero et al. find that Vav1 facilitates binding of Cbl-b to the intracellular domain of Notch1 (ICN1) and promotes ICN1 degradation. Loss of Vav1 induces T cell acute lymphoblastic leukemia (T-ALL) by increasing ICN1 signaling, and TLX inhibits Vav1 expression to stimulate ICN1 signaling in TLX + T-ALL.
Grants:	Ministerio de Economía y Competitividad SAF2015-64556-R Ministerio de Economía y Competitividad RD12-0036-0002 Ministerio de Economía y Competitividad PI13-00448 Ministerio de Economía y Competitividad SAF2013-40922-R Ministerio de Economía y Competitividad RD12-0036-0054 Ministerio de Economía y Competitividad SAF2013-44857-R Ministerio de Economía y Competitividad RD12-0036-0075
Note:	Altres ajuts: X.R.B. is supported by grants from the Castilla-León Government (BIO/SA01/15, CSI049U16), [...], Worldwide Cancer Research (14-1248), Ramón Areces Foundation, and Spanish Society Against Cancer.
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Notch1 ; Rho GTPases ; Cbl-b ; TLX ; Lymphoma ; Animal models ; Gene expression profiling
Published in:	Cancer Cell, Vol. 32 (november 2017) , p. 608-623.e9, ISSN 1878-3686

DOI: 10.1016/j.ccell.2017.10.004
PMID: 29136506

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