Robles-Valero Javier, Lorenzo-Martín L Francisco, Menacho-Márquez Mauricio, Fernández-Pisonero Isabel, Abad Antonio, Camós Mireia, Toribio María L, Espinosa Lluis, Bigas Anna, Bustelo Xosé R
Centro de Investigación del Cáncer, CSIC - University of Salamanca, 37007 Salamanca, Spain; Instituto de Biología Molecular y Celular del Cáncer, CSIC - University of Salamanca, 37007 Salamanca, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), CSIC - University of Salamanca, 37007 Salamanca, Spain.
Centro de Investigación del Cáncer, CSIC - University of Salamanca, 37007 Salamanca, Spain; Instituto de Biología Molecular y Celular del Cáncer, CSIC - University of Salamanca, 37007 Salamanca, Spain.
Cancer Cell. 2017 Nov 13;32(5):608-623.e9. doi: 10.1016/j.ccell.2017.10.004.
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.
Rho鸟嘌呤核苷酸交换因子（GEFs）是刺激Rho GTP酶的酶，由于其促肿瘤功能而被视为潜在的治疗靶点。然而，目前对它们在肿瘤中的病理生物学作用谱的了解仍然非常有限。我们在此报告，GEF Vav1在未成熟T细胞中意外地具有肿瘤抑制功能。该功能需要泛素连接酶Cbl-b与Notch1细胞内结构域（ICN1）之间形成复合物的非催化成核作用，这有利于ICN1的泛素化和降解。Vav1的缺失促进ICN1信号传导和T细胞急性淋巴细胞白血病（T-ALL）的发展。Vav1的下调对于TLX临床亚型的人类T-ALL发病机制至关重要，进一步强调了该途径的抑制作用。
Zotero 插件
