Rho guanosine nucleotide exchange factors are not such bad guys after all in cancera.
Javier Robles-ValeroL Francisco Lorenzo-MartínIsabel Fernández-PisoneroXosé R BusteloPublished in: Small GTPases (2018)
Rho GDP/GTP exchange factors (GEFs), the enzymes that trigger the stimulation of Rho GTPases during cell signaling, are widely deemed as potential therapeutic targets owing to their protumorigenic functions. However, the sparse use of animal models has precluded a full understanding of their pathophysiological roles at the organismal level. In a recent article in Cancer Cell, we have reported that the Vav1 GEF unexpectedly acts as a tumor suppressor by mediating the noncatalytic nucleation of cytoplasmic complexes between the E3 ubiquitin ligase Cbl-b and the active Notch1 intracellular domain (ICN1). These complexes favor the ubiquitinylation-mediated degradation of ICN1 in the proteosome and, therefore, the dampening of ICN1 signals in cells. The elimination of Vav1 in mice exacerbates ICN1 signaling in specific thymocyte subpopulations and, in collaboration with ancillary mutations, prompts the development of ICN1-driven T cell acute lymphoblastic leukemia (T-ALL). This new Vav1-dependent pathway antagonizes the fitness of T-ALL of the TLX+ clinical subtype in humans. As a result, VAV1 is found recurrently silenced in both TLX+ T-ALL cell lines and patients. These results call for an overall reevaluation of Rho GEF function in cancer.
Keyphrases
- acute lymphoblastic leukemia
- protein kinase
- smooth muscle
- end stage renal disease
- ejection fraction
- newly diagnosed
- induced apoptosis
- single cell
- physical activity
- prognostic factors
- cell proliferation
- body composition
- stem cells
- adipose tissue
- squamous cell
- squamous cell carcinoma
- allogeneic hematopoietic stem cell transplantation
- bone marrow
- risk assessment
- oxidative stress
- high fat diet induced
- patient reported outcomes
- neural network