RESUMEN
RhoA, Rac1 and CDC42 are small G proteins that play a crucial role in regulating various cellular processes, such as the formation of actin cytoskeleton, cell shape and cell migration. Our recent results suggest that MLL is responsible for maintaining the balance of these small Rho GTPases. MLL depletion affects the stability of Rho GTPases, leading to a decrease in their protein levels and loss of activity. These changes manifest in the form of abnormal cell shape and disrupted actin cytoskeleton, resulting in reduced cell spreading and migration. Interestingly, their chaperone protein RhoGDI1 but not the Rho GTPases, is under the direct transcriptional regulation of MLL. Here, we comment on the possible implications of these observations on the signalling by Rho GTPases protein network.
Asunto(s)
Citoesqueleto de Actina , Proteínas de Unión al GTP rho , Movimiento Celular , Forma de la Célula , Transducción de SeñalRESUMEN
Attainment of proper cell shape and the regulation of cell migration are essential processes in the development of an organism. The mixed lineage leukemia (MLL or KMT2A) protein, a histone 3 lysine 4 (H3K4) methyltransferase, plays a critical role in cell-fate decisions during skeletal development and haematopoiesis in higher vertebrates. Rho GTPases - RhoA, Rac1 and CDC42 - are small G proteins that regulate various key cellular processes, such as actin cytoskeleton formation, the maintenance of cell shape and cell migration. Here, we report that MLL regulates the homeostasis of these small Rho GTPases. Loss of MLL resulted in an abnormal cell shape and a disrupted actin cytoskeleton, which lead to diminished cell spreading and migration. MLL depletion affected the stability and activity of Rho GTPases in a SET domain-dependent manner, but these Rho GTPases were not direct transcriptional targets of MLL. Instead, MLL regulated the transcript levels of their chaperone protein RhoGDI1 (also known as ARHGDIA). Using MDA-MB-231, a triple-negative breast cancer cell line with high RhoGDI1 expression, we show that MLL depletion or inhibition by small molecules reduces tumour progression in nude mice. Our studies highlight the central regulatory role of MLL in Rho/Rac/CDC42 signalling pathways. This article has an associated First Person interview with the first author of the paper.
Asunto(s)
Proteínas de Unión al GTP rho , Inhibidor alfa de Disociación del Nucleótido Guanina rho , Ratones , Animales , Inhibidor alfa de Disociación del Nucleótido Guanina rho/genética , Inhibidor alfa de Disociación del Nucleótido Guanina rho/metabolismo , Proteínas de Unión al GTP rho/genética , Proteínas de Unión al GTP rho/metabolismo , Ratones Desnudos , Histonas/metabolismo , Lisina , Transducción de Señal/fisiología , Proteína de Unión al GTP cdc42/genética , Proteína de Unión al GTP cdc42/metabolismo , Proteína de Unión al GTP rhoA/genética , Proteína de Unión al GTP rhoA/metabolismo , Movimiento Celular/fisiología , Citoesqueleto de Actina/metabolismo , Metiltransferasas/metabolismo , Proteína de Unión al GTP rac1/metabolismo , Actinas/metabolismoRESUMEN
Mixed-lineage leukemia (MLL), along with multisubunit (WDR5, RbBP5, ASH2L, and DPY30) complex catalyzes the trimethylation of H3K4, leading to gene activation. Here, we characterize a chromatin-independent role for MLL during mitosis. MLL and WDR5 localize to the mitotic spindle apparatus, and loss of function of MLL complex by RNAi results in defects in chromosome congression and compromised spindle formation. We report interaction of MLL complex with several kinesin and dynein motors. We further show that the MLL complex associates with Kif2A, a member of the Kinesin-13 family of microtubule depolymerase, and regulates the spindle localization of Kif2A during mitosis. We have identified a conserved WDR5 interaction (Win) motif, so far unique to the MLL family, in Kif2A. The Win motif of Kif2A engages in direct interactions with WDR5 for its spindle localization. Our findings highlight a non-canonical mitotic function of MLL complex, which may have a direct impact on chromosomal stability, frequently compromised in cancer.