RAN GTPase Is a RASSF1A Effector Involved in Controlling Microtubule Organization

摘要: RASSF1A is a tumor suppressor gene that inactivated by hypermethylation of its promoter region in most types human cancers. The incidence spontaneous or induced tumors significantly higher Rassf1a(-/-) mice than wild-type mice, confirming the function RASSF1A. promotes apoptosis mainly through interaction with proapoptotic serine/threonine STE20-like kinases MST1 and 2. However, do not show overt signs deregulated apoptosis, suggesting other effectors are also critical for suppression. In proteomics screen, we identified RAN GTPase, 2 kinases, alpha- gamma-tubulin as RASSF1A-interacting proteins. We RASSF1A-induced microtubule hyperstability, hallmark expression, RAN-GTP dependent. accumulation GTP-bound form via MST2-induced phosphorylation RCC1. Depletion results mislocalization RCC1 to mitotic spindle poles, leading abnormalities prometaphase block. A similar delay observed MST2 depletion. These findings reveal mechanism how controls stability loss compromises integrity spindle, aneuploidy tumorigenesis.