RAN GTPase is a RASSF1A effector involved in controlling microtubule organization

Dallol, A., Hesson, L.B., Matallanas, D., Cooper, W.N., O'Neill, E., Maher, E.R., Kolch, W. and Latif, F. (2009) RAN GTPase is a RASSF1A effector involved in controlling microtubule organization. Current Biology, 19(14), pp. 1227-1232. (doi: 10.1016/j.cub.2009.05.064)

Abstract

Summary RASSF1A is a tumor suppressor gene that is inactivated by hypermethylation of its promoter region in most types of human cancers [1], [2] and [3]. The incidence of spontaneous or induced tumors is significantly higher in Rassf1a-/- mice than in wild-type mice, confirming the tumor suppressor function of RASSF1A [4] and [5]. RASSF1A promotes apoptosis mainly through its interaction with the proapoptotic serine/threonine STE20-like kinases MST1 and 2 [6] and [7]. However, Rassf1a-/- mice do not show overt signs of deregulated apoptosis [4] and [5], suggesting that other RASSF1A effectors are also critical for tumor suppression. In a proteomics screen, we identified RAN GTPase, MST1 and 2 kinases, and [alpha]- and [gamma]-tubulin as RASSF1A-interacting proteins. We show that RASSF1A-induced microtubule hyperstability, a hallmark of RASSF1A expression [8] and [9], is RAN-GTP dependent. RASSF1A promotes the accumulation of the GTP-bound form of RAN via the MST2-induced phosphorylation of RCC1. Depletion of RASSF1A results in mislocalization of RCC1 to the mitotic spindle and spindle poles, leading to mitotic spindle abnormalities and prometaphase block. A similar mitotic delay is also observed with MST2 depletion. These findings reveal a mechanism for how RASSF1A controls microtubule stability and for how its loss compromises the integrity of the mitotic spindle, leading to aneuploidy and tumorigenesis

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Kolch, Prof Walter
• Authors: Dallol, A., Hesson, L.B., Matallanas, D., Cooper, W.N., O'Neill, E., Maher, E.R., Kolch, W., and Latif, F.
• Subjects: Q Science > QH Natural history > QH301 Biology
• College/School: College of Medical Veterinary and Life Sciences
• Journal Name: Current Biology
• ISSN: 0960-9822
• Published Online: 25 June 2009