title: Subgroup II PAK-mediated phosphorylation regulates Ran activity during mitosis.
abstract: Ran is an essential GTPase that controls nucleocytoplasmic transport, mitosis, and nuclear envelope formation. These functions are regulated by interaction of Ran with different partners, and by formation of a Ran-GTP gradient emanating from chromatin. Here, we identify a novel level of Ran regulation. We show that Ran is a substrate for p21-activated kinase 4 (PAK4) and that its phosphorylation on serine-135 increases during mitosis. The endogenous phosphorylated Ran and active PAK4 dynamically associate with different components of the microtubule spindle during mitotic progression. A GDP-bound Ran phosphomimetic mutant cannot undergo RCC1-mediated GDP/GTP exchange and cannot induce microtubule asters in mitotic Xenopus egg extracts. Conversely, phosphorylation of GTP-bound Ran facilitates aster nucleation. Finally, phosphorylation of Ran on serine-135 impedes its binding to RCC1 and RanGAP1. Our study suggests that PAK4-mediated phosphorylation of GDP- or GTP-bound Ran regulates the assembly of Ran-dependent complexes on the mitotic spindle.
authors.affiliation: Universités Montpellier 2 et 1, IFR122, 34293 Montpellier, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Bompard
authors.forename: Gabriel
authors.initials: G
authors.lastname: Rabeharivelo
authors.forename: Marie
authors.initials: M
authors.lastname: Frank
authors.forename: Julien
authors.initials: J
authors.lastname: Cau
authors.forename: Claude
authors.initials: C
authors.lastname: Delsert
authors.forename: Nathalie
authors.initials: N
authors.lastname: Morin
mesh_terms: D000818:Animals; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism; D002875:Chromosomes / Q000378:metabolism; D005260:Female; D006153:Guanosine Diphosphate / Q000235:genetics / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000235:genetics / Q000378:metabolism; D008870:Microtubules / Q000235:genetics / Q000378:metabolism; D008938:Mitosis / Q000502:physiology*; D009154:Mutation; D009865:Oocytes / Q000378:metabolism; D010766:Phosphorylation; D011993:Recombinant Fusion Proteins / Q000302:isolation & purification / Q000378:metabolism; D008941:Spindle Apparatus / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D013379:Substrate Specificity; D014981:Xenopus / Q000235:genetics / Q000378:metabolism; D029867:Xenopus Proteins / Q000378:metabolism*; D014982:Xenopus laevis / Q000235:genetics / Q000378:metabolism; D054462:p21-Activated Kinases / Q000378:metabolism*; D020931:ran GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D002843:Chromatin; D011993:Recombinant Fusion Proteins; D029867:Xenopus Proteins; D006153:Guanosine Diphosphate; D006160:Guanosine Triphosphate; C554182:PAK4 protein, Xenopus; D054462:p21-Activated Kinases; D020931:ran GTP-Binding Protein
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