title: Dynamic microtubules catalyze formation of navigator-TRIO complexes to regulate neurite extension.
abstract: Neurite extension is regulated by multiple signaling cascades that ultimately converge on the actin and microtubule networks [1]. Rho GTPases, molecular switches that oscillate between an inactive, GDP-bound state and an active, GTP-bound state, play a pivotal role in controlling actin cytoskeleton dynamics in the growth cone, whereas the dynamic behavior and interactions of microtubules are largely regulated by proteins called plus-end-tracking proteins (+TIPs), which associate with the ends of growing microtubules. Here, we show that the +TIP Navigator 1 (NAV1) is important for neurite outgrowth and interacts and colocalizes with TRIO, a Rho guanine nucleotide exchange factor that enables neurite outgrowth by activating the Rho GTPases Rac1 and RhoG. We find that binding of NAV1 enhances the affinity of TRIO for Rac1 and RhoG, and that NAV1 regulates TRIO-mediated Rac1 activation and neurite outgrowth. TRIO is also a +TIP, as it interacts with the core +TIP EB1 and tracks microtubule plus ends via EB1 and NAV1. Strikingly, the EB1-mediated recruitment of TRIO to microtubule ends is required for proper neurite outgrowth, and stabilization of the microtubule network by paclitaxel affects both the TRIO-NAV1 interaction and the accumulation of these proteins in neurite extensions. We propose that EB1-labeled ends of dynamic microtubules facilitate the formation and localization of functional NAV1-TRIO complexes, which in turn regulate neurite outgrowth by selectively activating Rac1. Our data reveal a novel link between dynamic microtubules, actin cytoskeleton remodeling, and neurite extension.
authors: Department of Cell Biology and Genetics, Erasmus MC, P.O. Box 2040, 3000 CA Rotterdam, the Netherlands.
authors: Jeffrey
authors: J
authors: van Haren
authors: CRBM-CNRS, UMR 5237, University of Montpellier, 34293 Montpellier, France.
authors: Jérôme
authors: J
authors: Boudeau
authors: CRBM-CNRS, UMR 5237, University of Montpellier, 34293 Montpellier, France.
authors: Susanne
authors: S
authors: Schmidt
authors: Department of Cell Biology and Genetics, Erasmus MC, P.O. Box 2040, 3000 CA Rotterdam, the Netherlands.
authors: Sreya
authors: S
authors: Basu
authors: Department of Cell Biology and Genetics, Erasmus MC, P.O. Box 2040, 3000 CA Rotterdam, the Netherlands.
authors: Zhe
authors: Z
authors: Liu
authors: Department of Cell Biology and Genetics, Erasmus MC, P.O. Box 2040, 3000 CA Rotterdam, the Netherlands.
authors: Dave
authors: D
authors: Lammers
authors: Proteomics Centre, Erasmus MC, P.O. Box 2040, 3000 CA Rotterdam, the Netherlands.
authors: Jeroen
authors: J
authors: Demmers
authors: CRBM-CNRS, UMR 5237, University of Montpellier, 34293 Montpellier, France.
authors: Jabran
authors: J
authors: Benhari
authors: Department of Cell Biology and Genetics, Erasmus MC, P.O. Box 2040, 3000 CA Rotterdam, the Netherlands.
authors: Frank
authors: F
authors: Grosveld
authors: CRBM-CNRS, UMR 5237, University of Montpellier, 34293 Montpellier, France. Electronic address: anne.debant@crbm.cnrs.fr.
authors: Anne
authors: A
authors: Debant
authors: Department of Cell Biology and Genetics, Erasmus MC, P.O. Box 2040, 3000 CA Rotterdam, the Netherlands. Electronic address: n.galjart@erasmusmc.nl.
authors: Niels
authors: N
authors: Galjart
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D020439:Growth Cones / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D008869:Microtubule-Associated Proteins; D008870:Microtubules / Q000378:metabolism; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism*; D016501:Neurites / Q000502:physiology*; D011485:Protein Binding; D015398:Signal Transduction; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D008840:Microfilament Proteins; D008869:Microtubule-Associated Proteins; C477056:NAV1 protein, human; D009414:Nerve Growth Factors; C107953:RAC1 protein, human; C425471:TRIOBP protein, human; C075397:RHOG protein, human; D020830:rac1 GTP-Binding Protein; D020741:rho GTP-Binding Proteins