title: LMTK1/AATYK1 is a novel regulator of axonal outgrowth that acts via Rab11 in a Cdk5-dependent manner.
abstract: Axonal outgrowth is a coordinated process of cytoskeletal dynamics and membrane trafficking; however, little is known about proteins responsible for regulating the membrane supply. LMTK1 (lemur kinase 1)/AATYK1 (apoptosis-associated tyrosine kinase 1) is a serine/threonine kinase that is highly expressed in neurons. We recently reported that LMTK1 plays a role in recycling endosomal trafficking in CHO-K1 cells. Here we explore the role of LMTK1 in axonal outgrowth and its regulation by Cdk5 using mouse brain cortical neurons. LMTK1 was expressed and was phosphorylated at Ser34, the Cdk5 phosphorylation site, at the time of axonal outgrowth in culture and colocalized with Rab11A, the small GTPase that regulates recycling endosome traffic, at the perinuclear region and in the axon. Overexpression of the unphosphorylated mutant LMTK1-S34A dramatically promoted axonal outgrowth in cultured neurons. Enhanced axonal outgrowth was diminished by the inactivation of Rab11A, placing LMTK1 upstream of Rab11A. Unexpectedly, the downregulation of LMTK1 by knockdown or gene targeting also significantly enhanced axonal elongation. Rab11A-positive vesicles were transported anterogradely more quickly in the axons of LMTK1-deficient neurons than in those of wild-type neurons. The enhanced axonal outgrowth was reversed by LMTK1-WT or the LMTK1-S34D mutant, which mimics the phosphorylated state, but not by LMTK1-S34A. Thus, LMTK1 can negatively control axonal outgrowth by regulating Rab11A activity in a Cdk5-dependent manner, and Cdk5-LMTK1-Rab11 is a novel signaling pathway involved in axonal outgrowth.
authors.affiliation: Department of Biological Sciences, Tokyo Metropolitan University, Tokyo 192-0397, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Takano
authors.forename: Mineko
authors.initials: M
authors.lastname: Tomomura
authors.forename: Nozomu
authors.initials: N
authors.lastname: Yoshioka
authors.forename: Koji
authors.initials: K
authors.lastname: Tsutsumi
authors.forename: Yukichi
authors.initials: Y
authors.lastname: Terasawa
authors.forename: Taro
authors.initials: T
authors.lastname: Saito
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kawano
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kamiguchi
authors.forename: Mitsunori
authors.initials: M
authors.lastname: Fukuda
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Hisanaga
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D001369:Axons / Q000201:enzymology / Q000502:physiology*; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D051360:Cyclin-Dependent Kinase 5 / Q000502:physiology*; D005260:Female; D020439:Growth Cones / Q000201:enzymology / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D010766:Phosphorylation / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D020691:rab GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D000099193:rab11 GTP-Binding Proteins
chemical_list: D051017:Apoptosis Regulatory Proteins; D051360:Cyclin-Dependent Kinase 5; D011505:Protein-Tyrosine Kinases; D020691:rab GTP-Binding Proteins; D000099193:rab11 GTP-Binding Proteins; C485554:Aatk protein, mouse; C495906:Cdk5 protein, mouse