title: Kidins220/ARMS is transported by a kinesin-1-based mechanism likely to be involved in neuronal differentiation.
abstract: Kinase D-interacting substrate of 220 kDa/ankyrin repeat-rich membrane spanning (Kidins220/ARMS) is a conserved membrane protein mainly expressed in brain and neuroendocrine cells, which is a downstream target of the signaling cascades initiated by neurotrophins and ephrins. We identified kinesin light chain 1 (KLC1) as a binding partner for Kidins220/ARMS by a yeast two-hybrid screen. The interaction between Kidins220/ARMS and the kinesin-1 motor complex was confirmed by glutathione S-transferase-pull-down and coimmunoprecipitation experiments. In addition, Kidins220/ARMS and kinesin-1 were shown to colocalize in nerve growth factor (NGF)-differentiated PC12 cells. Using Kidins220/ARMS and KLC1 mutants, we mapped the regions responsible for the binding to a short sequence of Kidins220/ARMS, termed KLC-interacting motif (KIM), which is sufficient for the interaction with KLC1. Optimal binding of KIM requires a region of KLC1 spanning both the tetratricopeptide repeats and the heptad repeats, previously not involved in cargo recognition. Overexpression of KIM in differentiating PC12 cells impairs the formation and transport of EGFP-Kidins220/ARMS carriers to the tips of growing neurites, leaving other kinesin-1 dependent processes unaffected. Furthermore, KIM overexpression interferes with the activation of the mitogen-activated protein kinase signaling and neurite outgrowth in NGF-treated PC12 cells. Our results suggest that Kidins220/ARMS-positive carriers undergo a kinesin-1-dependent transport linked to neurotrophin action.
authors.affiliation: Molecular Neuropathobiology, Cancer Research UK London Research Institute, London WC2A 3PX, United Kingdom.
authors.forename: Aurora
authors.initials: A
authors.lastname: Bracale
authors.forename: Fabrizia
authors.initials: F
authors.lastname: Cesca
authors.forename: Veronika E
authors.initials: VE
authors.lastname: Neubrand
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Newsome
authors.forename: Michael
authors.initials: M
authors.lastname: Way
authors.forename: Giampietro
authors.initials: G
authors.lastname: Schiavo
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D016547:Kinesins; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008969:Molecular Sequence Data; D020932:Nerve Growth Factor / Q000494:pharmacology; D009474:Neurons / Q000166:cytology* / Q000187:drug effects; D016716:PC12 Cells; D010750:Phosphoproteins / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D051381:Rats
chemical_list: C000715688:KLC1 protein, human; C418610:Kidins220 protein, rat; C000715690:Klc1 protein, rat; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D010750:Phosphoproteins; D020932:Nerve Growth Factor; D020928:Mitogen-Activated Protein Kinases; D016547:Kinesins