DISC1 regulates neurotrophin-induced axon elongation via interaction with Grb2.
Disrupted-in-Schizophrenia-1 (DISC1) is a candidate gene for susceptibility of schizophrenia. In the accompanying paper (Taya et al., 2006), we report that DISC1 acts as a linker between Kinesin-1 and DISC1-interacting molecules, such as NudE-like, lissencephaly-1, and 14-3-3epsilon. Here we identified growth factor receptor bound protein 2 (Grb2) as a novel DISC1-interacting molecule. Grb2 acts as an adaptor molecule that links receptor tyrosine kinases and the Ras-extracellular signal-regulated kinase (ERK) pathway. DISC1 formed a ternary complex with Grb2 and kinesin heavy chain KIF5A of Kinesin-1. In cultured rat hippocampal neurons, both DISC1 and Grb2 partially colocalized at the distal part of axons. Knockdown of DISC1 or kinesin light chains of Kinesin-1 by RNA interference inhibited the accumulation of Grb2 from the distal part of axons. Knockdown of DISC1 also inhibited the neurotrophin-3 (NT-3)-induced phosphorylation of ERK-1/2 at the distal part of axons and inhibited NT-3-induced axon elongation. These results suggest that DISC1 is required for NT-3-induced axon elongation and ERK activation at the distal part of axons by recruiting Grb2 to axonal tips.
Shinoda
Tomoyasu
T
Department of Cell Pharmacology, Graduate School of Medicine, Nagoya University, Showa, Nagoya 466-8550, Japan.
Taya
Shinichiro
S
Tsuboi
Daisuke
D
Hikita
Takao
T
Matsuzawa
Reiko
R
Kuroda
Setsuko
S
Iwamatsu
Akihiro
A
Kaibuchi
Kozo
K
D000818:Animals; D001369:Axons / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure*; D001693:Biological Transport, Active / Q000187:drug effects; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D019556:COS Cells; D049108:Cell Enlargement; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D051380:GRB2 Adaptor Protein / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D020933:Neurotrophin 3 / Q000008:administration & dosage*; D025941:Protein Interaction Mapping; D051381:Rats
C498795:Disc1 protein, rat; D051380:GRB2 Adaptor Protein; C495950:Grb2 protein, rat; D009419:Nerve Tissue Proteins; D020933:Neurotrophin 3