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Vol. 18, Issue 1, 142-152, January 2007

This Article Full Text Full Text (PDF) Supplemental Material All Versions of this Article: E06-05-0453v1 E06-05-0453v2 18/1/142    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bracale, A. Articles by Schiavo, G. Search for Related Content PubMed PubMed Citation Articles by Bracale, A. Articles by Schiavo, G.

Kidins220/ARMS Is Transported by a Kinesin-1–based Mechanism Likely to be Involved in Neuronal Differentiation

Aurora Bracale^*,, Fabrizia Cesca^*,, Veronika E. Neubrand^*, Timothy P. Newsome, Michael Way, and Giampietro Schiavo^*

*Molecular Neuropathobiology and Cell Motility Laboratories, Cancer Research UK London Research Institute, London WC2A 3PX, United Kingdom

Submitted May 24, 2006; Revised September 18, 2006; Accepted October 19, 2006
Monitoring Editor: Erika Holzbaur

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.

This article was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E06-05-0453) on November 1, 2006.

* These authors contributed equally to this work.

Address correspondence to: Giampietro Schiavo (giampietro.schiavo{at}cancer.org.uk)

Abbreviations used: EGFP, enhanced green fluorescent protein; GST, glutathione S-transferase; HR, heptad repeat; KC, C-terminal part (aa 1209-1762) of Kidins220/ARMS; Kidins220/ARMS, kinase D-interacting substrate of 220 kDa/ankyrin repeat-rich membrane spanning; KLC, kinesin light chain; KHC, kinesin heavy chain; kinesin-3/KIF1A, kinesin family member 1A; KIM, KLC-interacting motif; MAPK, mitogen-activated protein kinase; MN, motor neuron; p75^NTR, p75 neurotrophin receptor; mRFP, monomeric red fluorescent protein; NGF, nerve growth factor; PKD, protein kinase D; P-MAPK, phosphorylated mitogen-activated protein kinase; Pp5, protein phosphatase 5; SyD/JIP-3, Sunday Driver/c-Jun NH₂-terminal kinase JNK interacting protein-3; Syt, synaptotagmin I; TPR, tetratricopeptide repeat.

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