TY - JOUR
T1 - KIF1Bβ mutations detected in hereditary neuropathy impair IGF1R transport and axon growth
AU - Xu, Fang
AU - Takahashi, Hironori
AU - Tanaka, Yosuke
AU - Ichinose, Sotaro
AU - Niwa, Shinsuke
AU - Wicklund, Matthew P.
AU - Hirokawa, Nobutaka
N1 - Funding Information:
This study was supported by the Japan Society for the Promotion of Science KAKENHI grants JP23000013 and JP16H06372 to N. Hirokawa. F. Xu was supported by a Honjo International Scholarship Foundation scholarship from Itoen Company and served as a research assistant at The University of Tokyo during the four years of PhD candidate period.
Publisher Copyright:
© 2018 Xu et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
PY - 2018/10/1
Y1 - 2018/10/1
N2 - KIF1Bβ is a kinesin-3 family anterograde motor protein essential for neuronal development, viability, and function. KIF1Bβ mutations have previously been reported in a limited number of pedigrees of Charcot-Marie-Tooth disease type 2A (CMT2A) neuropathy. However, the gene responsible for CMT2A is still controversial, and the mechanism of pathogenesis remains elusive. In this study, we show that the receptor tyrosine kinase IGF1R is a new direct binding partner of KIF1Bβ, and its binding and transport is specifically impaired by the Y1087C mutation of KIF1Bβ, which we detected in hereditary neuropathic patients. The axonal outgrowth and IGF-I signaling of Kif1b−/− neurons were significantly impaired, consistent with decreased surface IGF1R expression. The complementary capacity of KIF1Bβ-Y1087C of these phenotypes was significantly impaired, but the binding capacity to synaptic vesicle precursors was not affected. These data have supported the relevance of KIF1Bβ in IGF1R transport, which may give new clue to the neuropathic pathogenesis.
AB - KIF1Bβ is a kinesin-3 family anterograde motor protein essential for neuronal development, viability, and function. KIF1Bβ mutations have previously been reported in a limited number of pedigrees of Charcot-Marie-Tooth disease type 2A (CMT2A) neuropathy. However, the gene responsible for CMT2A is still controversial, and the mechanism of pathogenesis remains elusive. In this study, we show that the receptor tyrosine kinase IGF1R is a new direct binding partner of KIF1Bβ, and its binding and transport is specifically impaired by the Y1087C mutation of KIF1Bβ, which we detected in hereditary neuropathic patients. The axonal outgrowth and IGF-I signaling of Kif1b−/− neurons were significantly impaired, consistent with decreased surface IGF1R expression. The complementary capacity of KIF1Bβ-Y1087C of these phenotypes was significantly impaired, but the binding capacity to synaptic vesicle precursors was not affected. These data have supported the relevance of KIF1Bβ in IGF1R transport, which may give new clue to the neuropathic pathogenesis.
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U2 - 10.1083/JCB.201801085
DO - 10.1083/JCB.201801085
M3 - Article
C2 - 30126838
AN - SCOPUS:85054074602
VL - 217
SP - 3480
EP - 3496
JO - Journal of Cell Biology
JF - Journal of Cell Biology
SN - 0021-9525
IS - 10
ER -