title: IPP5 inhibits neurite growth in primary sensory neurons by maintaining TGF-β/Smad signaling.
abstract: During nerve regeneration, neurite growth is regulated by both intrinsic molecules and extracellular factors. Here, we found that inhibitor 5 of protein phosphatase 1 (IPP5), a newly identified inhibitory subunit of protein phosphatase 1 (PP1), inhibited neurite growth in primary sensory neurons as an intrinsic regulator. IPP5 was highly expressed in the primary sensory neurons of rat dorsal root ganglion (DRG) and was downregulated after sciatic nerve axotomy. Knocking down IPP5 with specific shRNA increased the length of the longest neurite, the total neurite length and the number of neurite ends in cultured rat DRG neurons. Mutation of the PP1-docking motif K(8)IQF(11) or the PP1-inhibiting motif at Thr(34) eliminated the IPP5-induced inhibition of neurite growth. Furthermore, biochemical experiments showed that IPP5 interacted with type I transforming growth factor-β receptor (TβRI) and PP1 and enhanced transforming growth factor-β (TGF-β)/Smad signaling in a PP1-dependent manner. Overexpressing IPP5 in DRG neurons aggravated TGF-β-induced inhibition of neurite growth, which was abolished by blocking PP1 or IPP5 binding to PP1. Blockage of TGF-β signaling with the TβRI inhibitor SB431542 or Smad2 shRNA attenuated the IPP5-induced inhibition of neurite growth. Thus, these data indicate that selectively expressed IPP5 inhibits neurite growth by maintaining TGF-β signaling in primary sensory neurons.
authors.affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Qing-Jian
authors.initials: QJ
authors.lastname: Han
authors.forename: Nan-Nan
authors.initials: NN
authors.lastname: Gao
authors.lastname: Guo-QiangMa
authors.forename: Zhen-Ning
authors.initials: ZN
authors.lastname: Zhang
authors.forename: Wen-Hui
authors.initials: WH
authors.lastname: Yu
authors.forename: Jing
authors.initials: J
authors.lastname: Pan
authors.forename: Qiong
authors.initials: Q
authors.lastname: Wang
authors.forename: Xu
authors.initials: X
authors.lastname: Zhang
authors.forename: Lan
authors.initials: L
authors.lastname: Bao
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018929:Cell Culture Techniques; D015536:Down-Regulation; D055785:Gene Knockdown Techniques; D006801:Humans; D007150:Immunohistochemistry; D008969:Molecular Sequence Data; D016501:Neurites / Q000378:metabolism / Q000502:physiology*; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011984:Sensory Receptor Cells / Q000166:cytology / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: C547313:IPP5 protein, human; D011506:Proteins; C497782:SMAD2 protein, human; D051899:Smad2 Protein; D016212:Transforming Growth Factor beta