2. Academic Validation
  3. Tankyrase Regulates Neurite Outgrowth through Poly(ADP-ribosyl)ation-Dependent Activation of β-Catenin Signaling

Tankyrase Regulates Neurite Outgrowth through Poly(ADP-ribosyl)ation-Dependent Activation of β-Catenin Signaling

  • Int J Mol Sci. 2022 Mar 4;23(5):2834. doi: 10.3390/ijms23052834.
Masato Mashimo 1,  Momoko Kita 1,  Arina Uno 1,  Moe Nii 1,  Moe Ishihara 1,  Takuya Honda 2,  Yuka Gotoh-Kinoshita 3,  Atsuo Nomura 1,  Hiroyuki Nakamura 2,  Toshihiko Murayama 2,  Ryoichi Kizu 3,  Takeshi Fujii 1
Affiliations

Affiliations

  • 1 Department of Pharmacology, Faculty of Pharmaceutical Sciences, Doshisha Women's College of Liberal Arts, Kyotanabe 610-0395, Japan.
  • 2 Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan.
  • 3 Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Doshisha Women's College of Liberal Arts, Kyotanabe 610-0395, Japan.
PMID: 35269974 DOI: 10.3390/ijms23052834
Abstract

Poly(ADP-ribosyl)ation is a post-translational modification of proteins by transferring poly(ADP-ribose) (PAR) to acceptor proteins by the action of poly(ADP-ribose) polymerase (PARP). Two tankyrase (TNKS) isoforms, TNK1 and TNK2 (TNKS1/2), are ubiquitously expressed in mammalian cells and participate in diverse cellular functions, including Wnt/β-catenin signaling, telomere maintenance, glucose metabolism and Mitosis regulation. For Wnt/β-catenin signaling, TNKS1/2 catalyze poly(ADP-ribosyl)ation of Axin, a key component of the β-catenin degradation complex, which allows Axin's ubiquitination and subsequent degradation, thereby activating β-catenin signaling. In the present study, we focused on the functions of TNKS1/2 in neuronal development. In primary hippocampal neurons, TNKS1/2 were detected in the soma and neurites, where they co-localized with PAR signals. Treatment with XAV939, a selective TNKS1/2 inhibitor, suppressed neurite outgrowth and synapse formation. In addition, XAV939 also suppressed norepinephrine uptake in PC12 cells, a rat pheochromocytoma cell line. These effects likely resulted from the inhibition of β-catenin signaling through the stabilization of Axin, which suggests TNKS1/2 enhance Axin degradation by modifying its poly(ADP-ribosyl)ation, thereby stabilizing Wnt/β-catenin signaling and, in turn, promoting neurite outgrowth and synapse formation.

Keywords

neurite outgrowth; poly(ADP-ribosyl)ation; tankyrase; β-catenin.

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