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

Masato Mashimo,Atsuo Nomura,Toshihiko Murayama,Momoko Kita,Hiroyuki Nakamura,Takeshi Fujii,Arina Uno,Moe Nii,Moe Ishihara,Ryoichi Kizu,Yuka Gotoh-Kinoshita,Takuya Honda

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.

Highlights

Introduction iationsPoly(ADP-ribose) polymerase (PARP) catalyzes ADP-ribosylation, a reversible posttranslational protein modification in which one or more ADP-ribose units are transferred from donor NAD+ to target proteins [1–3]
We investigated the effect of tankyrase 1 and 2 (TNKS1/2) on neurite outgrowth in mouse primary hippocampal neurons and rat adrenal medullary neuron-like cells, PC12 cells
To understand the role of poly(ADP-ribose) polymerase (PARP) isoforms in neurons, beginning one day after the start of culture, primary hippocampal neurons were incubated with various PARP inhibitors, including ABT888, a selective PARP1 and PARP2 inhibitor; PJ34, a nonselective PARP

Summary

Introduction

Poly(ADP-ribose) polymerase (PARP) catalyzes ADP-ribosylation, a reversible posttranslational protein modification in which one or more ADP-ribose units are transferred from donor NAD+ to target proteins [1–3]. This modification alters the activity and subcellular localization of the target proteins, thereby regulating diverse cellular functions. Tankyrase 1 and 2 (TNKS1/2), known as PARP5a and PARP5b, respectively, each contain two unique structural domains not contained by other PARP members: an ankyrin repeat domain and a sterile alpha motif (SAM). The ankyrin repeat domain serves as the interface for interaction with acceptor proteins, while the SAM regulates the polymerization of TNKS [4–7]. As TNKS1 and 2 are highly homologous and exhibit similar localizations at telomers, centrosomes, nuclear pores, Golgi complexes, cytoplasm and Licensee MDPI, Basel, Switzerland

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