Tankyrase-Binding Protein TNKS1BP1 Regulates Actin Cytoskeleton Rearrangement and Cancer Cell Invasion

• Published in: Cancer research (Chicago, Ill.) Ill.), 2017-05, Vol.77 (9), p.2328-2338
• Main Authors: Ohishi, Tomokazu, Yoshida, Haruka, Katori, Masamichi, Migita, Toshiro, Muramatsu, Yukiko, Miyake, Mao, Ishikawa, Yuichi, Saiura, Akio, Iemura, Shun-Ichiro, Natsume, Tohru, Seimiya, Hiroyuki
• Format: Article
• Language: English
• Subjects: Actin; Actin Cytoskeleton - genetics; Actin Cytoskeleton - pathology; Actin Depolymerizing Factors - genetics; Cancer; CapZ Actin Capping Protein - genetics; Cell Adhesion - genetics; Cell Line, Tumor; Cofilin; Cytoskeleton; Female; Filaments; Focal Adhesions - genetics; Gene Expression Regulation, Neoplastic; Humans; Invasiveness; Lamellipodia; Lim Kinases - genetics; Male; Malignancy; Neoplasm Invasiveness - genetics; Neoplasm Invasiveness - pathology; Pancreatic cancer; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - pathology; Phosphorylation; Poly (ADP-Ribose) Polymerase-1 - genetics; Proteins; Pseudopodia; rho-Associated Kinases - genetics; Telomeric Repeat Binding Protein 1 - biosynthesis; Telomeric Repeat Binding Protein 1 - genetics; Wnt protein; Wnt Signaling Pathway; β-Catenin
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-16-1846

Tankyrase, a PARP that promotes telomere elongation and Wnt/β-catenin signaling, has various binding partners, suggesting that it has as-yet unidentified functions. Here, we report that the tankyrase-binding protein TNKS1BP1 regulates actin cytoskeleton and cancer cell invasion, which is closely associated with cancer progression. TNKS1BP1 colocalized with actin filaments and negatively regulated cell invasion. In TNKS1BP1-depleted cells, actin filament dynamics, focal adhesion, and lamellipodia ruffling were increased with activation of the ROCK/LIMK/cofilin pathway. TNKS1BP1 bound the actin-capping protein CapZA2. TNKS1BP1 depletion dissociated CapZA2 from the cytoskeleton, leading to cofilin phosphorylation and enhanced cell invasion. Tankyrase overexpression increased cofilin phosphorylation, dissociated CapZA2 from cytoskeleton, and enhanced cell invasion in a PARP activity-dependent manner. In clinical samples of pancreatic cancer, TNKS1BP1 expression was reduced in invasive regions. We propose that the tankyrase-TNKS1BP1 axis constitutes a posttranslational modulator of cell invasion whose aberration promotes cancer malignancy. .