Arg-Gly-Asp-binding integrins activate hepatic stellate cells via the hippo signaling pathway

• Published in: Cellular signalling 2022-11, Vol.99, p.110437-110437, Article 110437
• Main Authors: Kitsugi, Kensuke, Noritake, Hidenao, Matsumoto, Moe, Hanaoka, Tomohiko, Umemura, Masahiro, Yamashita, Maho, Takatori, Shingo, Ito, Jun, Ohta, Kazuyoshi, Chida, Takeshi, Ulmasov, Barbara, Neuschwander-Tetri, Brent A., Suda, Takafumi, Kawata, Kazuhito
• Format: Article
• Language: English
• Subjects: Apoptosis; Cell proliferation; Focal adhesion kinase; Liver fibrosis; Transforming growth factor-β1; Yes-associated protein
• ISSN: 0898-6568; 1873-3913
• DOI: 10.1016/j.cellsig.2022.110437

Liver fibrosis characterizes advanced chronic liver disease, and persistent activation of hepatic stellate cells (HSCs) is the primary cause of excessive hepatic fibrogenesis. CWHM12, an analog of the arginine-glycine-aspartic acid (RGD) amino acid sequence found in specific integrins, improves liver fibrosis; however, the detailed mechanisms remain unclear. This study aimed to clarify the cell signaling mechanisms of CWHM12 in activated HSCs. Immortalized human HSC lines, LX-2 and TWNT-1, were used to evaluate the effects of CWHM12 on intracellular signaling via the disruption of RGD-binding integrins. CWHM12 strongly promoted phosphorylation and inhibited the nuclear accumulation of Yes-associated protein (YAP), which is a critical effector of the Hippo signaling pathway, leading to the inhibition of proliferation, suppression of viability, promotion of apoptosis, and induction of cell cycle arrest at the G1 phase in activated HSCs. Further investigations revealed that inhibition of TGF-β was involved in the consequences of CWHM12. Moreover, CWHM12 suppressed focal adhesion kinase (FAK) phosphorylation; consequently, Src, phosphatidylinositol 3-kinase, pyruvate dehydrogenase kinase 1, and serine-threonine kinase phosphorylation led to the translocation of YAP. These favorable effects of CWHM12 on activated HSCs were reversed by inhibiting FAK. These results indicate that pharmacological inhibition of RGD-binding integrins suppresses activated HSCs by blocking the Hippo signaling pathway, a cellular response which may be valuable in the treatment of hepatic fibrosis. •Inhibition of RGD-binding integrins prevents the activation of HSCs.•Inhibition of RGD-binding integrins induces apoptosis and cell cycle arrest of HSCs.•Inhibition of RGD-binding integrins reduces the YAP translocation into the nucleus.•RGD-binding integrins regulate the Hippo signaling pathway via TGF-β and FAK.