YAP nuclear translocation through dynein and acetylated microtubule controls fibroblast activation

Abstract

1Myofibroblasts are the major cell type that are responsible for increase the mechanical 2 stiffness in fibrotic tissues. It has well documented that the TGF-/Smad axis is required for 3 myofibroblast differentiation under the rigid substrate condition. However, the mechanism 4 driving myofibroblast differentiation in soft substrates remains unknown. In this research, we 5 demonstrated that interaction of yes-associated protein (YAP) and acetylated microtubule via 6 dynein, a microtubule motor protein drives nuclear localization of YAP in soft matrix, which in 7 turn increased TGF-1 induced transcriptional activity of Smad for myofibroblast 8 differentiation. Pharmacological and genetical disruption of dynein impaired the nuclear 9 translocation of YAP and decreased the TGF-1 induced Smad activity even though 10 phosphorylation and nuclear localization of Smad occurred normally in -tubulin 11 acetyltransferase (-TAT1) knockout cell. Moreover, microtubule acetylation prominently 12 appeared in the fibroblast-like cells nearby the blood vessel in the fibrotic liver induced by 13 CCl 4 administration which were conversely decreased by TGF-receptor inhibitor. As a 14

Potent Small-Molecule Inhibitors Targeting Acetylated Microtubules as Anticancer Agents Against Triple-Negative Breast Cancer

“…Studies have been conducted on cell mobility according to the characteristics of microtubules [ 37 ], and some studies have focused on the relationship between microtubule acetylation and cancer progression. We reported recently that acetylated microtubules are required for TGF-β-induced cancer-associated fibroblast activation in breast cancer tissues [ 38 ], suggesting that microtubule acetylation seems to be a prerequisite cellular factor for breast cancer progression and that the downregulation of microtubule acetylation is important in breast cancer therapy. In this regard, we attempted to screen small chemical inhibitors for interfering with microtubule acetylation.…”