Tyrosine phosphorylation of YAP‐1 in biliary epithelial cells mediates posthepatectomy liver regeneration and is affected by serotonin

Abstract

Experimental data suggested activation of yes-associated protein (YAP-1) as a critical regulator of liver regeneration (LR). Serotonin (5-HT) promotes LR in rodent models and has been proposed to act via YAP-1. How 5-HT affects LR is incompletely understood. A possible mechanism how 5-HT affects human LR was explored. Sixty-one patients were included. Tissue samples prior and 2 h after induction of LR were collected. Circulating levels of 5-HT and osteopontin (OPN) were assessed. YAP-1, its phosphorylation states, cytokeratin 19 (CK-19) and OPN were assessed using immunofluorescence. A mouse model of biliary epithelial cells (BECs) specific deletion of YAP/TAZ was developed. YAP-1 increased as early as 2 h after induction of LR (p = 0.025) predominantly in BECs. BEC specific deletion of YAP/TAZ reduced LR after 70% partial hepatectomy in mice (Ki67%, p < 0.001). SSRI treatment, depleting intra-platelet 5-HT, abolished YAP-1 and OPN induction upon LR. Portal vein 5-HT levels correlated with intrahepatic YAP-1 expression upon LR (R = 0.703, p = 0.035). OPN colocalized with YAP-1 in BECs and its circulating levels increased in the liver vein 2 h after induction of LR (p = 0.017). In the context of LR tyrosine-phosphorylated YAP-1 significantly increased (p = 0.042). Stimulating BECs with 5-HT resulted in increased YAP-1 activation via tyrosine-phosphorylation and subsequently increased OPN expression. BECs YAP-1 appears to be critical for LR in mice and humans.Our evidence suggests that 5-HT, at least in part, exerts its pro-regenerative effects via YAP-1 tyrosine-phosphorylation in BECs and subsequent OPNdependent paracrine immunomodulation.

YAP/TAZ: Molecular pathway and disease therapy

“…On the one hand, threonine and serine S127, S352, S274, S381 on YAP and S89/311 on TAZ can be phosphorylated so that YAP/TAZ can accumulate in the cytoplasm 121–123 . On the other hand, the latest research shows that in biliary epithelial cells, serotonin (5‐HT) plays an important role in activating YAP by phosphating tyrosine on YAP 124 …”

“…[121][122][123] On the other hand, the latest research shows that in biliary epithelial cells, serotonin (5-HT) plays an important role in activating YAP by phosphating tyrosine on YAP. 124 Acetylation and deacetylation of YAP also significantly affect its activity. Under the action of nuclear acetyltransferases CREB binding protein (CBP) and p300, the Lys-494 and Lys-497 at the C-terminal of YAP can be acetylated.…”

“… 121 , 122 , 123 On the other hand, the latest research shows that in biliary epithelial cells, serotonin (5‐HT) plays an important role in activating YAP by phosphating tyrosine on YAP. 124 …”