p120-catenin is an adherens junction-associated protein that controls E-cadherin function and stability. p120-catenin also binds intracellular proteins, such as the small GTPase RhoA. In this paper, we identify the p120-catenin N-terminal regulatory domain as the docking site for RhoA. Moreover, we demonstrate that the binding of RhoA to p120-catenin is tightly controlled by the Src family-dependent phosphorylation of p120-catenin on tyrosine residues. The phosphorylation induced by Src and Fyn tyrosine kinases on p120-catenin induces opposite effects on RhoA binding. Fyn, by phosphorylating a residue located in the regulatory domain of p120-catenin (Tyr112), inhibits the interaction of this protein with RhoA. By contrast, the phosphorylation of Tyr217 and Tyr228 by Src promotes a better affinity of p120-catenin towards RhoA. In agreement with these biochemical data, results obtained in cell lines support the important role of these phosphorylation sites in the regulation of RhoA activity by p120-catenin. Taken together, these observations uncover a new regulatory mechanism acting on p120-catenin that contributes to the fine-tuned regulation of the RhoA pathways during specific signaling events.E-cadherin function is controlled posttranslationally by a family of proteins, named catenins, that bind to its cytosolic tail. Two members of this family, p120-catenin and ␤-catenin, interact at different sites of the E-cadherin molecule and are engaged in distinct functions. Whereas ␤-catenin is required for recruiting the actin cytoskeleton, p120-catenin is necessary for the stabilization of E-cadherin at the cell membrane (3). As a consequence, E-cadherin is rapidly internalized and degraded in the absence of p120-catenin (7, 13). Consequently, p120-catenin ablation in vivo causes E-cadherin deficiency, leading to severe defects in adhesion, cell polarity, and epithelial morphogenesis (7).Besides this role in regulating E-cadherin stability, p120-catenin interacts with other proteins involved in the modulation of cell-to-cell contacts. For instance, p120-catenin associates with Fer and Fyn tyrosine kinases (16,27,36). These kinases specifically phosphorylate ␤-catenin in Tyr142 (27), a modification that promotes release of ␤-catenin from the adherens junctional complex and transport to the nucleus (2, 27). Moreover, p120-catenin can interact with the Yes tyrosine kinase (27) and with a number of phosphotyrosine (PTyr) phosphatases, such as PTP (39), DEP1 (12), and SHP-1 (14, 21). These multiple associations suggest a role for p120-catenin as a scaffold protein for enzymes regulating events such as the stability of the adherens junctional complex (29).p120-catenin modulates the activity of other cellular factors. Similarly to ␤-catenin, it can be detected in the nucleus (34), where it interacts with the transcriptional factor Kaiso (6). Studies performed with Xenopus laevis have demonstrated that association of p120-catenin relieves the repression caused by Kaiso on Wnt signaling (17,25).Several results indicate that p...

The IM exerts a direct influence in the development of PH in rats with diet-induced NASH and dysbiosis; PH, insulin resistance, and endothelial dysfunction revert when a healthy IM is restored. (Hepatology 2018;67:1485-1498).

In liver cirrhosis, the circulatory hemodynamic alterations of portal hypertension significantly contribute to many of the clinical manifestations of the disease. In the physiopathology of this vascular alteration, mesenteric splanchnic vasodilation plays an essential role by initiating the hemodynamic process. Numerous studies performed in cirrhotic patients and animal models have shown that this splanchnic vasodilation is the result of an important increase in local and systemic vasodilators and the presence of a splanchnic vascular hyporesponsiveness to vasoconstrictors. Among the molecules and factors known to be potentially involved in this arterial vasodilation, nitric oxide seems to have a crucial role in the physiopathology of this vascular alteration. However, none of the wide variety of mediators can be described as solely responsible, since this phenomenon is multifactorial in origin. Moreover, angiogenesis and vascular remodeling processes also seem to play a role. Finally, the sympathetic nervous system is thought to be involved in the pathogenesis of the hyperdynamic circulation associated with portal hypertension, although the nature and extent of its role is not completely understood. In this review, we discuss the different mechanisms known to contribute to this complex phenomenon.

Plakoglobin is a protein closely related to ␤-catenin that links desmosomal cadherins to intermediate filaments. Plakoglobin can also substitute for ␤-catenin in adherens junctions, providing a connection between E-cadherin and ␣-catenin. Association of ␤-catenin with E-cadherin and ␣-catenin is regulated by phosphorylation of specific tyrosine residues; modification of ␤-catenin Tyr654 and Tyr142 decreases binding to E-cadherin and ␣-catenin, respectively. We show here that plakoglobin can also be phosphorylated on tyrosine residues, but unlike ␤-catenin, this modification is not always associated with disrupted association with junctional components. Protein tyrosine kinases present distinct specificities on ␤-catenin and plakoglobin, and phosphorylation of ␤-catenin-equivalent Tyr residues of plakoglobin affects its interaction with components of desmosomes or adherens junctions differently. For instance, Src, which mainly phosphorylates Tyr86 in ␤-catenin, modifies Tyr643 in plakoglobin, decreasing the interaction with E-cadherin and ␣-catenin and increasing the interaction with the ␣-catenin-equivalent protein in desmosomes, desmoplakin. The tyrosine kinase Fer, which modifies ␤-catenin Tyr142, lessening its association with ␣-catenin, phosphorylates plakoglobin Tyr549 and exerts the contrary effect: it raises the binding of plakoglobin to ␣-catenin. These results suggest that tyrosine kinases like Src or Fer modulate desmosomes and adherens junctions differently. Our results also indicate that phosphorylation of Tyr549 and the increased binding of plakoglobin to components of adherens junctions can contribute to the upregulation of the transcriptional activity of the ␤-catenin-Tcf-4 complex observed in many epithelial tumor cells.␤-Catenin and plakoglobin (also known as ␥-catenin) are two closely related proteins essential for the establishment and maintenance of cell-cell contacts among epithelial cells. In adherens junctions, ␤-catenin links the cytosolic domain of the transmembrane protein E-cadherin to ␣-catenin, which in turn directly or indirectly associates with the actin cytoskeleton (2, 33, 38). Plakoglobin can substitute for ␤-catenin in adherens junctions. In addition, plakoglobin is a component of the desmosomes, where it mediates the association of desmosomal cadherins, desmocollin and desmoglein, to desmoplakin and the intermediate filament cytoskeleton (15,21). This role of plakoglobin is specific and cannot be exerted by ␤-catenin, even though both proteins are structurally similar. Besides this role, ␤-catenin also has a signaling activity as a member of the Wnt pathway. When released from E-cadherin and ␣-catenin, ␤-catenin can migrate to the nucleus where, through its interaction with the Tcf family of transcription factors, it can activate the transcription of a rapidly increasing number of genes involved in embryonic development and tumorigenesis (5, 37).Probably as a consequence of the importance of this pathway, the translocation of ␤-catenin to the nucleus is tightly controlled thro...

␤-Catenin plays a central role in the establishment and regulation of adherens junctions because it interacts with E-cadherin and, through ␣-catenin, with the actin cytoskeleton. ␤-Catenin is composed of three domains: a central armadillo repeat domain and two N-and Cterminal tails. The C-tail interacts with the armadillo domain and limits its ability to bind E-cadherin and other cofactors. The two ␤-catenin tails are mutually interregulated because the C-tail is also necessary for binding of the N-tail to the armadillo domain. Moreover, the N-tail restricts the interaction of the C-tail with the central domain. Depletion of either of the two tails has consequences for the binding of factors at the other end: deletion of the C-tail increases ␣-catenin binding, whereas deletion of the N-tail blocks E-cadherin interaction to the armadillo repeats. As an effect of the interconnection of the tails, the association of ␣-catenin and E-cadherin to ␤-catenin is interdependent. Thus, binding of ␣-catenin to the N-tail, through conformational changes that affect the C-tail, facilitates the association of E-cadherin. These results indicate that different cofactors of ␤-catenin bind coordinately to this protein and indicate how the two terminal ends of ␤-catenin exquisitely modulate intermolecular binding within junctional complexes.

Non-alcoholic steatohepatitis (NASH) is a common chronic liver disorder in developed countries, with the associated clinical complications driven by portal hypertension (PH). PH may precede fibrosis development, probably due to endothelial dysfunction at early stages of the disease. Our aim was to characterize liver sinusoidal endothelial cell (LSEC) dedifferentiation/capillarization and its contribution to PH in NASH, together with assessing statins capability to revert endothelial function improving early NASH stages. Sprague-Dawley rats were fed with high fat glucose-fructose diet (HFGFD), or control diet (CD) for 8 weeks and then treated with simvastatin (sim) (10 mg·kg−1·day−1), atorvastatin (ato) (10 mg·kg−1·day−1) or vehicle during 2 weeks. Biochemical, histological and hemodynamic determinations were carried out. Sinusoidal endothelial dysfunction was assessed in individualized sorted LSEC and hepatic stellate cells (HSC) from animal groups and in whole liver samples. HFGFD rats showed full NASH features without fibrosis but with significantly increased portal pressure compared with CD rats (10.47 ± 0.37 mmHg vs 8.30 ± 0.22 mmHg; p < 0.001). Moreover, HFGFD rats showed a higher percentage of capillarized (CD32b−/CD11b−) LSEC (8% vs 1%, p = 0.005) showing a contractile phenotype associated to HSC activation. Statin treatments caused a significant portal pressure reduction (sim: 9.29 ± 0.25 mmHg, p < 0.01; ato: 8.85 ± 0.30 mmHg, p < 0.001), NASH histology reversion, along with significant recovery of LSEC differentiation and a regression of HSC activation to a more quiescent phenotype. In an early NASH model without fibrosis with PH, LSEC transition to capillarization and HSC activation are reverted by statin treatment inducing portal pressure decrease and NASH features improvement.

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