Role of PINCH and Its Partner Tumor Suppressor Rsu-1 in Regulating Liver Size and Tumorigenesis

Abstract

Particularly interesting new cysteine-histidine-rich protein (PINCH) protein is part of the ternary complex known as the IPP (integrin linked kinase (ILK)-PINCH-Parvin-α) complex. PINCH itself binds to ILK and to another protein known as Rsu-1 (Ras suppressor 1). We generated PINCH 1 and PINCH 2 Double knockout mice (referred as PINCH DKO mice). PINCH2 elimination was systemic whereas PINCH1 elimination was targeted to hepatocytes. The genetically modified mice were born normal. The mice were sacrificed at different ages after birth. Soon after birth, they developed abnormal hepatic histology characterized by disorderly hepatic plates, increased proliferation of hepatocytes and biliary cells and increased deposition of extracellular matrix. After a sustained and prolonged proliferation of all epithelial components, proliferation subsided and final liver weight by the end of 30 weeks in livers with PINCH DKO deficient hepatocytes was 40% larger than the control mice. The livers of the PINCH DKO mice were also very stiff due to increased ECM deposition throughout the liver, with no observed nodularity. Mice developed liver cancer by one year. These mice regenerated normally when subjected to 70% partial hepatectomy and did not show any termination defect. Ras suppressor 1 (Rsu-1) protein, the binding partner of PINCH is frequently deleted in human liver cancers. Rsu-1 expression is dramatically decreased in PINCH DKO mouse livers. Increased expression of Rsu-1 suppressed cell proliferation and migration in HCC cell lines. These changes were brought about not by affecting activation of Ras (as its name suggests) but by suppression of Ras downstream signaling via RhoGTPase proteins. In conclusion, our studies suggest that removal of PINCH results in enlargement of liver and tumorigenesis. Decreased levels of Rsu-1, a partner for PINCH and a protein often deleted in human liver cancer, may play an important role in the development of the observed phenotype.

Fgf10-Hippo Epithelial-Mesenchymal Crosstalk Maintains and Recruits Lung Basal Stem Cells

“…Merlin has been shown to stabilized by binding integrin-linked kinase (Ilk) and Ilk-associated proteins such as paxillin and Rsu (Apte et al, 2009; Donthamsetty et al, 2013; Manetti et al, 2013; Serrano et al, 2013); it is degraded during cell spreading by mechanisms that are not fully understood (Cooper and Giancotti, 2014; Das et al, 2015; Okada et al, 2009). Intriguingly, we observed high expression of Merlin levels in secretory and ciliated cells of non-injured lungs and low expression in surviving, spreading epithelial cells after naphthalene-induced airway epithelial injury (Fig.…”

WNT5A Inhibits Hepatocyte Proliferation and Concludes β-Catenin Signaling in Liver Regeneration

“…ajp.amjpathol.org -The American Journal of Pathology such as particularly interesting new cysteine-histidineerich protein, showed defects in termination of LR after being subjected to PH. 8,22 Eventually, it is likely that the LR termination signal may not represent a single entity in the form of a molecular mechanism, but may, in the end, be a function of a cumulative effect of negative regulators of various hepatic mitogenic pathways that may be contributing in tandem to stop LR.…”

Signaling via PINCH: Functions, binding partners and implications in human diseases

“…Loss of PINCH1 diminished binding of Rsu1 to PINCH1 and decreased its expression, which led to increased hepatocyte proliferation (Figure 3). 45 This seems to be contradicted with the role of PINCH1 as discussed above. It should be noted that both PINCH1 and PINCH2 were deleted in hepatocyte in this study.…”