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.
Highlights
There has been a long standing question in liver biology as to what regulates the size of the liver
Our present studies show that PINCH and Ras suppressor 1 (Rsu-1) are a part of the growth termination signaling of Integrin Linked Kinase-PINCH-Parvin (IPP) which mediates signaling of extracellular matrix and integrins and which is activated in conjunction with termination of liver regeneration
All components of the IPP complex were downregulated at day 1 after partial hepatectomy (PH) when there is a peak in rat hepatocyte proliferation (Figure 1)
Summary
There has been a long standing question in liver biology as to what regulates the size of the liver. Recent studies in our lab have shown the important role of extracellular matrix (ECM) signaling via the Integrin Linked Kinase-PINCH-Parvin (IPP) complex in regulating the size of the liver. We have previously generated hepatocyte-specific integrin linked kinase (ILK) KO mice The impact of this deletion to the liver has given us many exciting results related to the role of ECM in regulating liver size and termination of liver regeneration after partial hepatectomy (Phx) [4,5,6]. The objective of the present study whether other components of IPP complex besides ILK have a role in regulating the size of the liver. This study shows that Rsu-1, whose expression is dramatically downregulated in the PINCH DKO mice, is as potentially a key molecule by which PINCH (and IPP complex) could exert its growth suppressing effects on hepatocytes. Our present studies show that PINCH and Rsu-1 are a part of the growth termination signaling of IPP which mediates signaling of extracellular matrix and integrins and which is activated in conjunction with termination of liver regeneration
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