PI3K/SHIP2/PTEN pathway in cell polarity and hepatitis C virus pathogenesis

Abstract

Hepatitis C virus (HCV) infects hepatocytes, polarized cells in the liver. Chronic HCV infection often leads to steatosis, fibrosis, cirrhosis and hepatocellular carcinoma, and it has been identified as the leading cause of liver transplantation worldwide. The HCV replication cycle is dependent on lipid metabolism and particularly an accumulation of lipid droplets in host cells. Phosphoinositides (PIs) are minor phospholipids enriched in different membranes and their levels are tightly regulated by specific PI kinases and phosphatases. PIs are implicated in a vast array of cellular responses that are central to morphogenesis, such as cytoskeletal changes, cytokinesis and the recruitment of downstream effectors to govern mechanisms involved in polarization and lumen formation. Important reviews of the literature identified phosphatidylinositol (PtdIns) 4-kinases, and their lipid products PtdIns(4)P, as critical regulators of the HCV life cycle. SH2-containing inositol polyphosphate 5-phosphatase (SHIP2), phosphoinositide 3-kinase (PI3K) and their lipid products PtdIns(3,4)P2 and PtdIns(3,4,5)P3, respectively, play an important role in the cell membrane and are key to the establishment of apicobasal polarity and lumen formation. In this review, we will focus on these new functions of PI3K and SHIP2, and their deregulation by HCV, causing a disruption of apicobasal polarity, actin organization and extracellular matrix assembly. Finally we will highlight the involvement of this pathway in the event of insulin resistance and nonalcoholic fatty liver disease related to HCV infection.

Involvement of Hepatic SHIP2 and PI3K/Akt Signalling in the Regulation of Plasma Insulin by Xiaoyaosan in Chronic Immobilization-Stressed Rats

“…As mentioned in the introduction, SHIP2 is a key regulator of glucose homeostasis and can be targeted when treating diseases that affect insulin metabolism [58]. Transgenic mice expressing catalytically inactive SHIP2 have displayed altered lipid metabolism and insulin secretion [59].…”

Upsetting the Balance: When Viruses Manipulate Cell Polarity Control

“…During infection, the HCV core protein has been shown to inhibit the SHIP2 phosphatase, leading to downregulation of Dlg1 and Scrib at the basolateral membrane. This disrupts both apico-basal and PCP and morphology and causes the formation of multilumen cysts, which compromise hepatocyte function [148,149]. The core protein also induces methylation of the E-cadherin promoter, leading to its downregulation [150], while the viral NS5A protein activates PI3 kinase activity, leading to increased β-catenin stability and upregulating c-Myc expression [151,152], these activities together tending to promote EMT-associated changes in cell polarity.…”

IQGAP2 Inhibits Migration and Invasion of Gastric Cancer Cells via Elevating SHIP2 Phosphatase Activity

“…The current evidence suggests that the pro-or anti-tumorigenic effect of SHIP2 largely depends on cell context, and SHIP2 multi-functional domains may account for its contradictory roles in different cancer cells. Besides the central 5-phosphatase catalytic domain, SHIP2 possesses an N-terminal SH2 domain, a C-terminal proline-rich domain (PRD), and a unique sterile alpha motif (SAM) domain, which affect a variety of biological functions, including cell adhesion, migration, invasion and receptor internalization [21][22][23]. Although our previous work indicated the reduced expression of SHIP2 and its tumor-suppressive role in GC [12], the precise role of SHIP2 in the migration and invasion of GC cells remains to be delineated.…”