SHIP2 regulates epithelial cell polarity through its lipid product, which binds to Dlg1, a pathway subverted by hepatitis C virus core protein

Awad, Aline; Sar, Sokhavuth; Barre, Ronan; Cariven, Clotilde; Marin, Mickaël; Salles, Jean Pierre; Erneux, Christophé; Samuel, Didier; Gassama‐Diagne, Ama

doi:10.1091/mbc.e12-08-0626

Cited by 46 publications

(63 citation statements)

References 75 publications

(47 reference statements)

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“…In polarized epithelial cells, PtdIns(3,4,5)P 3 and PI3Ks are mainly present on the basolateral membrane 21 while PTEN plays a central role in the formation of the apical membrane 22 . We have recently reported that SHIP2 is present at the basolateral membrane and regulates cell polarization 23 .…”

Section: Introductionmentioning

confidence: 99%

Phosphoinositide 3-kinase p110δ promotes lumen formation through the enhancement of apico-basal polarity and basal membrane organization

et al. 2015

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Signaling triggered by adhesion to the extracellular matrix plays a key role in the spatial orientation of epithelial polarity and formation of lumens in glandular tissues. Phosphoinositide 3-kinase signaling in particular is known to influence the polarization process during epithelial cell morphogenesis. Here, using Madin-Darby canine kidney epithelial cells grown in 3D culture, we show that the p110δ isoform of phosphoinositide 3-kinase colocalizes with focal adhesion proteins at the basal surface of polarized cells. Pharmacological, siRNA- or kinase-dead mediated inhibition of p110δ impair the early stages of lumen formation, resulting in inverted polarized cysts, with no laminin or type IV collagen assembly at cell/extracellular matrix contacts. p110δ also regulates the organization of focal adhesions and membrane localization of dystroglycan. Thus, we uncover a previously unrecognized role for p110δ in epithelial cells in the orientation of the apico-basal axis and lumen formation.

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Section: Introductionmentioning

confidence: 99%

Phosphoinositide 3-kinase p110δ promotes lumen formation through the enhancement of apico-basal polarity and basal membrane organization

et al. 2015

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“…Furthermore, the NS4B protein induces lipogenesis in infected cells by activating the Akt pathway[49]. It has been shown that HCV core protein is expressed at the basal membrane of polarized cells, which leads to a deregulation of actin organization and affects focal contacts by increasing the expression of phosphorylated paxillin at the basal membrane[50]. The same study showed that the deregulation of actin is due to RhoA inhibition and Rac1 activation in cells expressing HCV core protein.…”

Section: Pi3k Activity Cell Polarity and Hcv Infectionmentioning

confidence: 99%

“…This work focused on virus entry and replication and the epithelial to mesenchymal transition, but the effect of PI3K expression on the loss of cell polarity induced by HCV infection was not investigated. Nevertheless, the phenotype of cysts from MDCK cells expressing HCV core protein was of a multi-lumen type[50] which differed markedly from that of the inverted polarity cysts obtained from MDCK cells treated with the p100δ inhibitors IC87114 and CAL-101, but was similar to those from MDCK cells treated with the p110γ and p110β inhibitors AS-605240 and TGX115, respectively[41]. This observation reveals a potential role for p110γ and p110β in the loss of cell polarity induced by HCV infection.…”

Section: Pi3k Activity Cell Polarity and Hcv Infectionmentioning

confidence: 99%

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

Awad

Gassama‐Diagne

2017

WJH

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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.

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“…Another Par protein is liver kinase b1 (Lkb1, or Par4), which phosphorylates and activates a family of AMP-activated protein kinases to regulate cell growth, metabolism and polarity 1. Class I isoforms of phosphoinositide 3-kinases (PI3K)3 and their antagonising phosphatases phosphatase and tensin homologue4 (PTEN)) and SH2 domain containing inositol 5-phosphatase 25 (SHIP2) are crucial determinants of apicobasal polarity (figure 1A).…”

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confidence: 99%