PTEN lipid phosphatase inactivation links the hippo and PI3K/Akt pathways to induce gastric tumorigenesis

Abstract

BackgroundPhosphatase and tensin homolog (PTEN) is an important tumor suppressor gene, and its encoded protein has activities of both a protein phosphatase and a lipid phosphatase. However, the substitution effect of protein phosphatase activity remains unclear. PI3K/Akt is the most common pathway negatively regulated by PTEN. The Hippo and PI3K/Akt pathways have a joint effect in regulating cell proliferation and apoptosis. Therefore, how PTEN lipid phosphatase inactivation contributes to the occurrence and development of gastric cancer and the potential role of the Hippo and PI3K/Akt pathways in PTEN lipid phosphatase inactivation mediated gastric tumorigenesis remain to be explored.MethodsImmunohistochemical staining was performed to detect the expression of p-PTEN and YAP in a gastric cancer tissue microarray. Stable cell lines expressing a wild-type or dominant-negative mutant PTEN were established. The proliferation and migration of stable cells were detected by MTT, BrdU, and colony-formation, transwell assay and high content analysis in vitro, and tumor growth differences were observed in xenograft nude mice. Changes in the expression of key molecules in the Hippo and Akt signaling pathways were detected by western blot. Nuclear-cytoplasm separation, immunofluorescence and coimmunoprecipitation analyses were conducted to explore the dysregulation of Hippo in the stable cell lines.ResultsPTEN lipid phosphatase inactivation strongly promoted the proliferation and migration of gastric cancer cells in vitro and tumor growth in vivo. A immunohistochemical analysis of gastric cancer tissues revealed a significant correlation between phosphorylated PTEN and nuclear YAP expression, and both were determined to be independent prognostic factors for gastric cancer. Mechanistically, PTEN lipid phosphatase inactivation abolished the MOB1-LATS1/2 interaction, decreased YAP phosphorylation and finally promoted YAP nuclear translocation, which enhanced the synergistic effect of YAP-TEAD, thus inducing cell proliferation and migration. Moreover, PTEN lipid phosphatase inactivation promoted the PI3K/Akt pathway, and disruption of YAP-TEAD-driven transcription decreased the activation of Akt in a dose-dependent manner.ConclusionsTaken together, our findings indicate that PTEN lipid phosphatase inactivation links the Hippo and PI3K/Akt pathways to promote gastric tumorigenesis and cancer development.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0795-2) contains supplementary material, which is available to authorized users.

Multi-model functionalization of disease-associated PTEN missense mutations identifies multiple molecular mechanisms underlying protein dysfunction

“…Expression of C124S or G129E raised pAKT/AKT levels ( Fig. 5c), consistent with a dominant negative phenotype, as reported previously 15,21,56,57 .…”

“…While C124S and G129E have previously been established as dominant negatives, such a characterization of other PTEN variants is sparse 15,21,56,57 . Remarkably, we find 29 variants, including 17 ASD, showing dominant negativity in measures of activated AKT.…”

“…Identifying dominant negative variants is of significant clinical value since they may produce outcomes distinct from LoF variants producing haploinsufficiency. Whether phenotypes identified in an overexpression assay are conserved at physiological levels, as shown for C124S and G129E 56,57 , requires further study. Overall, these results suggest multiple mechanisms of MS mutation-induced PTEN dysfunction: instability producing haploinsufficiency, and loss of substrate binding or catalytic function leading to either complete LoF or dominant negativity.…”

Regulation of PTEN/AKT/FAK pathways by PPARγ impacts on fibrosis in diabetic nephropathy

“…We previously demonstrated that PTEN plays a significant role in DN . PI3K/Akt signaling is suppressed by PTEN and altered in DN . Meanwhile, PTEN downregulates FAK .…”

The Prospect of Identifying Resistance Mechanisms for Castrate-Resistant Prostate Cancer Using Circulating Tumor Cells: Is Epithelial-to-Mesenchymal Transition a Key Player?

“…More recently, the YAP1 transcriptional coactivator regulated by the Hippo pathway has emerged as an important player in this scenario and in regulating PCa cell motility [138]. In the context of gastric cancer, PTEN inactivation has been proposed to link the Hippo and PI3K/Akt pathways to promote cancer development and tumorigenesis [139]. In normal tissue, the Hippo signaling pathway appears central to cell growth control and limits organ size by coordinating cell proliferation, growth, and death [140].…”