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The Hippo signaling pathway is a central growth control mechanism in multicellular organisms. By integrating diverse mechanical, biochemical, and stress cues, the Hippo pathway orchestrates proliferation, survival, differentiation, and mechanics of cells, which in turn regulate organ development, homeostasis, and regeneration. A deep understanding of the regulation and function of the Hippo pathway therefore holds great promise for developing novel therapeutics in regenerative medicine. Here, we provide updates on the molecular organization of the mammalian Hippo signaling network, review the regulatory signals and functional outputs of the pathway, and discuss the roles of Hippo signaling in development and regeneration. Zhong et al. provide a comprehensive review of the mammalian Hippo signaling pathway. The composition, architecture, and upstream cues of the signaling network are analyzed. Moreover, a concept of helper and worker cell is proposed, and its implications in the development and regeneration of selected organs are discussed. [ABSTRACT FROM AUTHOR]

Oncogenic activation of the PI3K/Akt pathway is known to play an important role to promote glucose metabolism in cancer cells. However, the molecular mechanism through which the PI3K/Akt signalling pathway promotes glucose utilisation in cancer cells is still not well understood. It has recently been shown that the oncogenic activation of the PI3K/Akt/mTOR signalling in lung adenocarcinoma is important in promoting the localisation of glucose transporter 1 (GLUT1) at the plasma membrane. We thus hypothesised that the effect of constitutive activation of the PI3K/AKT signalling on glucose metabolism is mediated by thioredoxin interacting protein (TXNIP), a known regulator of the GLUT1 plasma membrane localisation. Consistent with previous studies, inhibition of the PI3K/Akt pathway decreased cellular glucose uptake. Furthermore, inhibition of PI3K/Akt signalling in non-small cell lung cancer (NSCLC) cell lines using clinically used tyrosine kinase inhibitors (TKIs) resulted in a decrease in GLUT1 membrane localisation. We also observed that inhibition of the PI3K/Akt pathway in various cell lines, including NSCLC cells, resulted in an increase in TXNIP expression. Importantly, knockdown of TXNIP using siRNA in the NSCLC cells promoted GLUT1 to be localised at the plasma membrane and reversed the effect of PI3K/Akt inhibitors. Together, our results suggest that the oncogenic activation of PI3K/Akt signalling promotes cellular glucose uptake, at least in part, through the regulation of TXNIP expression. This mechanism may contribute to the Warburg effect in cancer cells. [ABSTRACT FROM AUTHOR]

Summary: Uveal melanoma (UM) is the most common cancer in adult eyes. Approximately 80% of UMs harbor somatic activating mutations in GNAQ or GNA11 (encoding Gq or G11, respectively). Herein, we show in both cell culture and human tumors that cancer-associated Gq/11 mutants activate YAP, a major effector of the Hippo tumor suppressor pathway that is also regulated by G protein-coupled receptor signaling. YAP mediates the oncogenic activity of mutant Gq/11 in UM development, and the YAP inhibitor verteporfin blocks tumor growth of UM cells containing Gq/11 mutations. This study reveals an essential role of the Hippo-YAP pathway in Gq/11-induced tumorigenesis and suggests YAP as a potential drug target for UM patients carrying mutations in GNAQ or GNA11. [ABSTRACT FROM AUTHOR]

The Hippo tumor-suppressor pathway is frequently dysregulated in human cancers and represents a therapeutic target. However, strategies targeting the mammalian Hippo pathway are limited because of the lack of a well-established cell-surface regulator. Here, we show that transmembrane protein KIRREL1, by interacting with both SAV1 and LATS1/2, promotes LATS1/2 activation by MST1/2 (Hippo kinases), and LATS1/2 activation, in turn, inhibits activity of YAP/TAZ oncoproteins. Conversely, YAP/TAZ directly induce the expression of KIRREL1 in a TEAD1–4–dependent manner. Indeed, KIRREL1 expression positively correlates with canonical YAP/TAZ target gene expression in clinical tumor specimens and predicts poor prognosis. Moreover, transgenic expression of KIRREL1 effectively blocks tumorigenesis in a mouse intrahepatic cholangiocarcinoma model, indicating a tumor-suppressor role of KIRREL1. Hence, KIRREL1 constitutes a negative feedback mechanism regulating the Hippo pathway and serves as a cell-surface marker and potential drug target in cancers with YAP/TAZ dependency. [Display omitted] • Protein interactome and clinical data indicate KIRREL1 is a Hippo pathway regulator • KIRREL1 promotes junctional localization and activation of LATS1/2 by Hippo kinases • The expression of KIRREL1 gene is tightly regulated by YAP/TAZ and TEAD1-4 • Transgenic expression of KIRREL1 blocks intrahepatic cholangiocarcinoma in mice Gu et al. identify transmembrane protein KIRREL1 as a cell-surface marker of tumors with dysregulated Hippo signaling; meanwhile, KIRREL1 can effectively boost Hippo signaling and function as a tumor suppressor. [ABSTRACT FROM AUTHOR]

Collective cell migration (CCM) is involved in multiple biological processes, including embryonic morphogenesis, angiogenesis, and cancer invasion. However, the molecular mechanisms underlying CCM, especially leader cell formation, are poorly understood. Here, we show that a signaling pathway regulating angiomotin (AMOT) cleavage plays a role in CCM, using mammalian epithelial cells and mouse models. In a confluent epithelial monolayer, full-length AMOT localizes at cell-cell junctions and limits cell motility. After cleavage, the C-terminal fragment of AMOT (AMOT-CT) translocates to the cell-matrix interface to promote the maturation of focal adhesions (FAs), generate traction force, and induce leader cell formation. Meanwhile, decreased full-length AMOT at cell-cell junctions leads to tissue fluidization and coherent migration of cell collectives. Hence, the cleavage of AMOT serves as a molecular switch to generate polarized contraction, promoting leader cell formation and CCM. [Display omitted] • The AMOT cleavage signaling pathway is indispensable for collective cell migration • Cleavage product AMOT-CT induces focal adhesion maturation and leader cell formation • AMOT cleavage leads to cell monolayer fluidization and collective migration • AMOT-CT expression promotes cancer cell invasion and metastasis Wang et al. demonstrate that the cleavage of AMOT is essential for collective cell migration (CCM) and tumor metastasis. The cleavage of AMOT results in its spatial redistribution from apical junctions to focal adhesions (FAs), promoting leader cell formation, cell fluidization, and coherent cell migration. [ABSTRACT FROM AUTHOR]

Germline alterations of the NF2 gene cause neurofibromatosis type 2, a syndrome manifested with benign tumors, and Nf2 deletion in mice also results in slow tumorigenesis. As a regulator of the Hippo signaling pathway, NF2 induces LATS1/2 kinases and consequently represses YAP/TAZ. YAP/TAZ oncoproteins are also inhibited by motin family proteins (Motins). Here, we show that the Hippo signaling is fine-tuned by Motins in a NF2-dependent manner, in which NF2 recruits E3 ligase RNF146 to facilitate ubiquitination and subsequent degradation of Motins. In the absence of NF2, Motins robustly accumulate to restrict full activation of YAP/TAZ and prevent rapid tumorigenesis. Hence, NF2 deficiency not only activates YAP/TAZ by inhibiting LATS1/2 but also stabilizes Motins to keep YAP/TAZ activity in check. The upregulation of Motins upon NF2 deletion serves as a strategy for avoiding uncontrolled perturbation of the Hippo signaling and may contribute to the benign nature of most NF2 -mutated tumors. [Display omitted] • Motins are destabilized upon serum or LPA treatment in a NF2-dependent manner • NF2 recruits RNF146 to Motins, promoting ubiquitination and degradation of Motins • Inactivation of Motins in NF2 -deficient cells enhances oncogenic activity of YAP • High AMOT expression in NF2 -null mesotheliomas is associated with good prognosis NF2 is a regulator of the Hippo tumor suppressor pathway. Wang et al. show that motin family proteins (Motins) are stabilized in the absence of NF2 , which prevents full activation of YAP/TAZ oncoproteins and rapid tumorigenesis. This mechanism may contribute to the benign nature of tumors driven by NF2 deficiency. [ABSTRACT FROM AUTHOR]

Abstract: Metformin (dimethylbiguanide) is widely used among diabetic patients to lower the blood sugar level. Although several mechanisms have been proposed, its mode of action in enhancing peripheral glucose uptake and inhibiting hepatic glucose production is not fully understood. Thioredoxin-interacting protein (Txnip) is known to play important roles in glucose metabolism by inhibiting cellular glucose uptake and metabolism and promoting hepatic gluconeogenesis. The expression of the gene encoding Txnip is regulated in a glucose dependent manner via the Mondo:MLX transcription factor complex. In the present study, we report that Txnip mRNA as well as protein expression in cultured cells is markedly reduced upon metformin administration. The binding of Mondo:MLX to the Txnip gene promoter is reduced, suggesting that the transcription of the Txnip gene is repressed by metformin. Moreover, we show that the effect of metformin on Txnip gene transcription is due to the inhibition of mitochondrial complex I and increased glycolysis, and is partially mediated by the AMP activated kinase (AMPK). These observations prompt us to propose that the novel action of metformin on the Txnip gene expression may contribute to its therapeutic effects in the treatment of type II diabetes. [Copyright &y& Elsevier]

Proteasome inhibitors (PIs) are currently used in the clinic to treat cancers such as multiple myeloma (MM). However, cancer cells often rapidly develop drug resistance towards PIs due to a compensatory mechanism mediated by nuclear factor erythroid 2 like 1 (NFE2L1) and aspartic protease DNA damage inducible 1 homolog 2 (DDI2). Following DDI2-mediated cleavage, NFE2L1 is able to induce transcription of virtually all proteasome subunit genes. Under normal condition, cleaved NFE2L1 is constantly degraded by proteasome, whereas in the presence of PIs, it accumulates and induces proteasome synthesis which in turn promotes the development of drug resistance towards PIs. Here, we report that Nelfinavir (NFV), an HIV protease inhibitor, can inhibit DDI2 activity directly. Inhibition of DDI2 by NFV effectively blocks NFE2L1 proteolysis and potentiates cytotoxicity of PIs in cancer cells. Recent clinical evidence indicated that NFV can effectively delay the refractory period of MM patients treated with PI-based therapy. Our finding hence provides a specific molecular mechanism for combinatorial therapy using NFV and PIs for treating MM and probably additional cancers. • HIV protease inhibitor Nelfinavir directly targets human DDI2. • Nelfinavir potentiates cytotoxicity of proteasome inhibitors. • A molecular mechanism for combinatorial cancer therapy of Nelfinavir and proteasome inhibitors. • DDI2-NFE2L1 pathway's prognostic value in multiple myeloma patients. [ABSTRACT FROM AUTHOR]