Insulin/IGF signaling drives cell proliferation in part via Yorkie/YAP

Straßburger, Katrin; Tiebe, Marcel; Pinna, Federico; Breuhahn, Kai; Teleman, Aurelio A.

doi:10.1016/j.ydbio.2012.05.008

Cited by 133 publications

(116 citation statements)

References 74 publications

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“…By contrast, Drosophila stratified columnar epithelia such as the intestine require integrins, Src, EGFR and Yki to promote proliferation of basal layer stem/progenitor cells, suggesting that the regulatory connection between them described here is also conserved (Cordero et al, 2014;Jiang et al, 2011;Kohlmaier et al, 2015;Lin et al, 2013;Shaw et al, 2010;Staley and Irvine, 2010;Xu et al, 2011). Furthermore, ectopic activation of Src, EGFR, PI3K or Yki in simple columnar imaginal discs is sufficient to induce overproliferation of cells, whereas loss of PI3K or Yki strongly impairs imaginal disc tumour formation (Doggett et al, 2011;Enomoto and Igaki, 2013;Fernandez et al, 2014;Herranz et al, 2012Herranz et al, , 2014Strassburger et al, 2012;Willecke et al, 2011).…”

Section: Discussionmentioning

confidence: 87%

Integrin signalling regulates YAP and TAZ to control skin homeostasis

Elbediwy¹,

Vincent‐Mistiaen²,

Spencer‐Dene³

et al. 2016

Journal of Cell Science

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The skin is a squamous epithelium that is continuously renewed by a population of basal layer stem/progenitor cells and can heal wounds. Here, we show that the transcription regulators YAP and TAZ localise to the nucleus in the basal layer of skin and are elevated upon wound healing. Skin-specific deletion of both YAP and TAZ in adult mice slows proliferation of basal layer cells, leads to hair loss and impairs regeneration after wounding. Contact with the basal extracellular matrix and consequent integrin-Src signalling is a key determinant of the nuclear localisation of YAP/TAZ in basal layer cells and in skin tumours. Contact with the basement membrane is lost in differentiating daughter cells, where YAP and TAZ become mostly cytoplasmic. In other types of squamous epithelia and squamous cell carcinomas, a similar control mechanism is present. By contrast, columnar epithelia differentiate an apical domain that recruits CRB3, Merlin (also known as NF2), KIBRA (also known as WWC1) and SAV1 to induce Hippo signalling and retain YAP/TAZ in the cytoplasm despite contact with the basal layer extracellular matrix. When columnar epithelial tumours lose their apical domain and become invasive, YAP/TAZ becomes nuclear and tumour growth becomes sensitive to the Src inhibitor Dasatinib.

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Section: Discussionmentioning

confidence: 87%

Integrin signalling regulates YAP and TAZ to control skin homeostasis

Elbediwy¹,

Vincent‐Mistiaen²,

Spencer‐Dene³

et al. 2016

Journal of Cell Science

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“…4). The PI3K-PDK pathway was similarly found to mediate the inhibition of the Hippo pathway through IGF signaling in Drosophila (Straßburger et al, 2012). EGF signaling was also found to inhibit Hippo pathway signaling in Drosophila, but in this case it was found to be mediated by MAP-kinase and the regulation of Warts by Ajuba (Reddy and Irvine, 2013).…”

Section: Soluble Growth Factorsmentioning

confidence: 95%

“…In most cases, these soluble growth factors inhibit Hippo-YAP signaling and counteract the effects of cell contact (Straßburger et al, 2012;Yu et al, 2012;Fan et al, 2013;Reddy and Irvine, 2013), suggesting that the Hippo pathway mediates a reciprocal relationship between contact inhibition and mitogenic signaling (Fig. 3).…”

Section: Soluble Growth Factorsmentioning

confidence: 99%

“…In recent years there was a plethora of discoveries of molecules and pathways that act upstream of the core Hippo pathway, to either activate or inhibit YAP/TAZ, or the transcriptional activity of Yorkie. These include a variety of kinases (Harvey et al, 2013;, other signaling pathways, such as the Wnt (Varelas et al, 2010b) and RTK pathways (Straßburger et al, 2012;Fan et al, 2013;Reddy and Irvine, 2013), cell adhesion and cell junction proteins, cell polarity proteins, and the state of the actin cytoskeleton (Nishioka et al, 2009;Kim et al, 2011;Zhao et al, 2011;Boggiano and Fehon, 2012;Halder et al, 2012;Aragona et al, 2013;Hirate et al, 2013). The reader is referred to the numerous recent review articles cited above that describe these mechanisms in detail; these descriptions will not be repeated here, except when used to illustrate certain points.…”

Section: Introductionmentioning

confidence: 99%

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The Hippo-YAP signaling pathway and contact inhibition of growth

Gumbiner

Kim

2014

Journal of Cell Science

287

200

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The Hippo-YAP pathway mediates the control of cell proliferation by contact inhibition as well as other attributes of the physical state of cells in tissues. Several mechanisms sense the spatial and physical organization of cells, and function through distinct upstream modules to stimulate Hippo-YAP signaling: adherens junction or cadherincatenin complexes, epithelial polarity and tight junction complexes, the FAT-Dachsous morphogen pathway, as well as cell shape, actomyosin or mechanotransduction. Soluble extracellular factors also regulate Hippo pathway signaling, often inhibiting its activity. Indeed, the Hippo pathway mediates a reciprocal relationship between contact inhibition and mitogenic signaling. As a result, cells at the edges of a colony, a wound in a tissue or a tumor are more sensitive to ambient levels of growth factors and more likely to proliferate, migrate or differentiate through a YAP and/or TAZdependent process. Thus, the Hippo-YAP pathway senses and responds to the physical organization of cells in tissues and coordinates these physical cues with classic growth-factormediated signaling pathways. This Commentary is focused on the biological significance of Hippo-YAP signaling and how upstream regulatory modules of the pathway interact to produce biological outcomes.

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“…Increased YAP expression in human liver tumors is associated with high levels of p- AKT (30,31). This suggests that crosstalk between the Hippo and AKT pathways may be important in the maintenance of functional liver homeostasis.…”

Section: Introductionmentioning

confidence: 99%

Hippo-mediated suppression of IRS2/AKT signaling prevents hepatic steatosis and liver cancer

Jeong

Kim

et al. 2018

Journal of Clinical Investigation

149

102

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IntroductionNAFLD is characterized by an excessive accumulation of fat in the liver. The most severe form of NAFLD, NASH, often progresses to liver cancer (1-3). Tracking with the increasing prevalence of general obesity, 30% of the US population is now estimated to have NAFLD, and 25% of these individuals will develop NASH (1, 3). Currently, there are no effective therapies to prevent the incidence and progression of NAFLD or NASH (4). This makes clarification of the detailed mechanisms of disease progression using appropriate animal models that much more urgent.Insulin signaling begins with the binding of insulin to the insulin receptor (IR). This then phosphorylates insulin receptor substrates (IRSs) and subsequently triggers the recruitment of PI3K and the activation of AKT (5-9). Deletion of IRS1 and IRS2 in the mouse liver reduces AKT activity and gives rise to insulin resistance (10). Excessive AKT activation leads to the development of NAFLD by promoting the maturation of the transcription factor SREBP1c (11,12). In its mature form, SREBP1c contributes to the induction of fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC), which are key enzymes in de novo lipogenesis (13). Phosphatase and tensin homolog (PTEN) is a negative regulator of AKT signaling, and several human cancers are associated with mutations or downregulation of the PTEN gene (14-16). Liver-specific PTEN-knockout mice progressively develop NAFLD, NASH, and HCC (17, 18) as a result of increased AKT signaling (19).The Hippo signaling pathway has been implicated in the suppression of tissue regeneration, the proliferation of stem cells, and the development of cancer by inhibiting the oncogenic activity of the transcriptional coactivators YAP and TAZ (20,21). In mice, liverspecific knockout of the Hippo pathway components MST1/2, SAV1, or NF2 induces the expansion of hepatic progenitor cells via YAP/TAZ activation and leads eventually to the development of liver cancer (HCC, cholangiocarcinoma [CC], or both) (22)(23)(24)(25). Despite its importance in tumorigenesis, the role of Hippo signaling in the metabolic dysregulation that precedes the development of liver cancer remains unclear.Previous studies have suggested that YAP regulates components of the AKT pathway (i.e., PI3K, PTEN, and AKT) and that the Drosophila Hippo ortholog MST1 binds and inhibits AKT directly (26)(27)(28)(29). Increased YAP expression in human liver tumors is associated with high levels of p- AKT (30,31). This suggests that crosstalk between the Hippo and AKT pathways may be important in the maintenance of functional liver homeostasis. The molecular coordination of these 2 pathways in liver tumorigenesis, however, has not been revealed. Using several mouse models, we now show Nonalcoholic fatty liver disease (NAFLD) is a major risk factor for liver cancer; therefore, its prevention is an important clinical goal. Ablation of phosphatase and tensin homolog (PTEN) or the protein kinase Hippo signaling pathway induces liver cancer via activation of AKT or the transc...

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Insulin/IGF signaling drives cell proliferation in part via Yorkie/YAP

Cited by 133 publications

References 74 publications

Integrin signalling regulates YAP and TAZ to control skin homeostasis

Integrin signalling regulates YAP and TAZ to control skin homeostasis

The Hippo-YAP signaling pathway and contact inhibition of growth

Hippo-mediated suppression of IRS2/AKT signaling prevents hepatic steatosis and liver cancer

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