https://archive-ouverte.unige.ch/unige:18229/ATTACHMENT01

TOR signaling in growth and metabolism.

AKT/PKB signaling: navigating downstream.

Cells perceive their microenvironment not only through soluble signals but also through physical and mechanical cues, such as extracellular matrix (ECM) stiffness or confined adhesiveness. By mechanotransduction systems, cells translate these stimuli into biochemical signals controlling multiple aspects of cell behaviour, including growth, differentiation and cancer malignant progression, but how rigidity mechanosensing is ultimately linked to activity of nuclear transcription factors remains poorly understood. Here we report the identification of the Yorkie-homologues YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif, also known as WWTR1) as nuclear relays of mechanical signals exerted by ECM rigidity and cell shape. This regulation requires Rho GTPase activity and tension of the actomyosin cytoskeleton, but is independent of the Hippo/LATS cascade. Crucially, YAP/TAZ are functionally required for differentiation of mesenchymal stem cells induced by ECM stiffness and for survival of endothelial cells regulated by cell geometry; conversely, expression of activated YAP overrules physical constraints in dictating cell behaviour. These findings identify YAP/TAZ as sensors and mediators of mechanical cues instructed by the cellular microenvironment.

Role of YAP/TAZ in mechanotransduction

http://dipbsf.uninsubria.it/monti/BFPN%202009/mTOR.pdf

Defining the Role of mTOR in Cancer

The Hippo pathway plays a key role in organ size control by regulating cell proliferation and apoptosis in Drosophila. Although recent genetic studies have shown that the Hippo pathway is regulated by the NF2 and Fat tumor suppressors, the physiological regulations of this pathway are unknown. Here we show that in mammalian cells, the transcription coactivator YAP (Yes-associated protein), is inhibited by cell density via the Hippo pathway. Phosphorylation by the Lats tumor suppressor kinase leads to cytoplasmic translocation and inactivation of the YAP oncoprotein. Furthermore, attenuation of this phosphorylation of YAP or Yorkie (Yki), the Drosophila homolog of YAP, potentiates their growth-promoting function in vivo. Moreover, YAP overexpression regulates gene expression in a manner opposite to cell density, and is able to overcome cell contact inhibition. Inhibition of YAP function restores contact inhibition in a human cancer cell line bearing deletion of Salvador (Sav), a Hippo pathway component. Interestingly, we observed that YAP protein is elevated and nuclear localized in some human liver and prostate cancers. Our observations demonstrate that YAP plays a key role in the Hippo pathway to control cell proliferation in response to cell contact.

/pdf/inactivation-of-yap-oncoprotein-by-the-hippo-pathway-is-2kt35jh06l.pdf

Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control

Elucidation of a universal size-control mechanism in Drosophila and mammals.

https://www.cell.com/cell/pdf/S0092-8674(03)00549-X.pdf

hippo Encodes a Ste-20 Family Protein Kinase that Restricts Cell Proliferation and Promotes Apoptosis in Conjunction with salvador and warts

WRKY proteins are a recently identified class of DNA-binding proteins that recognize the TTGAC(C/T) W-box elements found in the promoters of a large number of plant defense-related genes. With oligo molecules containing the W-box sequences as probes, we detected a number of WRKY DNA-binding activities in Arabidopsis that were induced by salicylic acid (SA). Search of the Arabidopsis genome identifies 72 genes encoding proteins characteristic of WRKY DNA-binding transcription factors that can be divided into three groups based on the number and structures of their WRKY zinc-finger motifs. Northern blotting analysis revealed that 49 of the 72 AtWRKY genes were differentially regulated in the plants infected by an avirulent strain of the bacterial pathogen Pseudomonas syringae or treated by SA. These pathogen- and/or SA-regulated WRKY genes can be further categorized into groups based on their expression patterns in both wild-type plants and mutants defective in defense signaling pathways. Inspection of the 5' sequences upstream of the predicated translation start sites revealed a substantial enrichment of W boxes in the promoters of pathogen- and/or SA-regulated Arabidopsis WRKY genes. These results suggest that defense-regulated expression of WRKY genes involves extensive transcriptional activation and repression by its own members of the transcription factor superfamily.

Expression profiles of the Arabidopsis WRKY gene superfamily during plant defense response.

https://www.cell.com/developmental-cell/pdf/S1534-5807(10)00305-9.pdf

Jixin Dong

Papers

Elucidation of a universal size-control mechanism in Drosophila and mammals.

hippo Encodes a Ste-20 Family Protein Kinase that Restricts Cell Proliferation and Promotes Apoptosis in Conjunction with salvador and warts

Expression profiles of the Arabidopsis WRKY gene superfamily during plant defense response.

The Merlin/NF2 Tumor Suppressor Functions through the YAP Oncoprotein to Regulate Tissue Homeostasis in Mammals

The TEAD/TEF Family Protein Scalloped Mediates Transcriptional Output of the Hippo Growth-Regulatory Pathway