HIPPO signalling

  • Article
    | Open Access

    Targeting the interaction between transcription factor TEAD and its co-repressor VGL4 is an attractive strategy to chemically modulate Hippo signaling. Here, the authors develop a proteomimetic with stabilized tertiary structure that inhibits the TEAD:VGL4 interaction in vitro and in cells.

    • Hélène Adihou
    • , Ranganath Gopalakrishnan
    •  & Herbert Waldmann
  • Article
    | Open Access

    3D liver organoids hold great promise for regenerative medicine but the use of ill-defined matrices limits their potential. Here, the authors generate human and mouse liver organoids using a chemically defined matrix, and reveal a link between matrix stiffness and organoid growth that does not require acto-myosin contraction.

    • Giovanni Sorrentino
    • , Saba Rezakhani
    •  & Kristina Schoonjans
  • Article
    | Open Access

    Hippo TEAD-transcriptional regulators YAP1 and TAZ modulate cell growth, but the downstream networks are unclear. Here, the authors use a genetically-encoded inhibitor of YAP1/TAZ interaction with TEAD (TEADi) to disrupt transcriptional networks for cell cycle and terminal differentiation in human keratinocytes and mouse skin.

    • Yao Yuan
    • , Jeannie Park
    •  & Ramiro Iglesias-Bartolome
  • Article
    | Open Access

    Hippo pathway inactivation plays a role in many cancers, although how tumor cells depress signaling is unclear. Here, Lim et al. identify STK25, which activates LATS in a manner distinct from other upstream kinases and is focally deleted from a range of human cancers.

    • Sanghee Lim
    • , Nicole Hermance
    •  & Neil J. Ganem
  • Article
    | Open Access

    Hippo signaling leads to the phosphorylation of the key transcriptional effector, Yap/Yki, although how Yap/Yki stability is regulated has remained unclear. Here, Sun et al. identify HAUSP/Usp7 as a conserved and clinically relevant regulator of the Hippo pathway that increases Yap/Yki stability.

    • Xiaohan Sun
    • , Yan Ding
    •  & Zizhang Zhou
  • Article
    | Open Access

    Increased levels of the Yap oncoprotein stimulate liver growth and promote hepatocarcinogenesis. Here the authors show that hepatocyte-specific loss of Atg7 in mice leads to decreased autophagic degradation of Yap and liver overgrowth, and further establish this association in human liver cancer tissues.

    • Youngmin A. Lee
    • , Luke A. Noon
    •  & Scott L. Friedman
  • Article
    | Open Access

    The transcriptional co-factors Yap and TAZ are regulated by Hippo signalling and mechanical forces via their nucleocytoplasmic shuttling. Here the authors identify a RhoA-regulated C-terminal nuclear localization signal and a TEAD-regulated N-terminal nuclear export signal of TAZ in an epithelial cell line.

    • Michael Kofler
    • , Pam Speight
    •  & András Kapus
  • Article
    | Open Access

    Hippo-YAP pathway plays an important role in cancers; however the in vivo relevance of YAP/TAZ target genes is unclear. Here, the authors show that NUAK2 is a target of YAP and participates in a feedback loop to maximize YAP activity. Inhibition of NUAK2 suppresses YAP-driven hepatomegaly and liver cancer growth, offering a new target for cancer therapy.

    • Wei-Chien Yuan
    • , Brian Pepe-Mooney
    •  & Fernando D. Camargo
  • Article
    | Open Access

    The Hippo pathway is a major orchestrator of organ development and homeostasis. Here Azad and colleagues develop a biosensor to monitor the activity of the Hippo pathway component LATS and identify VEGF signalling as an upstream regulator of LATS, supporting a role for Hippo signalling during angiogenesis.

    • T. Azad
    • , H. J. Janse van Rensburg
    •  & X. Yang
  • Article
    | Open Access

    Drosophila neural stem cells (NSCs) are quiescent at early larval stages but how this is regulated is unclear. Here, Ding et al. show that quiescence of NSCs is mediated by cell-contact inhibition via the Hippo pathway transmembrane proteins Crumbs and Echinoid, which in turn are regulated by nutrient levels.

    • Rouven Ding
    • , Kevin Weynans
    •  & Christian Berger
  • Article
    | Open Access

    A variety of signals have been reported to either activate or inhibit the Hippo kinase cascade. Here, Meng et al. show that mitogen activated protein kinase kinase kinase kinase (MAP4K) family members function in parallel to and are partially redundant with MST1/2 in regulating LATS in response to upstream signals.

    • Zhipeng Meng
    • , Toshiro Moroishi
    •  & Kun-Liang Guan
  • Article
    | Open Access

    Components of the Hippo signalling pathway localize to apical junctions in epithelial cells, where they regulate growth in response to mechanical and biochemical cues. Sun et al. show that these proteins are organized into distinct junctional complexes, which reorganize up on Hippo pathway activation.

    • Shuguo Sun
    • , B. V. V. G. Reddy
    •  & Kenneth D. Irvine
  • Article |

    Angiogenesis is regulated by dynamic changes in endothelial cell contact. Here, the authors show that signals from endothelial cell junctions affect the subcellular localization and function of Yes-associated protein, ultimately modifying angiopoietin-2 expression and angiogenic activity of endothelial cells.

    • Hyun-Jung Choi
    • , Haiying Zhang
    •  & Young-Guen Kwon
  • Article |

    Transcriptional regulators Sox2 and YAP maintain expression of stemness genes in normal and cancerous cells. Here the authors show that, in osteosarcomas, Sox2 activates YAP by directly repressing transcription of its upstream negative regulators Nf2 and WWC1, promoting cancer cell stemness.

    • Upal Basu-Roy
    • , N. Sumru Bayin
    •  & Claudio Basilico
  • Article |

    The Hippo pathway plays a role in regulating organ size and stem cell renewal but the regulatory mechanisms that fine-tune this pathway are not well understood. Here the authors report on the role of NEDD4 as a negative regulator of the Hippo signalling components, WW45 and LATS kinase, and in controlling cell proliferation and intestinal stem cell homeostasis.

    • Sung Jun Bae
    • , Myungjin Kim
    •  & Jae Hong Seol
  • Article |

    The Yes-associated protein (YAP) is a core effector of the Hippo pathway, which regulates proliferation and apoptosis in organ development, but its function in adult skeletal muscle remains poorly defined. Here the authors show that YAP is an essential regulator of myofibre size in adult skeletal muscle, via interaction with TEAD transcription factors.

    • K. I. Watt
    • , B. J. Turner
    •  & P. Gregorevic
  • Article |

    Although much is known about the structural and trafficking molecules involved in generation of primary cilia, the signalling proteins that regulate ciliogenesis are poorly defined. Here, Kim et al. identify the MST1/2-SAV1 complex, a core component of the Hippo pathway, as a key regulator of ciliogenesis in cells and zebrafish.

    • Miju Kim
    • , Minchul Kim
    •  & Dae-Sik Lim
  • Article
    | Open Access

    Angiomotins retain the transcription co-activator YAP in the cytoplasm and thereby regulate the Hippo pathway in mammalian cultured cells. Here Leung and Zernicka-Goetz show that Angiomotin family members prevent the differentiation of inner cell mass cells in the mouse blastocyst, via both Hippo pathway-dependent and -independent mechanisms.

    • Chuen Yan Leung
    •  & Magdalena Zernicka-Goetz
  • Article
    | Open Access

    Tumour suppressors can be inactivated in cancer not only as a result of mutation, but also by proteolytic degradation. Here the authors show that, during glioma development, the accumulation of the ubiquitin ligase praja2 sustains tumour growth by degrading MOB1—a core component of the Hippo pathway.

    • Luca Lignitto
    • , Antonietta Arcella
    •  & Antonio Feliciello