The Hippo pathway in normal development and cancer

Marcello Maugeri-Saccà, Ruggero De Maria

Research output: Contribution to journalReview article

Abstract

The Hippo pathway is a central regulator of organ size and tissue homeostasis. Hippo kinases and adaptor proteins mediate the phosphorylation and inactivation of YAP and TAZ, two closely related transcription co-activators. The Hippo pathway responds to a variety of extracellular and intracellular signals, spanning from cell-cell contact and mechanical cues to ligands of G-protein-coupled receptors and metabolic avenues. In some instances, YAP/TAZ activation is tuned by forces that bypass the Hippo kinase module, adding further complexity to the biology of the pathway. Over the past two decades, the Hippo pathway has increasingly been connected with developmental processes and tissue repair, being intimately tied to the function of tissue-specific progenitor cells. Pervasive activation of YAP/TAZ has been recognized in a multitude of human tumors and connected with the acquisition of malignant traits, including resistance to anticancer therapies, distant dissemination and maintenance of cancer stem cells. On this ground, Hippo-related biomarkers are increasingly investigated in translational studies striving to identify prognostic and predictive factors. In addition, the dependency of many tumors on YAP/TAZ may be exploited for therapeutic purposes. Albeit no direct inhibitors are currently available, drug repositioning approaches provided hints that YAP/TAZ inhibition can be achieved with old drugs, such as cholesterol-lowering agents or compounds blocking bone resorption.

Original languageEnglish
Pages (from-to)60-72
Number of pages13
JournalPharmacology and Therapeutics
Volume186
DOIs
Publication statusPublished - Jun 2018

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Drug Repositioning
Neoplasms
Organ Size
Neoplastic Stem Cells
Bone Resorption
G-Protein-Coupled Receptors
Protein Kinases
Cues
Homeostasis
Phosphotransferases
Stem Cells
Biomarkers
Cholesterol
Maintenance
Phosphorylation
Ligands
Therapeutics
Pharmaceutical Preparations
Dependency (Psychology)
Inhibition (Psychology)

Keywords

  • Adaptor Proteins, Signal Transducing/metabolism
  • Animals
  • Homeostasis
  • Humans
  • Intracellular Signaling Peptides and Proteins/metabolism
  • Neoplasms/metabolism
  • Organogenesis/physiology
  • Phosphoproteins/metabolism
  • Phosphorylation
  • Protein-Serine-Threonine Kinases/genetics
  • Signal Transduction

Cite this

The Hippo pathway in normal development and cancer. / Maugeri-Saccà, Marcello; De Maria, Ruggero.

In: Pharmacology and Therapeutics, Vol. 186, 06.2018, p. 60-72.

Research output: Contribution to journalReview article

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AU - De Maria, Ruggero

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AB - The Hippo pathway is a central regulator of organ size and tissue homeostasis. Hippo kinases and adaptor proteins mediate the phosphorylation and inactivation of YAP and TAZ, two closely related transcription co-activators. The Hippo pathway responds to a variety of extracellular and intracellular signals, spanning from cell-cell contact and mechanical cues to ligands of G-protein-coupled receptors and metabolic avenues. In some instances, YAP/TAZ activation is tuned by forces that bypass the Hippo kinase module, adding further complexity to the biology of the pathway. Over the past two decades, the Hippo pathway has increasingly been connected with developmental processes and tissue repair, being intimately tied to the function of tissue-specific progenitor cells. Pervasive activation of YAP/TAZ has been recognized in a multitude of human tumors and connected with the acquisition of malignant traits, including resistance to anticancer therapies, distant dissemination and maintenance of cancer stem cells. On this ground, Hippo-related biomarkers are increasingly investigated in translational studies striving to identify prognostic and predictive factors. In addition, the dependency of many tumors on YAP/TAZ may be exploited for therapeutic purposes. Albeit no direct inhibitors are currently available, drug repositioning approaches provided hints that YAP/TAZ inhibition can be achieved with old drugs, such as cholesterol-lowering agents or compounds blocking bone resorption.

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