Abstract
Tumorigenesis is a highly complex process, involving many interrelated and cross-acting signalling pathways. One such pathway that has garnered much attention in the field of cancer research over the last decade is the Hippo signalling pathway. Consisting of two antagonistic modules, the pathway plays an integral role in both tumour suppressive and oncogenic processes, generally via regulation of a diverse set of genes involved in a range of biological functions. This review discusses the history of the pathway within the context of cancer and explores some of the most recent discoveries as to how this critical transducer of cellular signalling can influence cancer progression. A special focus is on the various recent efforts to therapeutically target the key effectors of the pathway in both preclinical and clinical settings.
Highlights
The Hippo pathway is an evolutionarily conserved signalling cascade regulated by a broad spectrum of upstream effectors and acts as an integral mechanosensory component of cells, transducing physical signals at the plasma membrane and regulating response via control of differentiation and proliferation in cells [1,2,3]
Genes identified include Warts (Wts, LATS1/2 in human) [4,5] and Hippo (Hpo, or STK4/3 encoding MST1/2 in human) [6,7], which encode the kinases that constitute the phosphorylation cascade central to the Hippo pathway, which is a central regulator of early stage development in embryogenesis
Hippo pathway dysregulation has been shown to result in tumorigenesis similar to that seen in cancer types involving YAP/TAZ fusion proteins, with both expression of constitutively active YAP or KO of LATS1/2 in a subpopulation of neuronal precursor cells in mice resulting in the formation of ependymoma-like tumours and up-regulation of YAP/TAZ target genes [109]
Summary
The Hippo pathway is an evolutionarily conserved signalling cascade regulated by a broad spectrum of upstream effectors and acts as an integral mechanosensory component of cells, transducing physical signals at the plasma membrane and regulating response via control of differentiation and proliferation in cells [1,2,3]. Hippo pathway dysregulation has been shown to result in tumorigenesis similar to that seen in cancer types involving YAP/TAZ fusion proteins, with both expression of constitutively active YAP or KO of LATS1/2 in a subpopulation of neuronal precursor cells in mice resulting in the formation of ependymoma-like tumours and up-regulation of YAP/TAZ target genes [109].
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