Hippo Pathway

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Hippo interactive pathway

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The Hippo signalling pathway has recently emerged as a fundamental regulator of organ size, stem cells function, tissue regeneration and tumor development 1-8. This highly conserved pathway throughout the animal kingdom has been extensively studied on Drosophila melanogaster, and took its name from the major kinase of the cascade, the Hippo kinase.

The core “canonical” Hippo pathway is composed of a cascade of kinases, MST1 and 2 being upstream of and activating Lats1 and 2 9-12. Lats kinase, upon activation, phosphorylate the transcriptional co-activators TAZ and YAP which leads to their retention in the cytoplasm. Once Lats are inactivated, the hypophosphorylated Yap/Taz translocate to the nucleus, associate with the Tead family of DNA binding proteins (Tead1 to 4) and activate the transcription of a set of target genes 13-14.

These genes are often linked to promotion of proliferation and inhibition of apoptosis. Several regulators of the pathway have been identified over the years, such as SAV1, MOB1A and MOB1B, FRMD6, the angiomotins, RASSF1, NF2/merlin etc., showing the regulation of Hippo activity to be complex. Indeed, inputs coming from cell surface receptors, adhesion molecules, actin cytoskeleton and metabolic cues were shown to modulate the activity of the pathway 15 for review. This results in a regulation of Hippo activity that is largely tissue-specific. For example, YAP is expressed in many tissues like the liver, intestine 16, heart 17, and pancreas 18, but Yap activity is not always linked to increased proliferation.

The role of the Hippo pathway in cancer is a rapidly growing field. Mutations of specific components of this signalling network have been identified in various cancers. NF2 is inactivated in a rare condition called neurofibromatosis type 2, Lats mutations have been reported in mesothelioma, RASSF1 mutations in lung cancer for example 19-20 for review. Their study holds the promise to identify new therapeutic targets leading to the development of better treatments.

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