Control of Tissue Growth and Cell Transformation by the Salvador/Warts/Hippo Pathway

Xiaomeng Zhang,Kieran F Harvey,Felix A Grusche,Madhuri Kango-Singh

doi:10.1371/journal.pone.0031994

Xiaomeng Zhang, Kieran F Harvey + Show 2 more

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https://doi.org/10.1371/journal.pone.0031994

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Journal: PloS one	Publication Date: Feb 16, 2012
Citations: 16	License type: CC BY 4.0

Affiliation: Peter MacCallum Cancer Centre, University of Melbourne

Abstract

The Salvador-Warts-Hippo (SWH) pathway is an important regulator of tissue growth that is frequently subverted in human cancer. The key oncoprotein of the SWH pathway is the transcriptional co-activator, Yes-associated protein (YAP). YAP promotes tissue growth and transformation of cultured cells by interacting with transcriptional regulatory proteins via its WW domains, or, in the case of the TEAD1-4 transcription factors, an N-terminal binding domain. YAP possesses a putative transactivation domain in its C-terminus that is necessary to stimulate transcription factors in vitro, but its requirement for YAP function has not been investigated in detail. Interestingly, whilst the WW domains and TEAD-binding domain are highly conserved in the Drosophila melanogaster YAP orthologue, Yorkie, the majority of the C-terminal region of YAP is not present in Yorkie. To investigate this apparent conundrum, we assessed the functional roles of the YAP and Yorkie C-termini. We found that these regions were not required for Yorkie's ability to drive tissue growth in vivo, or YAP's ability to promote anchorage-independent growth or resistance to contact inhibition. However, the YAP transactivation domain was required for YAP's ability to induce cell migration and invasion. Moreover, a role for the YAP transactivation domain in cell transformation was uncovered when the YAP WW domains were mutated together with the transactivation domain. This shows that YAP can promote cell transformation in a flexible manner, presumably by contacting transcriptional regulatory proteins either via its WW domains or its transactivation domain.

Highlights

The Yes-associated protein (YAP) is a transcription co-activator that mediates the transcriptional output of the Salvador/Warts/ Hippo (SWH) pathway, which is a tumour suppressor pathway that was first identified in Drosophila melanogaster [1]
Whilst D. melanogaster Yki displays strong conservation of the WW and TEAD-binding domains, it is bereft of the majority of C-terminal sequences found in YAP and has only 55 amino acids following the second WW domain compared with 242 amino acids in YAP2L
Given the high degree of functional conservation between these proteins and the mechanism by which they are regulated, we were intrigued by the lack of conservation in the Ctermini of these proteins, because the C-terminus of YAP contains a transactivation domain that is necessary for its ability to activate transcription factors in vitro [29]

Summary

Introduction

The Yes-associated protein (YAP) is a transcription co-activator that mediates the transcriptional output of the Salvador/Warts/ Hippo (SWH) pathway, which is a tumour suppressor pathway that was first identified in Drosophila melanogaster [1]. The SWH pathway restricts organ size in D. melanogaster and mammals, and deregulation of the pathway leads to egregious organ overgrowth [2,3,4]. In D. melanogaster, core components of the SWH pathway include the scaffold proteins, Salvador (Sav) and Mob as tumor suppressor (Mats), and the S/T kinases, Warts (Wts) and Hippo (Hpo). These proteins limit organ growth by phosphorylationmediated inhibition of Yorkie (Yki), which is homologous to YAP in mammals [5]. Upstream of the core kinase cassette, an increasing number of proteins, many of which reside at cell junctions, have been shown to regulate SWH pathway activity [9]

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