The Hippo pathway effectors TAZ and YAP in development, homeostasis and disease
Xaralabos Varelas
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Studies over the past 20 years have defined the Hippo signaling pathway as a major regulator of tissue growth and organ size. Diverse roles for the Hippo pathway have emerged, the majority of which in vertebrates are determined by the transcriptional regulators TAZ and YAP (TAZ/YAP). Key processes regulated by TAZ/YAP include the control of cell proliferation, apoptosis, movement and fate. Accurate control of the levels and localization of these factors is thus essential for early developmental events, as well as for tissue homeostasis, repair and regeneration. Recent studies have revealed that TAZ/YAP activity is regulated by mechanical and cytoskeletal cues as well as by various extracellular factors. Here, I provide an overview of these and other regulatory mechanisms and outline important developmental processes controlled by TAZ and YAP.
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Introduction
A coordinated balance between proliferation, apoptosis and
differentiation is essential for the accurate formation and maintenance
of tissues and organs. Recent studies have indicated that the fidelity
of these processes relies on cues transduced by the Hippo pathway, a
conserved signaling pathway crucial for integrating cytoskeletal
changes with the extracellular environment. The Hippo pathway was
identified in genetic studies of Drosophila melanogaster as a
suppressor of tissue overgrowth (Huang et al., 2005; Jia et al., 2003;
Justice et al., 1995; Pantalacci et al., 2003; Tapon et al., 2002; Udan
et al., 2003; Wu et al., 2003). This initial work outlined a core group
of factors that control transcriptional events important for cell
proliferation and apoptosis. A wealth of studies since then, including
those in vertebrates, has greatly expanded the complexity of the
Hippo pathway network.
This Review provides an overview of the Hippo pathway in
development, with a particular focus on the mammalian transcriptional
regulators TAZ (transcriptional co-activator with a PDZ-binding
domain; also known as WW domain containing transcription
regulator 1, or WWTR1) and YAP (Yes-associated protein; also
known as YAP1). TAZ and YAP function as key downstream effectors
of the Hippo pathway, and throughout this Review I refer to these
factors collectively as TAZ/YAP, as many aspects of their regulation
and function are shared. New mechanisms directing the nuclear/
cytoplasmic localization of TAZ/YAP have been revealed and will be
discussed. These regulatory mechanisms are closely integrated with
extracellular stimuli that influence cytoskeletal dynamics, such as
mechanical forces exerted by matrix stiffness (Dupont et al., 2011),
as well as modulators of G protein-coupled receptors (GPCRs)
(Yu et al., 2012). Notably, regulation of TAZ/YAP localization is
implicated in the control of various developmental processes, ranging
from pre-implantation embryogenesis to the patterning of many organs.
Clear redundancy in the developmental roles and molecular activity of
TAZ/YAP exist, but evidence also indicates that TAZ and YAP have
divergent functions, which are discussed below.
The core Hippo pathway: a conserved network of signals
A search for mutations that led to tissue overgrowth in
D. melanogaster identified a conserved kinase cascade that
comprises the Hippo kinase, the Warts kinase and the adaptor
proteins Salvador and Mob (Fig. 1A) (Jia et al., 2003; Justice et al.,
1995; Pantalacci et al., 2003; Tapon et al., 2002; Udan et al., 2003;
Wu et al., 2003). Activation of these signals promotes
phosphorylation of the transcriptional regulator Yorkie by the
Warts kinase, resulting in its exclusion from the nucleus (Huang
et al., 2005). Nuclear Yorkie promotes proliferation and inhibits
apoptosis by associating with the transcription factor Scalloped
(Goulev et al., 2008; Wu et al., 2008; Zhang et al., 2008). Nuclear
Yorkie relieves the action of transcriptional repressors associated
with Scalloped, thereby activating the expression of a variety of
target genes (Koontz et al., 2013). Uncontrolled nuclear Yorkie
activity induces cellular overgrowth phenotypes, acting as the
primary driver of phenotypes identified in the early genetic screens.
A wealth of additional studies in Drosophila, including recent mass
spectrometry-based proteomic approaches (Kwon et al., 2013), has
broadened the Drosophila Hippo pathway network, which now
extends to factors that respond to alterations in cell adhesion and
polarity, as well as to core regulators of the actin cytoskeleton
(Fernandez et al., 2011; Sansores-Garcia et al., 2011).
The conservation of the core Hippo pathway factors is striking, as
the kinase cascade is conserved throughout the eukaryotic kingdom.
These factors have taken on diverse essential roles (see Box 1), which
include the regulation of mitotic exit in Saccharomyces cerevisiae
(Fig. 1B), thermal stress resistance in Caenorhabditis elegans
(Fig. 1C) and control of cell fate in mammals (Fig. 1D). Much of
the insight into the molecular functi (...truncated)