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Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 115

Module 2: Figure hippo signalling pathway

CD44

NF2/Merlin

hWW45/
MST1/2
Sav1
P
P
Lats1/2 MOB1/
Mats
P 14-3-3
YAP TAZ
CKI
P
P YAP
YAP
P P 14-3-3
Lats1/2 TAZ
Ubiquitination
YAP AR, BIRC5, Proliferation
TEAD TAZ CTGF

Hippo signalling pathway.
The hippo signalling pathway is based on a protein phosphorylation cascade that functions to regulate the transcription of genes that play a role in
regulating proliferation and cell growth.

Yes-associated protein (YAP) Notch signalling pathway
The Yes-associated protein (YAP), which is the mam- The Notch signalling pathway is a highly conserved sig-
malian homologue of the Drosophila protein Yorkie (Yki), nalling system that functions in both development and
is a multifunction transcription factor that operates in the adulthood. Many of its functions relate to cell-fate de-
hippo signalling pathway (Module 2: Figure hippo sig- termination and this is particularly the case in its control
nalling pathway). YAP shares almost 50% sequence iden- of binary cell-fate decisions in stem cells. During the assy-
tity with TAZ and they both have two central WW do- metrical divisions of stem cells, one cell retains its stem cell
mains and a transactivation domain at the C-terminus. fate (self-renewal) while the daughter cell (progenitor cell)
The transcriptional activity of YAP functions together adopts a different state that will drive it towards prolifera-
with other co-activators such as the TEA domain (TEAD) tion and differentiation into a specific cell type (Module 8:
family, which has four closely related members TEAD1-- Figure stem cell function). As these progenitor cells adopt
4, peroxisome-proliferator-activated receptor γ (PPARγ), their new cell fate, they use the Notch signalling pathway
thyroid transcription factor-1 (TTF-1), Runx2 and some to feed information back to suppress their neighbour from
of the SMADs. The transactivation with TEAD seems to adopting a similar cell fate. This is a short-range informa-
be particularly important. tion transfer mechanism that depends upon direct contact
between the cells, which is a hallmark of this signalling
pathway. For example, the stimulus Jagged is an integral
membrane protein located on the surface of communic-
Transcriptional coactivator with PDZ binding ating cells, whereas the Notch receptor that responds to
motif (TAZ) Jagged is embedded in the surface of the receiving cell
The transcriptional coactivator with PDZ-binding motif (Module 2: Figure Notch signalling).
(TAZ) operates in the hippo signalling pathway (Module The main feature of the transduction mechanism is de-
2: Figure hippo signalling pathway). TAZ shares al- ceptively simple. When Jagged binds to Notch, the Notch
most 50% sequence identity with YAP and they both intracellular domain (NICD) is released into the cytoplasm
have two central WW domains and a transactivation do- and then diffuses into the nucleus where it induces the
main at the C-terminus. The TAZ/TEAD transcription transcription of multiple Notch target genes. Despite its
complex may increase the expression of Zeb1, which simplicity, this signalling system has an extensive number
plays a role in embryonic development by inducing the of interacting components (Module 2: Table Notch sig-
epithelial-to-mesenchymal transition (EMT). nalling components). Some of these function during the

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