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Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 114

Hedgehog signalling functions sterile-20-like kinase type 1 and type 2 (MST1/2),which
The Hedgehog signalling pathway functions both dur- is the first protein kinase of the core kinase cascade.
ing development and during adult life. Its function dur- In the next of part of the cascade, MST1/2 phos-
ing development is wide-ranging in that it can control phorylates Large tumour suppressor-1 and -2 (Lats1/2).
cell proliferation, cell determination and pattern forma- The activity of Lats1/2 is modulated by Mps one binding
tion of the developing embryo and the final processes of protein (MOB1). The ability of MOB1 to activate Lats1/2
cell differentiation. Hedgehog signalling seems to play an is enhanced by its phosphorylation by MST1/2. The activ-
important role in controlling the development of organs ated Lat1/2 then carries out the final step by phosphorylat-
such as the skin, brain, digestive tract, pancreas and pro- ing the closely related transcription factors Yes-activated
state. Mutations of components of this signalling pathway protein (YAP) and transcriptional coactivator with PDZ–
result in congenital malformations such as holoprosen- binding motif (TAZ). Once they are phosphorylated, YAP
cephaly, which is a cranial defect that occurs when the and TAZ are inactivated and leave the nucleus (Module 2:
midline structures of the brain and face fail to separate. Figure hippo signalling pathway). In the case of TAZ, ex-
The most dramatic phenotype of such malformation is port from the nucleus is carried out by protein 14-3-3.
cyclopia where only one eye is formed. YAP can also be inactivated by a ubiquitination pathway
The function of Hedgehog continues in the adult or- that begins with its phosphorylation by casein kinase Iδ
ganism, where it plays a major role in the formation and (CKIδ) or casein kinase Iε (CKIε) that marks it out for
maintenance of the stem cell population. Since Hedgehog ubiquitin ligase by SCF β-TRCP .
signalling plays such a major role in regulating cell prolif- The closely related transcription factors YAP and TAZ,
eration, it is not surprising that alterations in this signalling which have overlapping and distinct functions, operate to-
pathway have been detected in many cancers such as skin gether with other co-activators of which the TEA domain
cancer and some brain cancers. (TEAD) proteins are particulary important. This tran-
For example, patched (PTC) is a tumour suppressor that scriptional complex activates a number of target genes
is inactivated in basal cell carcinomas (BCCs), medullo- including amphiregulin (AR), cysteine-rich protein con-
blastomas, gliomas in the brain and prostate cancers. nective tissue factor (CTGF) and Baculoviral inhibitor of
Mutations of the PTC gene are responsible for Gorlin’s apoptosis repeat-containing 5 (BIRC5, also known as sur-
syndrome, which is also known as nevoid basal cell car- vivin). BIRC5 is a member of the inhibitor of apoptosis
cinoma syndrome (NBCC). The Hedgehog signalling (IAP) family.
pathway may also contribute to the growth of tumours Hippo signalling appears to have multiple functions in
by enhancing the activity of stromal cells that provide the mammalian cells. Many of these functions seem to be re-
tumour cell microenvironment that supports cancer cell lated to controlling cell proliferation and cell growth. For
survival and growth. Cancer cells release hedgehog that example, it can control the size of organs such as the liver.
then uses a paracrine mechanism to stimulate neighbouring Contact inhibition in cultured cells seems to require ac-
stromal cells such as the blood vessels, fibroblasts, immune tivation of this signalling cascade. Its role in cell prolifera-
cells and epithelial cells. These stromal cells assist cancer tion is apparent in numerous examples where uncontrolled
cell growth by providing both an extracellular matrix and growth occurs in many cancers when various compon-
essential growth factors such as insulin-like growth factor ents of the pathway are deleted. Hepatocellular carcinoma
(IGF) and Wnt. (HCC) can be induced by the overexpression of YAP.

Mammalian sterile-20-like kinase type 1 (MST1)
The mammalian sterile-20-like kinase type 1 and type
Hippo signalling pathway 2(MST1/2) function in the hippo signalling pathway where
The hippo signalling pathway was discovered initially in they function by phosphorylating the large tumour sup-
Drosophila where it functions to control proliferation, cell pressor-1 and -2 (Lats1/2), which is a serine/threonine pro-
growth and apoptosis. This signalling pathway is highly tein kinase that acts as a tumour suppressor (Module 2:
conserved and mammalian homologues of the Drosophila Figure hippo signalling pathway). The mammalian homo-
hippo signalling components, which connect transduc- logue of the Drosophila protein Salvador (Sav) is the
tion events at the plasma membrane to alterations in gene cofactor WW45 (also known as Sav1) that has an important
transduction, have now been identified. (Module 2: Figure role in the activation of MST1/2.
hippo signalling pathway).
In the case of the mammalian pathway, it seems likely Large tumour suppressor (Lats)
that there are cell-surface receptors that activate the core The Large tumour suppressor-1 and -2 (Lats1/2) is a
kinase cascade, but these remain to be identified. One pu- serine/threonine protein kinase that acts as a tumour
tative receptor is CD44, which is a receptor for hyaluronic suppressor by inhibiting the G1/S transition of the cell
acid and can also respond to osteopontin and collagen. The cycle (Module 8: Figure ES cell miRNAs). It functions
downstream target for such cell-surface receptors is likely by phosphorylating and inactivating the transcription
to be the tumour suppressor merlin (moesinezrin-radixin- factor Yes-associated protein (YAP), which operates in the
like protein), which is coded for by the neurofibromatosis hippo signalling pathway (Module 2: Figure hippo sig-
type 2 (Nf2) gene and is sometimes referred to as NF2. nalling pathway). The expression of Lats1/2 is reduced my
Merlin then acts to regulate the activity of mammalian miR372 and miR-373.

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