The Essence of the Hippo Signalling System - Therapeutic Strategies in Cancer Biology and Pathology - page 134

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The Essence of the Hippo
Signalling System

The Hippo signalling system has received much attention in recent years because
of the part it prominently plays in development, morphogenesis and growth but also
on account of its remarkable and conspicuous suppressor function in cancer patho-
genesis. The mainstay of the system is a quintessentially conserved kinase cascade
together with upstream activators and downstream effector transcription factors that
regulate target gene expression. Here the discussion is centred round the suppres-
sor function of Hippo and how the system interacts with several other developmental
signalling pathways and those that transduce cell proliferation signals in the context
of cell transformation, activation of EMT and possibly also metastasis. The Hippo
system with its component cascade of kinases represents a unique tumour suppres-
sor. The loss of any component element leads to unregulated growth, loss of differ-
entiation, induction of EMT and cell transformation ( Table 25.1 ). The significance
of this signalling network has been encapsulated succinctly and aptly by Halder
and Johnson (2011) by labelling the system as Hippo signalling: growth control and
beyond.

Lats (Large Tumour Suppressor) Gene Signals via Hippo

The Lats gene mammalian homologues Lats1 and Lats2 constitute a major compo-
nent of Hippo signalling and Lats are known to be tumour suppressors. Lats kinases
are aligned with the inhibition of cell proliferation, promotion of apoptosis, and with
chromosomal and cytoskeletal events that occur during mitosis. The kinases MST2/
STK (serine/threonine kinase) 3 and MST1/STK4 are in complex with and regu-
lated by Sav1 (human WW45). The pro-apoptosis MST2 and MST1 phosphorylate
and activate Lats occurring as a complex with the regulatory protein Mob (Mps one
binder) 1 phosphorylates and inhibits YAP1 and its translocation to the nucleus thus
affecting target gene regulation.
The p53-dependent checkpoint prevents cell cycle progression in G1. Loss of p53
function is known to result in tetraploid and aneuploid tumours capable of metastatic
progression. Lats also can activate this checkpoint. Lats and p53 both activate and
control this checkpoint and maintain genomic integrity. Lats2 binds Mdm2, a nega-
tive regulator of p53 and activates p53 (Aylon et al., 2006). Lats2 can inactivate the
transcriptional co-activator or co-repressor YAP, the downstream regulatory target of
Hippo signalling system to control morphogenesis, cell proliferation and apoptosis.
TAZ is also a downstream target of Lats.