Targeted Inhibition of Hh, Wnt, TGF-B Signalling Complex - Therapeutic Strategies in Cancer Biology and Pathology - page 34

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Targeted Inhibition of Hh, Wnt,
TGF- β Signalling Complex

The perceived integration of Hh, Wnt, TGF-β signalling pathways, cross talk and
mutual regulation has made this signalling complex a significant target for therapeu-
tic intervention. Several inhibitors of Hh have been designed, synthesised and clini-
cally tested with more than a modicum of success.

SMO Is a GPCR Component of Hh Signalling

GPCRs have been closely linked with the regulation of cell proliferation and possi-
bly also with cell motility and invasion. With the recognition that the major element
of the Hh signalling cascade the 7-pass SMO (Smoothened) might belong to the
GPCR Frizzled family, there is general agreement that drugs targeting GPCR might
provide a practical approach to the inhibition of deregulated Hh signalling in cancer.
The precise links of SMO with the G-protein-transduced signalling are continually
being elucidated. Recently a G-protein has been shown to be a direct downstream
effector of SMO signal transduction (Ogden et al., 2008). GPRK2 (G-protein-
coupled receptor kinase 2) participates in several cellular events. GPRK2 often mani-
fests divergent effects, for example blocking the regulation of cell proliferation and
apoptosis by TGF-β, but it promotes cell proliferation signalling by EGF or by SMO
activation (Ho et al., 2005; Meloni et al., 2006). In Drosophila, GPRK2 is required
for the regulation of SMO activity. Following upon its activation SMO is internal-
ised. Phosphorylation of SMO by GPRK2 is suggested to be involved here. SMO
is phosphorylated at several sites in the C-terminus; phosphorylation is induced or
blocked by SMO agonists and the natural antagonist cyclopamine respectively.
Whilst CK (casein kinase) 1α initiates phosphorylation, further phosphorylation is
promoted by CK1α and GPRK2 in a positive regulatory loop. GPRK2 is also said
to be able to bind to the C-terminal tail of SMO and stabilise its active conformation
quite independently of GPRK2 activity (Chen et al., 2010, 2011d). PTCH is said to
regulate SMO by a different mechanism (Cheng et al., 2010). Other factors such as
GAS8 (the growth arrest specific 8) could also be involved in this intracellular traf-
ficking and stimulation of SMO (Evron et al., 2011). GAS8 is regarded as a puta-
tive tumour suppressor. It is a microtubule associated protein and so involved in cell
motility and invasion. GAS proteins inhibit cell proliferation and motility. On the
other hand, GAS8 is described as a positive regulator of Hh signalling being able to
promote SMO function. Possibly the function of GAS as a cytoskeletal component