Hedgehog Signalling in EMT - Therapeutic Strategies in Cancer Biology and Pathology - page 31

No Hh PTCH PTCH-Hh

SMO

Cos2/Fused/Ci155

Truncation

Repressor Ci75 Active Ci155

Hh signalling Active Hh signalling

Figure 4.2 A flowchart of the Hh signalling cascade. SMO targets the protein complex
made up of Cos2/protein kinase Fused and the full-length transcription factor C155. In the
absence of Hh, the complex leads to the cleavage Ci155 to the truncated Ci75 which is a
genetic repressor and inhibits Hh signalling. PTCH regulates SMO function. When PTCH is
bound to Hh, it cannot inhibit SMO and this inhibits the truncation of Ci155 which allows the
transduction of active Hh signalling downstream to generate the phenotypic effects.

SMO-dependent and -independent routes. To reiterate, in the canonical pathway in
the absence of Hh SMO targets, the Cos2/Fused/Ci155 protein complex leading to
the truncation of Ci155 to the repressor Ci75 and as a consequence Gli is not acti-
vated. When Hh ligand binds PTCH this truncation does not take place and Ci155
can activate Gli and target downstream genes to generate the phenotypic effect.
The SH3 (src homology) domain are small domains occurring in signalling pro-
teins and said to function by binding to proline-rich motifs of proteins. SH3 domains
have been implicated many biological functions including signalling systems. In
the present functional view point, SH3 domains can provide links with cytoskel-
etal proteins thus influencing cell motility. The organisation of the actin cytoskel-
eton involves many SH3 domain proteins. The involvement of Rho/Rac GTPases in
membrane activity, for example promotion of focal clustering of integrins and cell
adhesion processes, is well established. It would follow from this that they would be
involved in cell motility. These functions are also dependent upon SH3 domains. The
C-terminal region of PTCH has SH3 domains which could be affecting the cytoskel-
etal organisation. PTCH can function independently of SMO to activate ERK1/2
(Chang et al., 2010). Activation of MEK/ERK is a requisite for integrin and cad-
herin-induced adhesion (Avizienyte et al., 2004). Equally, it has been advocated that
cytoskeletal changes mediated by Rho/Rac can also occur via the agency of SMO
(Polizio et al., 2011). These can be viewed as the non-canonical SMO-independent
and -dependent means of Hh signalling.
Sonic hedgehog (SHh) activates Gli1 as shown in Figure 4.1 . The transcription
of Gli1 is upregulated in many cancers. In gliomas levels of its expression have cor-
related with tumour grade. Suppression of SHh/Gli1 signalling suppressed in vitro