Hedgehog Signalling in EMT - Therapeutic Strategies in Cancer Biology and Pathology - page 30

Hedgehog

PTCH RTKs

SMO SH3

Cos2/Fused/Ci155 PI3K/Akt

MAPK/ERK

Rho/Rac Ci75 ERK1/2

GTPases

Gli

Target genes

Figure 4.1 The canonical Hh signalling pathway involving Gli activation and the non-
canonical SMO-dependent and independent routes. 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 activated. 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 (see Figure 4.2 ). Also shown here is the integration
of RTK signalling with SMO leading to positive transduction of signals via Gli. Overall the
phenotypic result is cell transformation and activation of EMT.

the infiltration of inflammatory cells and fibroblast into the tumour microenviron-
ment, which can quite conceivably modulate the signalling functions of regulatory
ligands. From a reading of the literature on CSCs, it is difficult to escape from a
general feeling that there is much teleological thinking in relation to the concept.
Notwithstanding the debate about the role of stem cells, there are overwhelming
arguments why modulation of Hh signalling can be justified and viewed as a poten-
tial path to therapy.
The major elements of the Hh signalling cascade are PTCH (PATCHED), the
12-pass trans-membrane receptor, 7-pass GPCR SMO (smoothened) of the Frizzled
family of receptors and Gli1. PTCH is the regulator of SMO activity. Hh binds to
PTCH and in this bound state SMO is able to activate the Kruppel family of zinc
finger transcription factor Gli1. When Hh is not present PTCH suppresses SMO and
Gli1 is not activated. SMO functions by signalling to an intracellular protein com-
plex composed of Cos2, the protein kinase Fused and the transcription factor the
full-length Ci155 (Cubitus interruptus) (Robbins et al., 1997). In the absence of Hh
binding PTCH is able to inhibit SMO and this complex triggers the cleavage of the
full-length Ci155 to a truncated Ci75 repressor form, in a process involving Ci155
phosphorylation by PKA (Price and Kalderon, 2002). When PTCH is bound by Hh,
SMO is active and reduces the cleavage of Ci155 to the repressor form, thus allow-
ing the transduction of downstream Hh signalling ( Figures 4.1 and 4.2 ).
As a general rule, Hh signalling can be distinguished into the canonical and
non-canonical systems which both seem eventually target genes whose activity or
suppression is required in cell transformation and activation of EMT. The canoni-
cal form of Hh signalling pathway involves Gli activation and the non-canonical