Diacylglycerol Signaling

268 N.A. Riobo
PTCH Patched
SMO Smoothened
13.1 Introduction
The Hedgehog (Hh) and Wnt signaling pathways are essential for embryonic
development; impairment of those pathways is lethal and even a subtle dysregulation
results in significant pattern abnormalities and in growth defects. Moreover,
deregulated hyperactivation of these pathways in adult organisms is often found in
association with cancer.
The hedgehog (hh) gene was discovered in a Drosophila melanogaster screening
for segment polarity mutants (Nüsslein-Volhard and Wieschaus 1980). Further
screening of mutants with similar phenotypes and genetic complementation analysis
led to the identification of additional components of the signal transduction
pathway. Homologs were later found in vertebrate model organisms, which were
shown to contain a large number of homologs of the secreted Hh proteins, as well
as a more complex receptor and intracellular signaling network than Drosophila
(Riobo et al. 2006a; Riobo and Manning 2007).
The wnt-1 gene was discovered in 1982 as a proto-oncogene activated by integration
of mouse mammary tumor virus (MMTV) in mammary tumors (Nusse and
Varmus 1982). With the identification of the Drosophila segment polarity gene wingless
(wg) as the ortholog of Wnt-1 (Cabrera et al. 1987; Rijsewijk et al. 1987), it
became clear that Wnt genes are important regulators of many developmental processes
and cancer (Nusse and Varmus 1992; Cadigan and Nusse 1996). Up to date,
about 20 Wnt genes have been identified in humans, all encoding a secreted glycoprotein
with an almost invariant motif of 23 cysteines named cysteine-rich domain.
The pattern formation role of Hh and Wnt is essential in mammals (although it is
conserved in other vertebrate groups like fish, amphibians, and birds), as well as their
function in balancing proliferation and survival of embryonic tissues during development.
As already mentioned, in adult mammals alterations of these two pathways are
very frequently found in many cancer types (Beachy et al. 2004). Hedgehog signaling
is upregulated in basal cell carcinoma, medulloblastoma, rhabdomyosarcoma;
the majority of GI-tract derived carcinomas, prostate, adenocarcinomas some lymphomas,
and lung cancers. Dysregulation of Wnt signaling has been frequently
found as the underlying cause of colon cancer and as a common event in breast
cancer. There is a very straightforward association of Hh or Wnt with cancer in those
tissues in which the same pathways are active during embryonic development.
The family of calcium-dependent protein kinases (PKCs) is implicated in
numerous cell responses, and the Hh and Wnt pathways are not the exception.
Understanding the mediators that transmit these signals and their crosstalk with
other oncogenic factors is of critical importance in the development of more effective
therapeutic approaches for cancer. Excellent reviews have been published on
Hh and Wnt signaling; therefore, this chapter introduces the pathways only for
background purposes and focuses on the role of PKC in those cascades.