The ubiquitin–proteasome system and signal transduction pathways regulating Epithelial Mesenchymal transition of cancer
Journal of Biomedical Science
The ubiquitin-proteasome system and signal transduction pathways regulating Epithelial Mesenchymal transition of cancer
Ioannis A Voutsadakis 0
0 Centre Pluridisciplinaire d'Oncologie, BH06, Centre Hospitalier Universitaire Vaudois , Bugnon 46, Lausanne 1011 , Switzerland
Epithelial to Mesenchymal transition (EMT) in cancer, a process permitting cancer cells to become mobile and metastatic, has a signaling hardwire forged from development. Multiple signaling pathways that regulate carcinogenesis enabling characteristics in neoplastic cells such as proliferation, resistance to apoptosis and angiogenesis are also the main players in EMT. These pathways, as almost all cellular processes, are in their turn regulated by ubiquitination and the Ubiquitin-Proteasome System (UPS). Ubiquitination is the covalent link of target proteins with the small protein ubiquitin and serves as a signal to target protein degradation by the proteasome or to other outcomes such as endocytosis, degradation by the lysosome or specification of cellular localization. This paper reviews signal transduction pathways regulating EMT and being regulated by ubiquitination.
Epithelial to mesenchymal transition; Ubiquitination; Ubiquitin-proteasome system; Signal transduction; Carcinogenesis
Introduction
Epithelial to Mesenchymal transition (EMT) describes
the process that allows an epithelial cell belonging in an
epithelial membrane to detach from its neighbors, to
transverse the dissolving basement membrane and move
through the extra-cellular matrix to other sites of the
tissue or even to distant organs. In order to facilitate
mobility during EMT, connections joining the cell to
adjacent epithelial cells are dissolved [
1
]. Concomitantly,
the cell acquires a fibroblast-like shape, down-regulates
epithelial markers and up-regulates mesenchymal
markers. EMT is a process that physiologically takes place
during development. Multi-cellular organisms derive
their variety of specialized cells and tissues from a single
cell, the fertilized ovum. This cell has to differentiate to
the three layers of differentiation, the ectoderm,
mesoderm and endoderm and further to different tissues and
cell types in complex but ordered patterns. During
development EMT takes place as an integral process of
differentiation to the various cell types in a highly
regulated in space and time manner. For example during
embryonal gastrulation the epiblast layer produces a
midline invagination, the primitive streak, from which
cells are mobilized by undergoing an EMT and produce
the mesoderm and endoderm. In another developmental
example, dorsal neural tube-derived neural crest cells
undergo an EMT and migrate to form components of
the peripheral nervous system, skin melanocytes, adrenal
medulla and facial bones and muscles [
2
].
Derived from a single cell, all cells of a multi-cellular
organism possess the same DNA sequences in their
whole genome and thus their various phenotypes must
be the result of differences in transcriptional and
posttranscriptional regulation of cellular proteins secondary
to intra-cellular and external signals. Post-translational
modifications can regulate function, localization and
turn-over of every cell protein impacting on cell
morphology, activity and interactions in the multi-cellular
organism. Ubiquitination is such a post-translational
modification. Ubiquitination is the covalent attachment
of molecules of the small 76 amino-acids protein
ubiquitin to a target protein which is then marked for
proteasome destruction or endocytosis or participation in a
range of processes. Ubiquitination along with other
post-translational modifications of proteins such as
phosphorylation, hydroxylation and acetylation is a
regulated process for the execution of which a multitude of
regulators exist. Many signal transducers and
transcription factors involved in EMT are regulated by
ubiquitination and the ubiquitin proteasome system. This review
will discuss EMT signal transduction pathways and
relationship with Ubiquitin-Proteasome system (UPS) while
the extensive network of transcription factors regulating
EMT and their relationship to UPS will not be discussed
here.
EMT in cancer
EMT is proposed to happen in three different scenarios
with different starting points and outcomes. In
development EMT is used by normal fetal cells for obtaining
the different specificities present in the multi-cellular
organism. In adult tissue injury repair, EMT is used to heal
open wounds and may lead to fibrosis. In a third
scenario, EMT happens during the tissue invasion and
metastatic process of malignant epithelial cells. These
three EMT types have recently been labelled by
convention type 1, 2 and 3 [
3
]. The starting point of type 1
EMT is, thus, epithelial progenitors in the embryo that
lose conduct with their initial site and move to become
a different structure with different morphology and
function. In type 2 EMT, epithel (...truncated)