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M. Tripodi - Molecular mechanisms of the epithelial to mesenchymal transition in hepatocyte
Current studies are aimed: i) to better define the contribution
of ERK5 activation by TGFβ to EMT, by
analyzing the modulation of already characterized
EMT markers, including known target of Snail such
as E-cadherin and HNF-4, and ii) to deeper characterize
the mechanisms involved in the regulation of
GSK-3β by ERK5.
Role of Src/FAK signalling in TGFβ-mediated
EMT of the hepatocytes
As previously described, while Snail is sufficient to
down-regulate epithelial markers is not sufficient for
the up-regulation of mesenchymal and invasivity
EMT markers. In order to unveil the signalling
involved in the acquisition of mesenchymal phenotype,
we recently showed that during EMT TGFb
induces a Src-dependent activation of the focal adhesion
protein FAK. Relevantly, we demonstrated that
FAK signaling is required for i) transcriptional upregulation
of mesenchymal and invasivity markers
and ii) delocalization of membrane-bound E-cadherin.
These data provide the first evidence for a FAK
role in TGFb-induced EMT. Our results are reported
in the selected publication Cicchini et al., 2008.
Current studies are focused on the mechanisms of
FAK-mediated regulation of the E-cadherin and its
implication in tumor onset and metastasis.
Isolation, characterization and establishment
in line of a resident liver stem cell (RLSC)
We recently reported the isolation, characterization
and establishment in line of a murine resident liver
stem cell (RLSC) with immunophenotype (Sca+,
CD34-, CD45-, α-fetoprotein+, albumin-) and differ-
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entiative potentiality typical of a pre-hepatoblast/liver
precursor cell. RLSCs in fact, spontaneously
differentiate into hepatocytes and cholangiocytes
both in vivo and in vitro, and, when cultured in
appropriate conditions, into mesenchymal and neuroectodermal
cell lineages.
RLSCs represent a versatile cellular model usable in
studies regarding the mechanisms controlling the
EMT/MET oscillations in stem cells. These results
are described in the selected publication Conigliaro
et al., 2008.
Current studies are focused to the identification of
microenviromental factors involved in stem cell maintenance,
expansion and lineage-specific differentiation.
Selected publications
Cicchini C, Laudadio I, Citarella F, Corazzari M,
Steindler C, Conigliaro A, Fantoni F, Amicone L,
Tripodi T. TGFβ-induced EMT requires Focal
Adhesion Kinase (FAK) signaling. Exp Cell Res. 2008,
314:143-52.
Conigliaro A, Colletti M, Cicchini C, Guerra MT,
Manfredini R, Zini R, Bordoni V, Siepi F, Leopizzi M,
Tripodi M, Amicone L. Isolation and characterization
of a murine liver resident stem cell. Cell Death
Differ. 2008, 15:123-33.
Marchetti A, Colletti M, Cozzolino AM, Steindler
C, Lunadei M, Mancone C, Tripodi M.
ERK5/MAPK is activated by TGFβ in hepatocytes
and required for the GSK-3β-mediated Snail protein
stabilization. Cell Signal 2008, 20:2113-8.