The liver represents a site of expression of
neurotrophins and their receptors. We have characterized
the expression and intracellular localization of the nerve
growth factor (NGF) receptor, Trk-A, in liver cells in
vivo and in vitro. In both normal and fibrotic liver tissue,
Trk-A immunostaining was present in different cell
types, including parenchymal cells and cells of the
inflammatory infiltrate. In hepatocytes and activated
stellate cells (HSC), Trk-A showed a predominant
nuclear localization, both in the presence and absence of
injury. In cultured HSC, Trk-A was found to be
functional, because exposure of the cells to recombinant
NGF resulted in stimulation of cell migration and
activation of intracellular signaling pathways, including
Ras-ERK and PI3K/Akt. Remarkably, in cultured HSC,
Trk-A staining was found constitutively in the nucleus.
In these cells, Trk-A could be stained only by antibodies
directed against the intracellular domain but not by those
recognizing the extracellular portion of Trk-A
suggesting that the intracellular portion of the receptor is
the major determinant of nuclear Trk-A staining. In contrast to HSC, freshly isolated hepatocytes did not
show any nuclear localization of the intracellular portion
of Trk-A. In pheocromocytoma cells, nuclear staining
for Trk-A was not present in conditions of serum
deprivation, but could be induced by exposure to NGF or
to a mixture of soluble mediators. We conclude that
nuclear localization of the intracellular domain of Trk-A
is observed constitutively in liver cells such as HSC,
while in other cell types it could be induced in response
to soluble factors