Plasmin-mediated Proteolysis Is Required for Hepatocyte Growth Factor
Activation during Liver
Repair |
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Authors: | Kumar Shanmukhappa Ursula Matte Jay L Degen and Jorge A Bezerra |
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Institution: | Divisions of ‡Pediatric Gastroenterology, Hepatology, and Nutrition and ¶Developmental Biology, Cincinnati Children''s Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio, 45229-3039 and the §Hospital de Clinicas, Porto Alegre, RS 90035-903, Brazil |
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Abstract: | The physiological relevance of the activation of hepatocyte growth factor
(Hgf) by the plasminogen (Plg) system of proteases and its contribution to
tissue repair are largely undefined. Here, we investigated whether the
defective liver repair in mice lacking Plg is due to impaired activation of
Hgf. Loss of Plg in vivo suppressed Hgf activation and signaling
through its Met tyrosine kinase receptor. Without Plg, hepatocytes were
unresponsive to Hgf-induced proliferation and migration, with a more
pronounced impairment in hepatocyte movement within the hepatic environment.
Most notably, circumventing the defect in proteolytic activation of Hgf by the
downstream expression of an activated Met receptor corrected the functional
deficits and improved liver repair in Plg-deficient mice. These findings
support a fibrinolysis-unrelated role for Plg in modulating cell proliferation
and migration by activation of Hgf.Tissue repair requires a prompt proliferative response in concert with the
timely reorganization of the extracellular matrix. Each one of these processes
can be disrupted by the loss of individual growth factors or proteases, but
the precise regulatory relationship between these molecules in supporting
tissue repair is not fully understood. Multiple in vitro studies have
inferred that proteases in the plasminogen
(Plg)2 activation
system may be important in the proteolytic activation of the hepatocyte growth
factor (Hgf)
(1–4),
the ligand for the Met tyrosine kinase receptor that exerts potent mitogenic
and motogenic properties to mesenchymal and epithelial cells. This concept is
made even more attractive by the fact that Hgf is structurally related to Plg,
with multiple kringle domains and a catalytically inactive serine
protease-like domain. However, the physiological relevance of Plg to Hgf
activation and Hgf-related reparative processes are controversial and
effectively unexplored in vivo.We previously reported that a genetically imposed loss of circulating Plg
severely impairs clearance of necrotic cells and the repopulation of injured
zones by newly formed cells but without compromising the general hepatic
proliferative response (5).
Despite the indisputable role of Plg in fibrin clearance
(6), complementary studies in
mice with no capacity for fibrin deposition have shown that the loss of
fibrinolytic function alone in Plg-deficient mice cannot account for the
impediment in tissue repair
(5). Multiple nonfibrin targets
of plasmin-mediated proteolysis are known (e.g. serine and
metalloprotease zymogens, and extracellular matrix glycoproteins, latent
growth factors), and it is feasible that they may contribute to the focal
clearance of necrotic tissue. However, based on recent findings pointing to a
strikingly similar defect in hepatic repair in mice lacking Plg or a
conditional loss of Met (7), an
attractive hypothesis emerged that the Plg activation system supports
physiological liver repair by activation of the Met ligand, Hgf. Testing this
hypothesis, we found that the loss of Plg impairs Hgf activation, suppresses
Met phosphorylation and signaling, and prevents Hgf-induced migration of
hepatocytes. Most notably, consistent with a physiologically relevant
contribution of Plg to Hgf-Met signaling, the expression of an
autophosphorylated Met largely corrected the defective repair in Plg-deficient
livers. |
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