Abstract
The interaction of hepatocyte growth factor (HGF) with c-Met has been implicated in morphogenesis of the kidney, lung, mammary gland, liver, placenta, and limb bud. HGF is secreted as an inactive zymogen and must be cleaved by a serine protease to initiate Met signaling. We show here that a serine protease specific for HGF, HGF activator (HGFA), is expressed and activated by the ureteric bud of the developing kidney in vivo and in vitro. Inhibition of HGFA activity with serine protease inhibitors reduced ureteric bud branching and inhibited glomerulogenesis and nephrogenesis. Activated HGF rescued developing kidneys from the effects of inhibitors. HGFA was localized around the tips of the ureteric bud in developing kidneys, while HGF was expressed diffusely throughout the mesenchyme. These data show that expression of HGF is not sufficient for development, but that its activation is also required. The localization of HGFA to the ureteric bud and the mesenchyme immediately adjacent to it suggests that HGFA creates a gradient of HGF activity in the developing kidney. The creation and shape of gradients of activated HGF by the localized secretion of HGF activators could play an important role in pattern formation by HGF responsive tissues.
Highlights
The interaction of hepatocyte growth factor (HGF)1 with the receptor tyrosine kinase c-Met is a prototype of mesenchymal to epithelial signaling
The thrombin cleavage site at Arg405-Ile406 that is required for activation of HGF activator (HGFA) was conserved, as were all the amino acids required for catalytic activity
We present the sequence of the murine HGFA gene
Summary
The interaction of hepatocyte growth factor (HGF) with the receptor tyrosine kinase c-Met is a prototype of mesenchymal to epithelial signaling. Other serine proteases, including urokinase, factor XIIa, and tissue plasminogen activator have been shown to activate HGF in vitro, but their biologic role in HGF activation is unknown [11, 15, 16]. Like other serine proteases in the coagulation and fibrinolytic cascades, HGF activator is secreted as an inactive single chain zymogen. Immortalized UB cells expressed HGFA message, protein, and an HGF hydrolyzing activity that was inhibited by a variety of serine protease inhibitors including leupeptin. UB cells scattered in response to the single chain zymogen of HGF; this scattering activity was inhibited by the same concentrations of leupeptin that blocked HGF activation. Leupeptin at concentrations that blocked the hydrolysis of HGF by ureteric bud in vitro inhibited renal morphogenesis in organ culture.
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