Activation of Hepatocyte Growth Factor (HGF) by Endogenous HGF Activator Is Required for Metanephric Kidney Morphogenesis in Vitro

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.

Unusual Proteolytic Activation of Pro-hepatocyte Growth Factor by Plasma Kallikrein and Coagulation Factor XIa

“…However, prekallikrein (Fletcher factor) deficiency in humans is not associated with any apparent pathology (46), and homozygote FXI null mice develop normally (53), leading us to conclude that neither kallikrein nor FXIa are important pro-HGF activators during embryogenesis. Therefore, the proteolytic conversion of pro-HGF in this biological process has to be mediated by other HGFactivating enzymes, possibly by HGFA, which was suggested to play a role in morphogenesis (27,28).…”

“…Both activators follow classic enzyme kinetics and efficiently cleave pro-HGF at enzyme:substrate ratios of Ͻ1/ 1000 (20). HGFA is the best described pro-HGF activator and was suggested to play a role in generating active HGF during tissue regeneration (25,26), morphogenesis (27,28), and tumorigenesis (29 -31). A common feature of all known pro-HGF activators is that they also undergo proteolytic activation to become active enzymes, a process that is mediated by yet another set of proteases.…”

Follicular Dendritic Cells Catalyze Hepatocyte Growth Factor (HGF) Activation in the Germinal Center Microenvironment by Secreting the Serine Protease HGF Activator

“…In brief, scHGF (R&D Systems) was incubated with FDC-conditioned medium. Conditioned medium was obtained as described previously (28). For HGF activation, 20 l of conditioned medium were pretreated with 1 U of thrombin and added to 0.1 g of scHGF.…”

The von Hippel–Lindau tumor suppressor gene product represses oncogenic β-catenin signaling in renal carcinoma cells

“…␤-Catenin and E-cadherin are also expressed during renal development, specifically upon transition of the mesenchyme surrounding the branching ureteric buds to the epithelium that will form the tubules of the nephron (18). This mesenchymal-to-epithelial transition and the ensuing tubule formation involve several Wnt family members acting in an autocrine manner (19,20), as well as HGF acting in a paracrine mode (21). Dysregulated ␤-catenin signaling in the adult can be potently oncogenic.…”