Activation of hepatocyte growth factor (HGF) by endogenous HGF activator is required for metanephric kidney morphogenesis in vitro
Activation of hepatocyte growth factor (HGF) by endogenous HGF activator is required for metanephric kidney morphogenesis in vitro
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DOI：
10.1074/jbc.m006634200
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发表时间：
2001-05-04
影响因子：
4.8
通讯作者：
Huan, YH
中科院分区：
文献类型：
--
作者：
van Adelsberg, J;Sehgal, S;Huan, YH
肝细胞生长因子(HGF)与c-Met的相互作用与肾脏、肺、乳腺、肝脏、胎盘和肢芽的形态发生有关。HGF是作为一种非活性的酶原分泌的，必须被丝氨酸蛋白酶切割才能启动Met信号。我们在这里展示了一种专用于HGF的丝氨酸蛋白酶，HGF激活物(HGFA)，在体内和体外由发育中的肾脏的输尿管芽表达和激活。丝氨酸蛋白酶抑制剂抑制HGFA活性可减少输尿管芽分枝，抑制肾小球形成和肾形成。激活的HGF将发育中的肾脏从抑制剂的影响中拯救出来。在发育中的肾脏中，HGFA定位于输尿管芽尖部，而HGF则弥漫地表达于整个间质。这些数据表明，HGF的表达不足以发育，但它的激活也是必需的。HCFA在输尿管芽和紧邻输尿管的间质中的定位表明，HGFA在发育中的肾脏中产生了HGF活性的梯度。HGF激活物的局部分泌所产生的激活的HGF梯度的形成和形状在HGF反应组织的模式形成中起着重要作用。
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 HCFA 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.