van Adelsberg J, Sehgal S, Kukes A, Brady C, Barasch J, Yang J, Huan Y
Columbia University College of Physicians and Surgeons, Department of Medicine, New York, New York 10032, USA.
J Biol Chem. 2001 May 4;276(18):15099-106. doi: 10.1074/jbc.M006634200. Epub 2000 Oct 13.
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.
肝细胞生长因子（HGF）与c-Met的相互作用已被证实与肾脏、肺、乳腺、肝脏、胎盘和肢芽的形态发生有关。HGF以无活性的酶原形式分泌，必须被丝氨酸蛋白酶切割才能启动Met信号传导。我们在此表明，一种对HGF具有特异性的丝氨酸蛋白酶，即HGF激活剂（HGFA），在体内和体外发育中的肾脏输尿管芽中表达并被激活。用丝氨酸蛋白酶抑制剂抑制HGFA活性会减少输尿管芽分支，并抑制肾小球生成和肾发生。激活的HGF可使发育中的肾脏免受抑制剂的影响。HGFA定位于发育中肾脏输尿管芽的尖端周围，而HGF则在整个间充质中弥散表达。这些数据表明，HGF的表达不足以促进发育，其激活也是必需的。HGFA定位于输尿管芽及其紧邻的间充质，这表明HGFA在发育中的肾脏中形成了HGF活性梯度。通过局部分泌HGF激活剂形成激活的HGF梯度及其形状，可能在HGF反应性组织的模式形成中发挥重要作用。
