Antithrombin regulates matriptase activity involved in plasmin generation, syndecan shedding, and HGF activation in keratinocytes.
Antithrombin regulates matriptase activity involved in plasmin generation, syndecan shedding, and HGF activation in keratinocytes.
复制标题
DOI：
10.1371/journal.pone.0062826
复制
发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Lin CY
中科院分区：
文献类型：
--
作者：
Chen YW;Xu Z;Baksh AN;Wang JK;Chen CY;Swanson R;Olson ST;Kataoka H;Johnson MD;Lin CY
膜相关丝氨酸蛋白酶——膜型丝氨酸蛋白酶（Matriptase）通过激活糖基磷脂酰肌醇（GPI）锚定的丝氨酸蛋白酶前列腺素（Prostasin），在表皮屏障功能中发挥关键作用。膜型丝氨酸蛋白酶 - 前列腺素蛋白水解级联受到肝细胞生长因子激活物抑制剂（HAI - 1）的严格调控，使得膜型丝氨酸蛋白酶的自身激活和前列腺素的激活同时发生，并且紧接着这两种酶都被HAI - 1抑制。然而，膜型丝氨酸蛋白酶作用于细胞外底物的机制仍然不清楚。在此我们报道，一些有活性的膜型丝氨酸蛋白酶能够通过从细胞表面快速脱落而逃避HAI - 1的抑制。在细胞周环境中，脱落的有活性的膜型丝氨酸蛋白酶能够激活肝细胞生长因子（HGF），加速纤溶酶原激活，并使多配体聚糖 - 1（syndecan 1）脱落。脱落的有活性的膜型丝氨酸蛋白酶的量与结合在角质形成细胞表面的抗凝血酶（AT）的量呈负相关。抗凝血酶与角质形成细胞表面的结合依赖于一个功能性的肝素结合位点——赖氨酸 - 125，并且N - 糖基化位点天冬酰胺 - 135未被糖基化。这表明是β - 抗凝血酶，而非α - 抗凝血酶，负责调节角质形成细胞中细胞周膜型丝氨酸蛋白酶的活性。角质形成细胞似乎比乳腺和前列腺上皮细胞更依赖抗凝血酶来调节细胞周有活性的膜型丝氨酸蛋白酶的水平，在乳腺和前列腺上皮细胞中，抗凝血酶对膜型丝氨酸蛋白酶活性的调节水平比角质形成细胞低得多。这些结果表明，角质形成细胞利用两种不同的丝氨酸蛋白酶抑制剂来控制两组不同的膜型丝氨酸蛋白酶底物的激活和加工，从而导致不同的生物学事件：1）HAI - 1用于前列腺素的激活/抑制，以及2）抗凝血酶用于涉及肝细胞生长因子激活、加速纤溶酶原激活和多配体聚糖脱落的细胞周蛋白水解。
Matriptase, a membrane-associated serine protease, plays an essential role in epidermal barrier function through activation of the glycosylphosphatidylinositol (GPI)-anchored serine protease prostasin. The matriptase-prostasin proteolytic cascade is tightly regulated by hepatocyte growth factor activator inhibitor (HAI)-1 such that matriptase autoactivation and prostasin activation occur simultaneously and are followed immediately by the inhibition of both enzymes by HAI-1. However, the mechanisms whereby matriptase acts on extracellular substrates remain elusive. Here we report that some active matriptase can escape HAI-1 inhibition by being rapidly shed from the cell surface. In the pericellular environment, shed active matriptase is able to activate hepatocyte growth factor (HGF), accelerate plasminogen activation, and shed syndecan 1. The amount of active matriptase shed is inversely correlated with the amount of antithrombin (AT) bound to the surface of the keratinocytes. Binding of AT to the surface of keratinocytes is dependent on a functional heparin binding site, Lys-125, and that the N-glycosylation site Asn-135 be unglycosylated. This suggests that β-AT, and not α-AT, is responsible for regulation of pericellular matriptase activity in keratinocytes. Keratinocytes appear to rely on AT to regulate the level of pericellular active matriptase much more than breast and prostate epithelial cells in which AT regulation of matriptase activity occurs at much lower levels than keratinocytes. These results suggest that keratinocytes employ two distinct serine protease inhibitors to control the activation and processing of two different sets of matriptase substrates leading to different biological events: 1) HAI-1 for prostasin activation/inhibition, and 2) AT for the pericellular proteolysis involved in HGF activation, accelerating plasminogen activation, and shedding of syndecans.
登录
查看更多内容
DOI：
10.1152/ajplung.00437.2007
发表时间：
2008-05-01
影响因子：
4.9
作者：
Myerburg, Mike M.;McKenna, Erin E.;Pilewski, Joseph M.
通讯作者：
Pilewski, Joseph M.
影响因子：
4.8
作者：
Chen, Ya-Wen;Wang, Jehng-Kang;Lin, Chen-Yong
通讯作者：
Lin, Chen-Yong
影响因子：
4.8
作者：
Lin, CY;Anders, J;Dickson, RB
通讯作者：
Dickson, RB
影响因子：
20.3
作者：
Kilpatrick, Lynette M.;Harris, Roger L.;Ellis, Vincent
通讯作者：
Ellis, Vincent
影响因子：
7.8
作者：
Leyvraz, Celine;Charles, Roch-Philippe;Rubera, Isabelle;Guitard, Marjorie;Rotman, Samuel;Breiden, Bernadette;Sandhoff, Konrad;Hummler, Edith
通讯作者：
Hummler, Edith