上皮组织通过激活上皮细胞运动性和快速炎症而对损伤作出反应。这种反应也在过表达膜结合蛋白酶时引起,间质蛋白酶,或其抑制剂的突变,Hai1.不受限制的基质蛋白酶活性也易患癌症。基质蛋白酶如何导致这些细胞结果是未知的。我们证明斑马鱼hai1a突变体显示增加的H2O2,NFκB信号,和IP3R介导的钙闪烁,这些促进炎症,但不产生上皮细胞运动。相比之下,在hai1a突变体中Gq亚基的抑制挽救了炎症和上皮表型,后者由DAG类似物概括,PMA。我们证明hai1a具有升高的MAPK通路活性,抑制其挽救表皮缺陷。最后,我们将RSK激酶鉴定为MAPK靶向破坏hai1a突变体中的粘附连接。我们的工作绘制了新的信号级联,介导了基质蛋白酶对上皮的有效作用,与组织损伤反应和癌症进展有关。
当细胞中的正常过程被破坏或不受调节时,就会发生癌症。许多蛋白质可以做出贡献,包括一种叫做基质蛋白酶的酶,它可以在特定部位切割其他蛋白质。基质蛋白酶活性由一种叫做Hai1的蛋白质严格控制。在老鼠和斑马鱼中,当Hai1不能充分控制基质蛋白酶活性时,侵袭性癌症与严重的炎症发展。然而,目前尚不清楚未调节的基质蛋白酶如何导致炎症和癌症侵袭。基质蛋白酶活性的一个结果是从细胞表面去除称为钙黏着蛋白的蛋白质。这些蛋白质在细胞粘附中起作用:它们像胶水一样将细胞粘在一起。没有他们,细胞可以从组织中分离并离开,癌细胞侵入其他器官的关键步骤。然而,目前尚不清楚基质蛋白酶是如何触发钙黏着蛋白从细胞表面去除以促进侵袭的。以前的工作表明,间质蛋白酶在称为蛋白酶激活受体2或简称Par2的受体上切换,已知可以激活许多酶,包括一种叫做磷脂酶C的酶。这种酶向细胞释放两种信号:一种叫做肌醇三磷酸的糖,IP3;和一种叫做二酰基甘油的脂质或脂肪,DAG.这两种信号可能在基质蛋白酶如何从细胞表面去除钙黏着蛋白中起作用。为了找出答案,Maetal.绘制了缺乏Hai1蛋白的斑马鱼中基质蛋白酶的作用。这表明基质蛋白酶会增加IP3和DAG水平,引发炎症和入侵。IP3通过打开细胞内的促炎信号如化学过氧化氢来促进炎症。同时,DAG通过激活称为MAPK的众所周知的癌症信号通路来促进细胞侵袭。该途径激活称为RSK的蛋白质。Maetal.表明这种蛋白质是从细胞表面去除钙黏着蛋白所必需的,从而将基质蛋白酶对磷脂酶C的激活与其在破坏细胞粘附中的作用联系起来。在许多癌症中存在基质蛋白酶与HAI-1(Hai1的人类等效物)的比率的增加。出于这个原因,Ma等人描述的信号级联。可能对开发这些癌症的治疗方法感兴趣。了解这些信号如何协同工作可能会导致未来更直接的靶向抗癌方法。
Epithelial tissues are primed to respond to insults by activating epithelial cell motility and rapid inflammation. Such responses are also elicited upon overexpression of the membrane-bound protease,
Matriptase, or mutation of its inhibitor, Hai1. Unrestricted
Matriptase activity also predisposes to carcinoma. How
Matriptase leads to these cellular outcomes is unknown. We demonstrate that zebrafish hai1a mutants show increased H2O2, NfκB signalling, and IP3R -mediated calcium flashes, and that these promote inflammation, but do not generate epithelial cell motility. In contrast, inhibition of the Gq subunit in hai1a mutants rescues both the inflammation and epithelial phenotypes, with the latter recapitulated by the DAG analogue, PMA. We demonstrate that hai1a has elevated MAPK pathway activity, inhibition of which rescues the epidermal defects. Finally, we identify RSK kinases as MAPK targets disrupting adherens junctions in hai1a mutants. Our work maps novel signalling cascades mediating the potent effects of Matriptase on epithelia, with implications for tissue damage response and carcinoma progression.
Cancer occurs when normal processes in the cell become corrupted or unregulated. Many proteins can contribute, including one enzyme called Matriptase that cuts other proteins at specific sites.
Matriptase activity is tightly controlled by a protein called Hai1. In mice and zebrafish, when Hai1 cannot adequately control Matriptase activity, invasive cancers with severe inflammation develop. However, it is unclear how unregulated Matriptase leads to both inflammation and cancer invasion. One outcome of Matriptase activity is removal of proteins called Cadherins from the cell surface. These proteins have a role in cell adhesion: they act like glue to stick cells together. Without them, cells can dissociate from a tissue and move away, a critical step in cancer cells invading other organs. However, it is unknown exactly how Matriptase triggers the removal of Cadherins from the cell surface to promote invasion. Previous work has shown that Matriptase switches on a receptor called Proteinase-activated receptor 2, or Par2 for short, which is known to activate many enzymes, including one called phospholipase C. When activated, this enzyme releases two signals into the cell: a sugar called inositol triphosphate, IP3; and a lipid or fat called diacylglycerol, DAG. It is possible that these two signals have a role to play in how Matriptase removes Cadherins from the cell surface. To find out, Ma et al. mapped the effects of
Matriptase in zebrafish lacking the Hai1 protein. This revealed that Matriptase increases IP3 and DAG levels, which initiate both inflammation and invasion. IP3 promotes inflammation by switching on pro-inflammatory signals inside the cell such as the chemical hydrogen peroxide. At the same time, DAG promotes cell invasion by activating a well-known cancer signalling pathway called MAPK. This pathway activates a protein called RSK. Ma et al. show that this protein is required to remove Cadherins from the surface of cells, thus connecting Matriptase’s activation of phospholipase C with its role in disrupting cell adhesion. An increase in the ratio of Matriptase to HAI-1 (the human equivalent of Hai1) is present in many cancers. For this reason, the signal cascades described by Ma et al. may be of interest in developing treatments for these cancers. Understanding how these signals work together could lead to more direct targeted anti-cancer approaches in the future.