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首页> 外文OA文献 >The cytoplasmic domains of TNF alpha-converting enzyme (TACE/ADAM17) and L-selectin are regulated differently by p38 MAPK and PKC to promote ectodomain shedding
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The cytoplasmic domains of TNF alpha-converting enzyme (TACE/ADAM17) and L-selectin are regulated differently by p38 MAPK and PKC to promote ectodomain shedding

机译：TNFα转换酶（TACE / ADAM17）和L-选择素的胞质域受p38 MAPK和PKC的调控不同，以促进胞外域脱落

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L-selectin mediates the initial tethering and subsequent rolling of leucocytes along lumina' walls of inflamed venules. TACE [TNF alpha (tumour necrosis factor alpha)-converting enzyme] is responsible for cleaving the membrane-proximal extracellular domain of L-selectin (also known as shedding), which reduces the efficiency of leucocyte recruitment to sites of inflammation. Many reports have highlighted roles for PKC (protein kinase C) and p38 MAPK (mitogen-activated protein kinase) in promoting L-selectin shedding with little insight into the mechanism involved. By using PM A and the phosphatase inhibitors cantharidin and calyculin A, we could selectively activate PKC or p38 MAPK respectively to promote TACE-dependent shedding of L-selectin. Interestingly, the intracellular mechanisms leading to the shedding event differed dramatically. For example, regulatory elements within the L-selectin cytoplasmic tail, such as ERM (ezrin/radixin/moesin)-binding and serine residues, were important for PKC- but not p38 MAPK-dependent shedding. Also, increased and sustained cell surface levels of TACE, and phosphorylation of its cytoplasmic tail (a hallmark of TACE activation), occurred in lymphocytes and monocytes following p38 MAPK activation. Finally, we showed that TNF alpha-induced shedding of L-selectin in monocytes was strikingly similar to cantharidin-induced shedding and suggest that this newly characterized mechanism could be physiologically relevant in inflammatory cells.
机译：L-选择蛋白介导白细胞的初始束缚和随后沿发炎的小静脉腔壁滚动。 TACE [TNFα（肿瘤坏死因子α）转换酶]负责裂解L-选择素的膜近细胞外结构域（也称为脱落），这降低了白细胞募集到炎症部位的效率。许多报道都强调了PKC（蛋白激酶C）和p38 MAPK（丝裂原激活的蛋白激酶）在促进L-选择蛋白脱落方面的作用，但对所涉及的机制知之甚少。通过使用PM A和磷酸酶抑制剂cantharidin和calyculin A，我们可以分别选择性激活PKC或p38 MAPK，从而促进L-选择蛋白的TACE依赖性脱落。有趣的是，导致脱落事件的细胞内机制差异很大。例如，L-选择蛋白胞质尾巴中的调控元件，例如ERM（ezrin / radixin / moesin）结合和丝氨酸残基，对于PKC依赖但对p38 MAPK依赖的脱落并不重要。同样，在p38 MAPK激活后的淋巴细胞和单核细胞中，TACE的细胞表面水平持续升高，并且其胞质尾磷酸化（TACE激活的标志）。最后，我们证明了TNFα诱导的单核细胞L-选择蛋白的脱落与斑th素诱导的脱落极为相似，并表明这种新表征的机制在炎症细胞中可能与生理相关。

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