The cytoplasmic domains of TNFα-converting enzyme (TACE/ADAM17) and L-selectin are regulated differently by p38 MAPK and PKC to promote ectodomain shedding
The cytoplasmic domains of TNFα-converting enzyme (TACE/ADAM17) and L-selectin are regulated differently by p38 MAPK and PKC to promote ectodomain shedding
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DOI：
10.1042/bj20091611
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发表时间：
2010-06-01
影响因子：
4.1
通讯作者：
Ivetic, Aleksandar
中科院分区：
文献类型：
--
作者：
Killock, David J.;Ivetic, Aleksandar
L-选择素介导白细胞最初的束缚和随后的沿沿着腔壁的发炎小静脉滚动。TACE [TNF α（肿瘤坏死因子α）转化酶]负责切割L-选择素的近膜胞外结构域（也称为脱落），这降低了白细胞募集至炎症部位的效率。许多报道强调了PKC（蛋白激酶C）和p38 MAPK（丝裂原活化蛋白激酶）在促进L-选择素脱落中的作用，但对所涉及的机制了解甚少。通过使用PMA和磷酸酶抑制剂藜芦苷和calyculin A，我们可以分别选择性地激活PKC或p38 MAPK，以促进TACE依赖的L-选择素脱落。有趣的是，导致脱落事件的细胞内机制显著不同。例如，L-选择素胞质尾内的调节元件，如ERM（ezrin/radixin/moesin）结合和丝氨酸残基，对于PKC依赖性脱落而不是p38 MAPK依赖性脱落是重要的。此外，在p38 MAPK激活后，淋巴细胞和单核细胞中发生TACE的细胞表面水平增加和持续，以及其胞质尾区的磷酸化（TACE激活的标志）。最后，我们发现TNF α诱导的单核细胞中L-选择素脱落与藜芦醇苷诱导的脱落惊人相似，并表明这种新的特征性机制可能与炎症细胞的生理学相关。
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.