Stimulation of cleavage of membrane proteins by calmodulin inhibitors
Stimulation of cleavage of membrane proteins by calmodulin inhibitors
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DOI：
10.1042/0264-6021:3460359
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发表时间：
2000-03-01
影响因子：
4.1
通讯作者：
Pandiella, A
中科院分区：
文献类型：
--
作者：
Díaz-Rodríguez, E;Esparís-Ogando, A;Pandiella, A
几种膜结合蛋白的胞外结构域可以通过蛋白水解性切割而脱落。细胞内蛋白激酶C(PKC)和细胞内钙离子等第二信使通路高度调控着参与细胞脱落的蛋白水解酶的活性。最近发现，黏附分子L-选择素的脱落受钙调蛋白(CaM)与L-选择素胞浆尾巴相互作用的调节。CaM抑制剂或突变CaM结合位点阻止CaM-L-选择素相互作用引起的L-选择素胞外结构域脱落。CaM抑制剂的这种作用是否也影响其他膜结合蛋白尚不清楚。在本文中，我们发现CaM抑制剂还可以刺激其他几种跨膜蛋白的切割，如膜结合的生长因子前体转化生长因子-α和神经调节蛋白-α2c，受体酪氨酸激酶TrkA和β-淀粉样前体蛋白。CaM抑制剂诱导的切割是一个快速的事件，是一种独立于PKC或细胞内钙离子增加的机制的激活，但对基于异羟肟酸的金属蛋白酶抑制剂高度敏感。TrkA受体胞内结构域的突变分析表明，CaM抑制剂可能通过不依赖于CaM-底物相互作用的机制来促进膜-蛋白质胞外结构域的切割。
The ectodomain of several membrane-bound proteins can be shed by proteolytic cleavage. The activity of the proteases involved in shedding is highly regulated by several intracellular second messenger pathways, such as protein kinase C (PKC) and intracellular Ca2+. Recently, the shedding of the adhesion molecule L-selectin has been shown to be regulated by the interaction of calmodulin (CaM) with the cytosolic tail of L-selectin. Prevention of CaM-L-selectin interaction by CaM inhibitors or mutation of a CaM binding site in L-selectin induced L-selectin ectodomain shedding. Whether this action of CaM inhibitors also affects other membrane-bound proteins is not known. In the present paper we show that CaM inhibitors also stimulate the cleavage of several other transmembrane proteins, such as the membrane-bound growth factor precursors pro-transforming growth factor-alpha and pro-neuregulin-alpha 2c, the receptor tyrosine kinase, TrkA, and the beta-amyloid precursor protein. Cleavage induced by CaM inhibitors was a rapid event, and resulted from the activation of a mechanism that was independent of PKC or intracellular Ca2+ increases, but was highly sensitive to hydroxamic acid-based metalloprotease inhibitors. Mutational analysis of the intracellular domain of the TrkA receptor indicated that CaM inhibitors may stimulate membrane-protein ectodomain cleavage by mechanisms independent of CaM-substrate interaction.