Phosphorylation of FADD/MORT1 and Fas by kinases that associate with the membrane-proximal cytoplasmic domain of Fas.
Phosphorylation of FADD/MORT1 and Fas by kinases that associate with the membrane-proximal cytoplasmic domain of Fas.
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DOI：
10.4049/jimmunol.160.10.4881
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发表时间：
1998-05
影响因子：
4.4
通讯作者：
N. Kennedy;R. Budd
中科院分区：
文献类型：
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作者：
N. Kennedy;R. Budd
Fas(Apo-1，CD95)是肿瘤坏死因子受体家族的成员之一，表达于多种细胞上，传递细胞凋亡信号。由于Fas不具有已知的酶活性，因此与Fas的细胞质区域相互作用的蛋白质调节死亡信号。已经鉴定了几种蛋白质，主要是使用酵母双杂交系统，它们与Fas的死亡区域有关。其中一种蛋白质，FADD/MORT1，可以被磷酸化，尽管负责的激酶尚未确定。此外，Fas与其激活的鞘磷脂酶或核因子-kappaB之间的直接信号联系尚未建立，这表明其他蛋白可能与Fas有关。本研究构建了一系列含小鼠Fas胞浆结构域的谷胱甘肽-S-转移酶融合蛋白。这些蛋白质被用来寻找与Fas相关的其他蛋白质。新的蛋白质，包括激酶，被鉴定为与Fas膜近端的细胞质尾巴特异相关，但不与死亡区域相关。其中一种激酶使FADD/MORT1磷酸化。此外，Fas的膜-近端区域本身也被其中一个结合酶磷酸化。这些发现表明，与Fas相关的p55TNFR类似，Fas的膜近端区域可能参与信号转导。
Fas (Apo-1, CD95), a member of the TNFR family, is expressed on a variety of cell types and transduces an apoptotic signal. Since Fas does not possess known enzymatic activities, proteins that interact with the cytoplasmic domain of Fas regulate the death signal. Several proteins have been identified, primarily using the yeast two-hybrid system, that associate with the death domain of Fas. One of these proteins, FADD/MORT1, can be phosphorylated, although the kinase that is responsible has not been identified. Furthermore, direct signaling connections between Fas and its known activation of sphingomyelinase or NF-kappaB have not been made, suggesting that other proteins may associate with Fas. In this study, a series of glutathione S-transferase fusion proteins was constructed that contained the cytoplasmic domain of murine Fas. These proteins were used to search for additional proteins that associate with Fas. Novel proteins, including kinases, were identified that associated specifically with the membrane-proximal, cytoplasmic tail of Fas but not with the death domain. One of these kinases phosphorylates FADD/MORT1. Moreover, the membrane-proximal region of Fas itself was phosphorylated by one of the associating kinases. These findings suggest that, similar to the Fas-related p55 TNFR, the membrane-proximal region of Fas likely participates in signaling.