Activation of phosphatidylinositol 3-kinase by a complex of p59fyn and the receptor tyrosine kinase Xmrk is involved in malignant transformation of pigment cells.
Activation of phosphatidylinositol 3-kinase by a complex of p59fyn and the receptor tyrosine kinase Xmrk is involved in malignant transformation of pigment cells.
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p59fyn 和受体酪氨酸激酶 Xmrk 的复合物激活磷脂酰肌醇 3-激酶参与色素细胞的恶性转化。
DOI：
10.1046/j.1432-1327.2000.01378.x
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发表时间：
2000
期刊：
影响因子：
--
通讯作者：
Manfred Schartl
中科院分区：
文献类型：
--
作者：
C. Wellbrock;Manfred Schartl
剑尾鱼恶性黑色素瘤是由编码亚类I受体酪氨酸激酶的Xmrk癌基因过表达诱导的。突变激活的Xmrk蛋白在鱼黑素瘤细胞中触发组成性促有丝分裂信号传导。在最近的研究中，我们发现，在黑色素瘤细胞磷脂酰肌醇（PtdIns）3-激酶，以及p59 fyn，具有升高的激酶活性水平。两者均通过其SH 2结构域直接结合Xmrk受体C-末端的不同磷酸酪氨酸残基。为了分析黑色素瘤中这些Xmrk相关激酶的调节机制，我们详细描述了PtdIns 3-激酶、p59 fyn和Xmrk受体之间的蛋白质-蛋白质相互作用。鉴定了一种三元复合物，其中PtdIns 3-激酶的p85亚基与p59 fyn以及Xmrk相关。与其他受体所描述的复合物相反，衔接蛋白p120 Cbl不参与这些相互作用。因此，我们在这里描述了一种新的机制，激活PtdIns 3-激酶的表皮生长因子受体家族的受体，其中p59 fyn作为一个适配器，以及激活PtdIns 3-激酶。在体内也发现fyn对PtdIns 3-激酶活性的激活。事实上，这只在高度转化的Xmrk过表达的黑色素瘤中检测到，而在良性病变中检测不到，这表明Xmrk受体在这种调节机制中起着重要作用。
Malignant melanoma in the fish Xiphophorus is induced by overexpression of the Xmrk-oncogene, encoding a subclass I receptor tyrosine kinase. The mutationally activated Xmrk protein triggers constitutive mitogenic signalling in fish melanoma cells. In recent studies we showed that in melanoma cells phosphatidylinositol (PtdIns) 3-kinase, as well as p59fyn, has elevated levels of kinase activity. Both bind directly to different phosphotyrosine residues in the Xmrk receptor C-terminus through their SH2 domains. To analyse the mechanism of regulation of these Xmrk-associated kinases in melanoma we characterized the protein-protein interactions between PtdIns 3-kinase, p59fyn and the Xmrk receptor in detail. A ternary complex in which the p85 subunit of PtdIns 3-kinase is associated with p59fyn as well as with Xmrk was identified. Contrary to complexes described for other receptors, the adaptor protein p120Cbl was not involved in these interactions. Thus, we describe here a new mechanism of activation of PtdIns 3-kinase by a receptor of the epidermal growth factor receptor family in which p59fyn acts as an adaptor as well as an activator of PtdIns 3-kinase. Activation of PtdIns 3-kinase activity by fyn was also found in vivo. The fact that this was only detectable in highly transformed Xmrk overexpressing melanomas but not in benign lesions points to the essential role of the Xmrk receptor in this mechanism of regulation.
DOI：
10.1073/pnas.90.15.7366
发表时间：
1993-08-01
影响因子：
11.1
作者：
PRASAD, KVS;JANSSEN, O;RUDD, CE
通讯作者：
RUDD, CE
DOI：
10.1016/s0021-9258(17)42115-6
发表时间：
1994-01
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
R. Kapeller;K. Prasad;Ottmar Janssen;W. Hou;Brian Schaffhausen;Christopher E. Rudd;L. Cantley
通讯作者：
R. Kapeller;K. Prasad;Ottmar Janssen;W. Hou;Brian Schaffhausen;Christopher E. Rudd;L. Cantley