Mitogenic signaling by Ret/ptc2 requires association with enigma via a LIM domain
Mitogenic signaling by Ret/ptc2 requires association with enigma via a LIM domain
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DOI：
10.1074/jbc.271.22.12691
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发表时间：
1996-05-31
影响因子：
4.8
通讯作者：
Taylor, SS
中科院分区：
文献类型：
--
作者：
Durick, K;Wu, RY;Taylor, SS
ret/ptc2乳头状甲状腺癌癌基因是c-Ret受体酪氨酸激酶的一种致癌形式，是环amp依赖性蛋白激酶（RI） I型α调节亚基二聚化结构域与c-Ret酪氨酸激酶结构域融合的体细胞交叉事件的产物。Ret/ptc2的有丝分裂活性需要通过RI的N端和位于Ret， Tyr-586激酶核心c端的酪氨酸残基进行二聚化（Durick， K., Yao， V. J, Borrello， M. G., Bongarzone， I., Pierotti， M. a . and Taylor， S. S., 1995）。化学，270,24642 -24645)。利用酵母双杂交系统，鉴定了Ret/ptc2结合蛋白，并绘制了与Ret/ptc2相互作用位点。我们发现了磷脂酶C γ和Grb10的SH2结构域，它们的结合分别依赖于tyr1 -539和tyr1 -429的磷酸化。然而，这些相互作用并不是有丝分裂信号传导所必需的。Enigma中三个LIM域中的第二个(Wu， R. Y., and Gill， G. N.（1994）。Chem. 269, 25085-25090)也被鉴定为Ret/ptc2结合域。Enigma是一种455残基蛋白，它通过c端LIM结构域与胰岛素受体相互作用而被发现。虽然与Enigma的关联需要Ret/ptc2的tyr1 -586，但这种相互作用是磷酸化无关的。与SH2相互作用相反，与Enigma相互作用的破坏破坏了Ret/ptc2有丝分裂信号传导，这表明Ret信号转导需要LIM结构域识别未磷酸化的酪氨酸基序。
The ret/ptc2 papillary thyroid cancer oncogene, an oncogenic form of the c-Ret receptor tyrosine kinase, is the product of a somatic crossover event fusing the dimerization domain of the type I alpha regulatory subunit of cyclic AMP-dependent protein kinase (RI) with the tyrosine kinase domain of c-Ret. Mitogenic activity of Ret/ptc2 required dimerization via the N terminus of RI and a tyrosine residue located C-terminal to the kinase core of Ret, Tyr-586 (Durick, K., Yao, V. J., Borrello, M. G., Bongarzone, I., Pierotti, M. A. and Taylor, S. S. (1995) J. Biol. Chem. 270, 24642-24645). Using the yeast two-hybrid system, Ret/ptc2 binding proteins were identified, and the sites of interaction with Ret/ptc2 were mapped. The SH2 domains of phospholipase C gamma and Grb10 were both identified, and binding depended on phosphorylation of Tyr-539 and Tyr-429, respectively. These interactions, however, were not required for mitogenic signaling. The second of the three LIM domains in Enigma (Wu, R. Y., and Gill, G. N. (1994) J. Biol. Chem. 269, 25085-25090) was also identified as a Ret/ptc2 binding domain. Enigma, a 455-residue protein, was discovered based on its interaction with the insulin receptor through the C-terminal LIM domain. Although the association with Enigma required Tyr-586 of Ret/ptc2, the interaction was phosphorylation-independent. In contrast to the SH2 interactions, disruption of the interaction with Enigma abolished Ret/ptc2 mitogenic signaling, suggesting that LIM domain recognition of an unphosphorylated tyrosine-based motif is required for Ret signal transduction.