Negative regulation of PI 3-kinase by Ruk, a novel adaptor protein
Negative regulation of PI 3-kinase by Ruk, a novel adaptor protein
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DOI：
10.1093/emboj/19.15.4015
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发表时间：
2000-08-01
期刊：
影响因子：
11.4
通讯作者：
Buchman, VL
中科院分区：
文献类型：
--
作者：
Gout, I;Middleton, G;Buchman, VL
I-A类磷脂酰肌醇3-激酶（PI 3-激酶）是重要的细胞内信号级联的关键组分。我们已经鉴定了一种衔接蛋白，Ruk（1），它在体外和体内与PI 3-激酶全酶形成复合物。这种相互作用涉及Ruk的富含脯氨酸区域和I-A类PI 3-激酶的p85 α调节亚基的SH 3结构域。与许多其他激活PI 3-激酶的衔接蛋白相反，与Ruk（1）的相互作用基本上抑制了该酶的脂质激酶活性。Ruk（1）在培养的原代神经元中的过表达可诱导细胞凋亡，这种作用可通过PI 3-激酶的p110 α催化亚基或其下游效应物PKB/Akt的组成性激活形式的共表达来逆转。我们的数据为PI 3-激酶信号通路的负调节剂的存在提供了证据，该负调节剂对于维持细胞内稳态是必不可少的。Ruk，CIN 85和CD 2AP/CMS之间的结构相似性表明，这些蛋白质形成了一个新的家庭的衔接分子，参与各种细胞内信号传导途径。
Class I-A phosphatidylinositol 3-kinase (PI3-kinase) is a key component of important intracellular signalling cascades. We have identified an adaptor protein, Ruk(1), which forms complexes with the PI 3-kinase holoenzyme in vitro and in vivo. This interaction involves the proline-rich region of Ruk and the SH3 domain of the p85 alpha regulatory subunit of the class I-A PI 3-kinase. In contrast to many other adaptor proteins that activate PI 3-kinase, interaction with Ruk(1) substantially inhibits the lipid kinase activity of the enzyme. Overexpression of Ruk(1) in cultured primary neurons induces apoptosis, an effect that could be reversed by co-expression of constitutively activated forms of the p110 alpha a catalytic subunit of PI 3-kinase or its downstream effector PKB/Akt, Our data provide evidence for the existence of a negative regulator of the PI 3-kinase signalling pathway that is essential for maintaining cellular homeostasis. Structural similarities between Ruk, CIN85 and CD2AP/CMS suggest that these proteins form a novel family of adaptor molecules that are involved in various intracellular signalling pathways.