Cbl-c ubiquitin ligase activity is increased via the interaction of its RING finger domain with a LIM domain of the paxillin homolog, Hic 5.
Cbl-c ubiquitin ligase activity is increased via the interaction of its RING finger domain with a LIM domain of the paxillin homolog, Hic 5.
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DOI：
10.1371/journal.pone.0049428
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Lipkowitz S
中科院分区：
文献类型：
--
作者：
Ryan PE;Kales SC;Yadavalli R;Nau MM;Zhang H;Lipkowitz S
Cbl蛋白（Cbl、Cbl-b和Cbl-c）是泛素连接酶，其是酪氨酸激酶信号传导的关键调节剂。在这项研究中，我们确定了一个新的Cbl-c相互作用蛋白，过氧化氢诱导的结构5（Hic-5）。这两种蛋白质通过由Cbl-c的RING指和Hic-5的LIM 2结构域介导的新型相互作用相互作用。此外，这种相互作用是介导的，并依赖于环指和LIM结构域内的特定锌配位复合物。一旦Cbl-c被Src磷酸化或通过激活磷酸化模拟物突变激活，Hic-5与Cbl-c的结合导致Cbl-c的泛素连接酶活性增加。此外，Hic-5与Cbl-c的共转染导致Cbl-c介导的EGFR泛素化增加。这些数据表明，一旦Cbl-c被磷酸化和激活，Hic-5增强Cbl-c泛素连接酶活性。异源RING指之间的相互作用已显示激活E3。这是通过LIM锌配位结构域的直接相互作用增强RING指泛素连接酶的泛素连接酶活性的第一个证明。
Cbl proteins (Cbl, Cbl-b and Cbl-c) are ubiquitin ligases that are critical regulators of tyrosine kinase signaling. In this study we identify a new Cbl-c interacting protein, Hydrogen peroxide Induced Construct 5 (Hic-5). The two proteins interact through a novel interaction mediated by the RING finger of Cbl-c and the LIM2 domain of Hic-5. Further, this interaction is mediated and dependent on specific zinc coordinating complexes within the RING finger and LIM domain. Binding of Hic-5 to Cbl-c leads to an increase in the ubiquitin ligase activity of Cbl-c once Cbl-c has been activated by Src phosphorylation or through an activating phosphomimetic mutation. In addition, co-transfection of Hic-5 with Cbl-c leads to an increase in Cbl-c mediated ubiquitination of the EGFR. These data suggest that Hic-5 enhances Cbl-c ubiquitin ligase activity once Cbl-c has been phosphorylated and activated. Interactions between heterologous RING fingers have been shown to activate E3s. This is the first demonstration of enhancement of ubiquitin ligase activity of a RING finger ubiquitin ligase by the direct interaction of a LIM zinc coordinating domain.
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