Regulation of the PI3K pathway through a p85α monomer-homodimer equilibrium.
Regulation of the PI3K pathway through a p85α monomer-homodimer equilibrium.
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通过p85α单体二聚体平衡对PI3K途径进行调节。
DOI：
10.7554/elife.06866
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发表时间：
2015-07-29
期刊：
影响因子：
7.7
通讯作者：
Mills GB
中科院分区：
文献类型：
--
作者：
Cheung LW;Walkiewicz KW;Besong TM;Guo H;Hawke DH;Arold ST;Mills GB
磷脂酰肌醇3-激酶（PI 3 K）的p85α调节亚基的典型作用是与p110α催化亚基结合，以允许PI 3 K途径的刺激依赖性激活。我们阐明了同源二聚化的p85α在PTEN稳定性和活性的正向调节中的非p110α依赖性作用。p110α-free p85α通过两种分子间相互作用（SH 3：脯氨酸富集区和BH：BH）同源二聚化以选择性结合未磷酸化的活化的PTEN。因此，同源二聚体而非单体p85α通过保护PTEN免受E3连接酶WWP 2介导的蛋白酶体降解而抑制PI 3 K途径。此外，p85α同二聚体增强了PTEN的脂质磷酸酶活性和膜结合。引人注目的是，我们发现了癌症患者来源的致癌p85α突变，靶向同源二聚化或PTEN相互作用表面。总的来说，我们的数据表明p85α单体-二聚体的平衡调节PI 3 K通路，破坏这种平衡可能导致疾病的发展。DOI：http://dx.doi.org/10.7554/eLife.06866.001许多癌症的发生是由于基因突变使细胞无法控制地增殖。细胞增殖和许多其他细胞过程可以通过涉及称为PI 3 K的酶的信号通路来调节。这种“异二聚体”酶由两个蛋白质亚基组成，其中一个称为p85α，并抑制酶的另一个亚基（称为p110）以防止不受控制的细胞增殖。同时，p85α稳定p110，并允许PI 3 K通路在适当时短暂激活。许多癌细胞在编码p85α的基因中含有突变，从而阻止蛋白质抑制p110。这导致PI 3 K的激活并促进癌症形成。一种称为PTEN的蛋白质是PI 3 K通路的关键抑制剂。癌细胞中常见的PTEN基因突变会阻止PTEN蛋白有效工作，或阻止PTEN的产生。最近的研究表明，两个不含p110的p85α分子可以相互结合形成“同源二聚体”。Cheung等人现在已经使用生物化学、细胞生物学和计算方法来研究这些p85α同源二聚体的作用。这表明，p85α同源二聚体通过与之结合而阻止了PTEN的分解，因此，细胞中有足够的PTEN来抑制PI 3 K通路。通过检查癌症患者中存在的突变，Cheung等人接下来确定了阻止p85α蛋白形成同源二聚体或阻止同源二聚体与PTEN相互作用的突变。因此，PTEN降解，不能抑制PI 3 K通路，这使得细胞增殖。因此，增加p85α同源二聚体形成或增强p85α同源二聚体与PTEN结合的能力的方法可能为开发癌症治疗提供新的方法。更一般地说，似乎维持细胞中p110结合的异二聚体和p110游离的同源二聚体形式的p85α的量之间的正确平衡对于预防涉及PI 3 K通路的疾病可能是重要的。DOI：http://dx.doi.org/10.7554/eLife.06866.002网站
The canonical action of the p85α regulatory subunit of phosphatidylinositol 3-kinase (PI3K) is to associate with the p110α catalytic subunit to allow stimuli-dependent activation of the PI3K pathway. We elucidate a p110α-independent role of homodimerized p85α in the positive regulation of PTEN stability and activity. p110α-free p85α homodimerizes via two intermolecular interactions (SH3:proline-rich region and BH:BH) to selectively bind unphosphorylated activated PTEN. As a consequence, homodimeric but not monomeric p85α suppresses the PI3K pathway by protecting PTEN from E3 ligase WWP2-mediated proteasomal degradation. Further, the p85α homodimer enhances the lipid phosphatase activity and membrane association of PTEN. Strikingly, we identified cancer patient-derived oncogenic p85α mutations that target the homodimerization or PTEN interaction surface. Collectively, our data suggest the equilibrium of p85α monomer–dimers regulates the PI3K pathway and disrupting this equilibrium could lead to disease development. DOI: http://dx.doi.org/10.7554/eLife.06866.001 Many cancers arise due to genetic mutations that allow cells to proliferate uncontrollably. Cell proliferation and many other cell processes can be regulated through a signaling pathway that involves an enzyme called PI3K. This ‘heterodimeric’ enzyme is made up of two protein subunits, one of which is called p85α and inhibits the other subunit of the enzyme (known as p110) to prevent uncontrolled cell proliferation. At the same time, p85α stabilizes p110 and allows the PI3K pathway to be briefly activated when appropriate. Many cancer cells contain mutations in the gene that encodes p85α that prevent the protein from inhibiting p110. This results in the activation of PI3K and promotes cancer formation. A protein called PTEN is a key inhibitor of the PI3K pathway. Common mutations to the PTEN gene in cancer cells stop the PTEN protein working efficiently, or prevent PTEN production. Recent research has revealed that two molecules of p85α that are free from p110 can bind to each other to form a ‘homodimer’. Cheung et al. have now used biochemical, cell biological and computational methods to investigate the role of these p85α homodimers. This revealed that p85α homodimers stop PTEN being broken down by binding to it. As a consequence, there is enough PTEN in the cell to inhibit the PI3K pathway. By examining the mutations present in cancer patients, Cheung et al. next identified mutations that prevent the p85α protein from forming homodimers, or that prevent the homodimers from interacting with PTEN. PTEN therefore degrades and cannot inhibit the PI3K pathway, which allows the cells to proliferate. Methods that increase p85α homodimer formation or enhance the ability of p85α homodimers to bind to PTEN may therefore provide new approaches for developing cancer treatments. More generally, it appears that maintaining the correct balance between the amount of p85α in the form of p110-bound heterodimers and p110-free homodimers in a cell may be important for preventing diseases involving the PI3K pathway. DOI: http://dx.doi.org/10.7554/eLife.06866.002