Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, USA.
PLoS One. 2013 May 29;8(5):e63833. doi: 10.1371/journal.pone.0063833. Print 2013.
The PI3-kinase pathway is commonly activated in tumors, most often by loss of PTEN lipid phosphatase activity or the amplification or mutation of p110α. Oncogenic mutants have commonly been found in p110α, but rarely in any of the other catalytic subunits of class I PI3-kinases. We here characterize a p110β helical domain mutation, E633K, first identified in a Her2-positive breast cancer. The mutation increases basal p110β activity, but does not affect activation of p85/p110β dimers by phosphopeptides or Gβγ. Expression of the mutant causes increases in Akt and S6K1 activation, transformation, chemotaxis, proliferation and survival in low serum. E633 is conserved among class I PI3 Ks, and its mutation in p110β is also activating. Interestingly, the E633K mutant occurs near a region that interacts with membranes in activated PI 3-kinases, and its mutation abrogates the requirement for an intact Ras-binding domain in p110β-mediated transformation. We propose that the E633K mutant activates p110β by enhancing its basal association with membranes. This study presents the first analysis of an activating oncogenic mutation of p110β.
PI3-激酶途径在肿瘤中通常被激活，最常见的原因是 PTEN 脂质磷酸酶活性丧失或 p110α 的扩增或突变。致癌突变通常发生在 p110α 中，但在 I 类 PI3-激酶的其他催化亚基中很少发现。我们在这里描述了一种 p110β 螺旋结构域突变，E633K，最初在 Her2 阳性乳腺癌中发现。该突变增加了 p110β 的基础活性，但不影响磷酸肽或 Gβγ 对 p85/p110β 二聚体的激活。突变体的表达导致 Akt 和 S6K1 的激活增加，在低血清中转化、趋化、增殖和存活。E633 在 I 类 PI3Ks 中保守，其在 p110β 中的突变也是激活的。有趣的是，E633K 突变发生在与激活的 PI3-激酶中与膜相互作用的区域附近，其突变使 Ras 结合结构域在 p110β 介导的转化中不再必需。我们提出，E633K 突变通过增强其与膜的基础结合来激活 p110β。本研究首次分析了 p110β 的致癌激活突变。
