Rabinovsky Rosalia, Pochanard Panisa, McNear Chontelle, Brachmann Saskia M, Duke-Cohan Jonathan S, Garraway Levi A, Sellers William R
Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney St., Boston, MA 02115, USA.
Mol Cell Biol. 2009 Oct;29(19):5377-88. doi: 10.1128/MCB.01649-08. Epub 2009 Jul 27.
The lipid phosphatase PTEN functions as a tumor suppressor by dephosphorylating the D3 position of phosphoinositide-3,4,5-trisphosphate, thereby negatively regulating the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway. In mammalian cells, PTEN exists either as a monomer or as a part of a >600-kDa complex (the PTEN-associated complex [PAC]). Previous studies suggest that the antagonism of PI3K/AKT signaling by PTEN may be mediated by a nonphosphorylated form of the protein resident within the multiprotein complex. Here we show that PTEN associates with p85, the regulatory subunit of PI3K. Using newly generated antibodies, we demonstrate that this PTEN-p85 association involves the unphosphorylated form of PTEN engaged within the PAC and also includes the p110beta isoform of PI3K. The PTEN-p85 association is enhanced by trastuzumab treatment and linked to a decline in AKT phosphorylation in some ERBB2-amplified breast cancer cell lines. Together, these results suggest that integration of p85 into the PAC may provide a novel means of downregulating the PI3K/AKT pathway.
脂质磷酸酶PTEN通过使磷酸肌醇-3,4,5-三磷酸的D3位去磷酸化发挥肿瘤抑制作用，从而负向调节磷酸肌醇3-激酶（PI3K）/AKT信号通路。在哺乳动物细胞中，PTEN以单体形式存在，或作为大于600 kDa复合物（PTEN相关复合物[PAC]）的一部分存在。先前的研究表明，PTEN对PI3K/AKT信号的拮抗作用可能由多蛋白复合物中未磷酸化形式的蛋白质介导。在此我们表明，PTEN与PI3K的调节亚基p85相关联。使用新生成的抗体，我们证明这种PTEN-p85关联涉及PAC中未磷酸化形式的PTEN，并且还包括PI3K的p110β亚型。曲妥珠单抗治疗可增强PTEN-p85关联，并与某些ERBB2扩增的乳腺癌细胞系中AKT磷酸化的下降有关。总之，这些结果表明将p85整合到PAC中可能提供一种下调PI3K/AKT通路的新方法。
