Mohan Maradumane L, Chatterjee Arunachal, Ganapathy Swetha, Mukherjee Sromona, Srikanthan Sowmya, Jolly George P, Anand Rohit S, Naga Prasad Sathyamangla V
Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195
Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195.
Mol Biol Cell. 2017 Nov 1;28(22):3112-3122. doi: 10.1091/mbc.E16-12-0864. Epub 2017 Sep 6.
Classically Class IB phosphoinositide 3-kinase (PI3Kγ) plays a role in extracellular signal-regulated kinase (ERK) activation following G-protein coupled receptor (GPCR) activation. Knock-down of PI3Kγ unexpectedly resulted in loss of ERK activation to receptor tyrosine kinase agonists such as epidermal growth factor or insulin. Mouse embryonic fibroblasts (MEFs) or primary adult cardiac fibroblasts isolated from PI3Kγ knock-out mice (PI3KγKO) showed decreased insulin-stimulated ERK activation. However, expression of kinase-dead PI3Kγ resulted in rescue of insulin-stimulated ERK activation. Mechanistically, PI3Kγ sequesters protein phosphatase 2A (PP2A), disrupting ERK-PP2A interaction, as evidenced by increased ERK-PP2A interaction and associated PP2A activity in PI3KγKO MEFs, resulting in decreased ERK activation. Furthermore, β-blocker carvedilol-mediated β-arrestin-dependent ERK activation is significantly reduced in PI3KγKO MEF, suggesting accelerated dephosphorylation. Thus, instead of classically mediating the kinase arm, PI3Kγ inhibits PP2A by scaffolding and sequestering, playing a key parallel synergistic step in sustaining the function of ERK, a nodal enzyme in multiple cellular processes.
传统上，I B类磷酸肌醇3激酶（PI3Kγ）在G蛋白偶联受体（GPCR）激活后，参与细胞外信号调节激酶（ERK）的激活过程。然而，敲低PI3Kγ却意外导致对受体酪氨酸激酶激动剂（如表皮生长因子或胰岛素）的ERK激活丧失。从PI3Kγ基因敲除小鼠（PI3KγKO）分离的小鼠胚胎成纤维细胞（MEFs）或原代成年心脏成纤维细胞，胰岛素刺激的ERK激活降低。然而，激酶失活的PI3Kγ的表达可挽救胰岛素刺激的ERK激活。从机制上讲，PI3Kγ隔离蛋白磷酸酶2A（PP2A），破坏ERK与PPA2的相互作用，PI3Kγ基因敲除的MEFs中ERK与PP2A相互作用及相关的PP2A活性增加证明了这一点，导致ERK激活降低。此外，在PI3Kγ基因敲除的MEF中，β受体阻滞剂卡维地洛介导的β抑制蛋白依赖性ERK激活显著降低，提示去磷酸化加速。因此，PI3Kγ并非经典地介导激酶臂，而是通过支架作用和隔离来抑制PP2A，在维持ERK功能方面发挥关键的平行协同作用，ERK是多种细胞过程中的节点酶。
