EGFR-Phosphorylated Platelet Isoform of Phosphofructokinase 1 Promotes PI3K Activation.
EGFR-Phosphorylated Platelet Isoform of Phosphofructokinase 1 Promotes PI3K Activation.
复制标题
DOI：
10.1016/j.molcel.2018.03.018
复制
发表时间：
2018-04-19
期刊：
影响因子：
16
通讯作者：
Lu Z
中科院分区：
文献类型：
--
作者：
Lee JH;Liu R;Li J;Wang Y;Tan L;Li XJ;Qian X;Zhang C;Xia Y;Xu D;Guo W;Ding Z;Du L;Zheng Y;Chen Q;Lorenzi PL;Mills GB;Jiang T;Lu Z
EGFR可激活磷脂酰肌醇3-激酶(PI3K)，但其激活机制尚不完全清楚。我们在这里证明了EGFR的激活导致赖氨酸乙酰转移酶5(KAT5)介导的K395磷酸化果糖激酶1亚型(PFKP)的乙酰化，随后PFKP被移位到质膜，其中PFKP在Y64被EGFR磷酸化。不同于GAB1与P85α的C端SH2结构域的结合，磷酸化的PfKP与P85α的N端SH2结构域结合，并将P85α募集到质膜上导致PI3K激活。依赖PI3K的AKT激活导致磷酸果糖激酶2(PFK2)的磷酸化和果糖-2，6-二磷酸的产生，进而促进PFK1的激活。PFKP Y64磷酸化增强依赖PI3K/AKT的pFK1激活和GLUT1表达促进Warburg效应、肿瘤细胞增殖和脑肿瘤的发生。这些发现强调了PFKP通过依赖于PI3K/AKT的正反馈调节在PI3K激活和糖酵解增强中的重要作用。Lee等人。证明KAT5介导的PFKP乙酰化和随后的EGFR磷酸化的PFKP结合到P85α的SH2N端结构域以激活PI3K，导致依赖AKT的PFK2激活，依赖F-2，6-BP产物的PFK1激活和GLUT1的表达。PFKP的非代谢功能通过依赖PI3K/AKT的正反馈调节促进Warburg效应。
EGFR activates phosphatidylinositide 3-kinase (PI3K), but the mechanism underlying this activation is not completely understood. We demonstrated here that EGFR activation resulted in lysine acetyltransferase 5 (KAT5)-mediated K395 acetylation of the platelet isoform of phosphofructokinase 1 (PFKP) and subsequent translocation of PFKP to the plasma membrane, where the PFKP was phosphorylated at Y64 by EGFR. Phosphorylated PFKP binds to the N-terminal SH2 domain of p85α, which is distinct from binding of Gab1 to the C-terminal SH2 domain of p85α, and recruited p85α to the plasma membrane resulting in PI3K activation. PI3K-dependent AKT activation results in enhanced phosphofructokinase 2 (PFK2) phosphorylation and production of fructose-2,6-bisphosphate, which in turn promotes PFK1 activation. PFKP Y64 phosphorylation–enhanced PI3K/AKT-dependent PFK1 activation and GLUT1 expression promoted the Warburg effect, tumor cell proliferation, and brain tumorigenesis. These findings underscore the instrumental role of PFKP in PI3K activation and enhanced glycolysis through PI3K/AKT-dependent positive-feedback regulation. Lee et al. demonstrate that KAT5-mediated PFKP acetylation and subsequent EGFR-phosphorylated PFKP binds to the N-terminal SH2 domain of p85α to activate PI3K, leading to enhanced AKT-dependent PFK2 activation, F-2,6-BP production–dependent PFK1 activation, and GLUT1 expression. Non-metabolic function of PFKP promotes the Warburg effect through PI3K/AKT-dependent positive-feedback regulation.
登录
查看更多内容
影响因子：
16.6
作者：
Jiang, Yuhui;Wang, Yugang;Wang, Ting;Hawke, David H.;Zheng, Yanhua;Li, Xinjian;Zhou, Qin;Majumder, Sadhan;Bi, Erfei;Liu, David X.;Huang, Suyun;Lu, Zhimin
通讯作者：
Lu, Zhimin
影响因子：
4.8
作者：
Barthel, A;Okino, ST;Roth, RA
通讯作者：
Roth, RA
影响因子：
64.5
作者：
Hsu, Peggy P.;Sabatini, David M.
通讯作者：
Sabatini, David M.
影响因子：
56.9
作者：
KOCH, CA;ANDERSON, D;PAWSON, T
通讯作者：
PAWSON, T
影响因子：
4.8
作者：
Moon, Jong-Seok;Kim, Hee Eun;Kim, Kyung-Sup
通讯作者：
Kim, Kyung-Sup