Abstract
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 bind 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 197-210.e7 |
| Journal | Molecular Cell |
| Volume | 70 |
| Issue number | 2 |
| DOIs | |
| State | Published - Apr 19 2018 |
| Externally published | Yes |
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Keywords
- EGFR
- PFKP
- phosphorylation
- PI3K
- the Warburg effect
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology
Cite this
EGFR-Phosphorylated Platelet Isoform of Phosphofructokinase 1 Promotes PI3K Activation. / Lee, Jong Ho; Liu, Rui; Li, Jing; Wang, Yugang; Tan, Lin; Li, Xin Jian; Qian, Xu; Zhang, Chuanbao; Xia, Yan; Xu, Daqian; Guo, Wei; Ding, Zhiyong; Du, Linyong; Zheng, Yanhua; Chen, Qianming; Lorenzi, Philip L.; Mills, Gordon; Jiang, Tao; Lu, Zhimin.
In: Molecular Cell, Vol. 70, No. 2, 19.04.2018, p. 197-210.e7.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - EGFR-Phosphorylated Platelet Isoform of Phosphofructokinase 1 Promotes PI3K Activation
AU - Lee, Jong Ho
AU - Liu, Rui
AU - Li, Jing
AU - Wang, Yugang
AU - Tan, Lin
AU - Li, Xin Jian
AU - Qian, Xu
AU - Zhang, Chuanbao
AU - Xia, Yan
AU - Xu, Daqian
AU - Guo, Wei
AU - Ding, Zhiyong
AU - Du, Linyong
AU - Zheng, Yanhua
AU - Chen, Qianming
AU - Lorenzi, Philip L.
AU - Mills, Gordon
AU - Jiang, Tao
AU - Lu, Zhimin
PY - 2018/4/19
Y1 - 2018/4/19
N2 - 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 bind 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.
AB - 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 bind 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.
KW - EGFR
KW - PFKP
KW - phosphorylation
KW - PI3K
KW - the Warburg effect
UR - http://www.scopus.com/inward/record.url?scp=85045312199&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85045312199&partnerID=8YFLogxK
U2 - 10.1016/j.molcel.2018.03.018
DO - 10.1016/j.molcel.2018.03.018
M3 - Article
C2 - 29677490
AN - SCOPUS:85045312199
VL - 70
SP - 197-210.e7
JO - Molecular Cell
JF - Molecular Cell
SN - 1097-2765
IS - 2
ER -