Journal
MOLECULAR CELL
Volume 70, Issue 2, Pages 197-+Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2018.03.018
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Funding
- National Cancer Institute [2R01 CA109035, 1R0 CA169603]
- National Institute of Neurological Disorders and Stroke [1R01 NS089754]
- NIH/NCI [P30CA016672, 1S10OD012304-01, 2P50 CA127001]
- Cancer Prevention Research Institute of Texas (CPRIT) Core Facility Award [RP130397]
- Sister Institution Network Fund from MD Anderson
- NATIONAL CANCER INSTITUTE [R01CA169603, P30CA016672, P50CA127001, R01CA109035] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS089754] Funding Source: NIH RePORTER
- OFFICE OF THE DIRECTOR, NATIONAL INSTITUTES OF HEALTH [S10OD012304] Funding Source: NIH RePORTER
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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 p85 alpha, which is distinct from binding of Gab1 to the C-terminal SH2 domain of p85 alpha, and recruited p85a 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.
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