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.
Keywords:
EGFR; PFKP; PI3K; phosphorylation; the Warburg effect.
Published by Elsevier Inc.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Acetylation
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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Brain Neoplasms / enzymology*
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Brain Neoplasms / genetics
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Brain Neoplasms / pathology
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Cell Line, Tumor
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Class Ia Phosphatidylinositol 3-Kinase
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Enzyme Activation
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ErbB Receptors / genetics
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ErbB Receptors / metabolism
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Feedback, Physiological
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Fructosediphosphates / metabolism
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Glioblastoma / enzymology*
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Glioblastoma / genetics
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Glioblastoma / pathology
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Glucose Transporter Type 1 / genetics
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Glucose Transporter Type 1 / metabolism
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Glycolysis*
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Humans
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Lysine Acetyltransferase 5 / genetics
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Lysine Acetyltransferase 5 / metabolism
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Male
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Mice, Inbred BALB C
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Mice, Nude
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Phosphatidylinositol 3-Kinases / genetics
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Phosphatidylinositol 3-Kinases / metabolism*
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Phosphofructokinase-1, Type C / genetics
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Phosphofructokinase-1, Type C / metabolism*
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Phosphofructokinase-2 / genetics
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Phosphofructokinase-2 / metabolism
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Phosphorylation
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Protein Binding
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Proto-Oncogene Proteins c-akt / metabolism
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Signal Transduction
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src Homology Domains
Substances
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Adaptor Proteins, Signal Transducing
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Fructosediphosphates
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GAB1 protein, human
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Glucose Transporter Type 1
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SLC2A1 protein, human
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fructose 2,6-diphosphate
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KAT5 protein, human
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Lysine Acetyltransferase 5
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PIK3R1 protein, human
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Phosphofructokinase-1, Type C
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Phosphofructokinase-2
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PFKP protein, human
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Class Ia Phosphatidylinositol 3-Kinase
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EGFR protein, human
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ErbB Receptors
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Proto-Oncogene Proteins c-akt