Tyrosine phosphorylation inhibits PKM2 to promote the Warburg effect and tumor growth.
The Warburg effect describes a pro-oncogenic metabolism switch such that cancer cells take up more glucose than normal tissue and favor incomplete oxidation of glucose even in the presence of oxygen. To better understand how tyrosine kinase signaling, which is commonly increased in tumors, regulates the Warburg effect, we performed phosphoproteomic studies. We found that oncogenic forms of fibroblast growth factor receptor type 1 inhibit the pyruvate kinase M2 (PKM2) isoform by direct phosphorylation of PKM2 tyrosine residue 105 (Y(105)). This inhibits the formation of active, tetrameric PKM2 by disrupting binding of the PKM2 cofactor fructose-1,6-bisphosphate. Furthermore, we found that phosphorylation of PKM2 Y(105) is common in human cancers. The presence of a PKM2 mutant in which phenylalanine is substituted for Y(105) (Y105F) in cancer cells leads to decreased cell proliferation under hypoxic conditions, increased oxidative phosphorylation with reduced lactate production, and reduced tumor growth in xenografts in nude mice. Our findings suggest that tyrosine phosphorylation regulates PKM2 to provide a metabolic advantage to tumor cells, thereby promoting tumor growth.
Hitosugi
Taro
T
Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA.
Kang
Sumin
S
Vander Heiden
Matthew G
MG
Chung
Tae-Wook
TW
Elf
Shannon
S
Lythgoe
Katherine
K
Dong
Shaozhong
S
Lonial
Sagar
S
Wang
Xu
X
Chen
Georgia Z
GZ
Xie
Jianxin
J
Gu
Ting-Lei
TL
Polakiewicz
Roberto D
RD
Roesel
Johannes L
JL
Boggon
Titus J
TJ
Khuri
Fadlo R
FR
Gilliland
D Gary
DG
Cantley
Lewis C
LC
Kaufman
Jonathan
J
Chen
Jing
J
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005635:Fructosediphosphates / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis / Q000502:physiology*; D006801:Humans; D015151:Immunoblotting; D020014:K562 Cells; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010101:Oxygen Consumption; D010766:Phosphorylation; D040901:Proteomics / Q000379:methods; D011770:Pyruvate Kinase / Q000235:genetics / Q000378:metabolism*; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics / Q000378:metabolism; D014183:Transplantation, Heterologous; D047368:Tumor Burden; D014443:Tyrosine / Q000378:metabolism*
D005635:Fructosediphosphates; D014443:Tyrosine; D000255:Adenosine Triphosphate; D011770:Pyruvate Kinase; D051496:Receptor, Fibroblast Growth Factor, Type 1; D005947:Glucose; C029063:fructose-1,6-diphosphate