Pyruvate kinase M2 is a phosphotyrosine-binding protein

被引:815
作者
Christofk, Heather R. [1 ]
Vander Heiden, Matthew G. [1 ,3 ]
Wu, Ning [1 ]
Asara, John M. [2 ,4 ]
Cantley, Lewis C. [1 ,4 ]
机构
[1] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA
[2] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA
[3] Dana Farber Canc Inst, Boston, MA 02115 USA
[4] Beth Israel Deaconess Med Ctr, Div Signal Transduct, Boston, MA 02115 USA
关键词
D O I
10.1038/nature06667
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Growth factors stimulate cells to take up excess nutrients and to use them for anabolic processes. The biochemical mechanism by which this is accomplished is not fully understood but it is initiated by phosphorylation of signalling proteins on tyrosine residues. Using a novel proteomic screen for phosphotyrosine- binding proteins, we have made the observation that an enzyme involved in glycolysis, the human M2 ( fetal) isoform of pyruvate kinase ( PKM2), binds directly and selectively to tyrosine- phosphorylated peptides. We show that binding of phosphotyrosine peptides to PKM2 results in release of the allosteric activator fructose- 1,6- bisphosphate, leading to inhibition of PKM2 enzymatic activity. We also provide evidence that this regulation of PKM2 by phosphotyrosine signalling diverts glucose metabolites from energy production to anabolic processes when cells are stimulated by certain growth factors. Collectively, our results indicate that expression of this phosphotyrosine- binding form of pyruvate kinase is critical for rapid growth in cancer cells.
引用
收藏
页码:181 / U27
页数:8
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