Pyruvate kinase M2 is a phosphotyrosine-binding protein

@article{Christofk2008PyruvateKM,
  title={Pyruvate kinase M2 is a phosphotyrosine-binding protein},
  author={Heather R. Christofk and Matthew G. Vander Heiden and Ning Wu and John M. Asara and Lewis C. Cantley},
  journal={Nature},
  year={2008},
  volume={452},
  pages={181-186}
}
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… Expand

Paper Mentions

Blog Post
Pyruvate kinase M2 regulates gene transcription by acting as a protein kinase.
TLDR
The study reveals an important link between metabolism alteration and gene expression during tumor transformation and progression and suggests that PKM2 dimer is an active protein kinase, while the tetramer is anactive pyruvate kinase. Expand
Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis
TLDR
It is shown that expression of PKM1, the pyruvate kinase isoform with high constitutive activity, or exposure to published small molecule PKM2 activators inhibit growth of xenograft tumors and support the notion that small molecule activation ofPKM2 can interfere with anabolic metabolism. Expand
Multiple functions of pyruvate kinase M2 in various cell types.
TLDR
It is proposed that pyruvate kinase M2 along with its different posttranslational modifications has specific purposes for a variety of cell types, performing unique functions. Expand
Pyruvate Kinase M2: Multiple Faces for Conferring Benefits on Cancer Cells
TLDR
Induction of PKM2 is induced translocation into the nucleus, where it activates transcription of various genes by interacting with and phosphorylating specific nuclear proteins, endowing cancer cells with a survival and growth advantage. Expand
PKM2 Tyrosine Phosphorylation and Glutamine Metabolism Signal a Different View of the Warburg Effect
  • C. Dang
  • Biology, Medicine
  • Science Signaling
  • 2009
TLDR
The apparent paradoxical effect of growth signaling through tyrosine phosphorylation, which decreases rather than increases PKM2 activity, stimulates a revised perspective of the Warburg effect, which must now accommodate links among glycolysis, the tricarboxylic acid cycle, and glutamine metabolism in cancer cells. Expand
Death-associated protein kinase increases glycolytic rate through binding and activation of pyruvate kinase
TLDR
It is reported that DAPk directly binds and functionally activates pyruvate kinase M2, a key glycolytic enzyme, which contributes to the regulation of cancer cell metabolism and a novel mechanism to activate PKM2 by protein–protein interaction is documents. Expand
Metabolism: Warburg effect revisited
the difference between metabolism in cancer cells and that in normal adult tissues: cancer cells take up glucose at higher rates than normal tissue but use a smaller fraction of this glucose forExpand
Pyruvate kinase type M2: a key regulator of the metabolic budget system in tumor cells.
  • S. Mazurek
  • Biology, Medicine
  • The international journal of biochemistry & cell biology
  • 2011
TLDR
An intervention in the regulation mechanisms of the expression, activity and tetramer to dimer ratio of pyruvate kinase M2 has severe consequences for metabolism as well as proliferation and tumorigenic capacity of the cells which makes this enzyme a promising target for potential therapeutic approaches. Expand
Lack of Evidence for PKM2 Protein Kinase Activity.
TLDR
Findings argue against a role for PKM2 as a protein kinase in cell proliferation through direct transfer of phosphate from ATP directly to protein. Expand
Serine is a natural ligand and allosteric activator of pyruvate kinase M2
TLDR
It is shown that serine can bind to and activate human PKM2, and thatPKM2 activity in cells is reduced in response to serine deprivation, which shifts cells to a fuel-efficient mode in which more pyruvate is diverted to the mitochondria and more glucose-derived carbon is channelled into serine biosynthesis to support cell proliferation. Expand
...
1
2
3
4
5
...

References

SHOWING 1-10 OF 20 REFERENCES
Pyruvate kinase type M2: a crossroad in the tumor metabolome
TLDR
Tumor cells are usually characterized by a high amount of the dimeric form leading to a strong accumulation of all glycolytic phosphometabolites above pyruvate kinase, and the tetramer-dimer ratio is regulated by ATP, FBP and serine and by direct interactions with different oncoproteins. Expand
Five enzymes of the glycolytic pathway serve as substrates for purified epidermal-growth-factor-receptor kinase.
TLDR
It is shown that purified EGF (epidermal growth factor)-receptor kinase phosphorylates the enzymes PGM and enolase and also the key regulatory enzymes of the glycolytic pathway, phosphofructokinase and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), in an EGF-dependent manner. Expand
Double role for pyruvate kinase type M2 in the expansion of phosphometabolite pools found in tumor cells.
TLDR
The amount of the dimeric form in tumor cells closely correlates with the degree of malignancy and can be used for a nonspecific detection of tumors based on assays performed with patient's plasma. Expand
Structural basis for tumor pyruvate kinase M2 allosteric regulation and catalysis.
TLDR
Significant structural differences among the human M2, rabbit muscle M1, and the human R isozymes are observed, especially in the orientation of the FBP-activating loop, which is in a closed conformation when FBP is bound. Expand
The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth
TLDR
It is demonstrated that M2 expression is necessary for aerobic glycolysis and that this metabolic phenotype provides a selective growth advantage for tumour cells in vivo. Expand
The allosteric regulation of pyruvate kinase by fructose-1,6-bisphosphate.
TLDR
The structure and location of the allosteric activator site agrees with the pattern of alternate genetic splicing of the PK gene in multicellular eukaryotes that distinguishes between a non-regulated isozyme and the regulated fetal isozymes. Expand
Pyruvate kinase type M2 is phosphorylated at tyrosine residues in cells transformed by Rous sarcoma virus
TLDR
Transformation of CECs by Rous sarcoma virus leads to a reduction in the affinity of PK for the substrate phosphoenolpyruvate, and kinetic changes were correlated with tyrosine phosphorylation of M2‐PK, but there is no direct evidence that they are caused by post‐translational modification of the enzyme. Expand
ATP citrate lyase inhibition can suppress tumor cell growth.
TLDR
ACL inhibition by RNAi or the chemical inhibitor SB-204990 limits in vitro proliferation and survival of tumor cells displaying aerobic glycolysis, and these treatments also reduce in vivo tumor growth and induce differentiation. Expand
Nutrient and hormonal regulation of pyruvate kinase gene expression.
Mammalian pyruvate kinase (PK), a key glycolytic enzyme, has two genes named PKL and PKM, which produce the L- and R-type isoenzymes by means of alternative promoters, and the M1-and M2-types byExpand
Phosphorylation of glycolytic and gluconeogenic enzymes by the insulin receptor kinase
TLDR
Phosphofructokinase and phosphoglycerate mutase were found to be the best substrates for the insulin receptor kinase, and phosphorylation of these enzymes was rapid, stimulated 2‐ to 6‐fold by 10−7 M insulin and occurred exclusively on tyrosine residues. Expand
...
1
2
...