Tyrosine Phosphorylation Inhibits PKM2 to Promote the Warburg Effect and Tumor Growth

By T. Hitosugi, Sumin Kang, M. V. Vander Heiden, Tae-Wook Chung, Shannon E Elf, Katherine Lythgoe, Shaozhong Dong, S. Lonial, Xu Wang, G. Chen and 10 more. Science Signaling, 2009

782 citations recorded by the source corpus.

Tyrosine phosphorylation of pyruvate kinase M2 gives tumor cells a metabolic advantage. A Malignant Metabolic Switch Cancer cells show aberrant metabolism, consuming more glucose than do healthy cells and producing lactate even in the presence of abundant oxygen, rather than shifting to oxidative phosphorylation. This phenomenon is called the Warburg effect, after Otto Warburg, who described it many years ago. Building on recent research implicating inhibition of the M2 isoform of the glycolytic enzyme pyruvate kinase (PKM2) by phosphotyrosine binding as critical to the Warburg effect—and tumorigenesis—Hitosugi et al. explored the role of signaling from oncogenic forms of the fibroblast growth factor receptor type 1 (FGFR1) in mediating this metabolic switch. They found that FGFR1, a receptor tyrosine kinase, phosphorylated a tyrosine residue (Y105) on PKM2 itself. Further analysis revealed that this tyrosine residue was commonly phosphorylated in human cancers and that a mutant form of PKM2 lacking this tyrosine residue inhibited both “Warburg metabolism” and tumor growth. They thus propose that phosphorylation of PKM2 by oncogenic tyrosine kinases provides the very phosphotyrosine that binds to and inhibits PKM2 to induce the Warburg effect and promote 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 (Y105). 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 Y105 is common in human cancers. The presence of a PKM2 mutant in which phenylalanine is substituted for Y105 (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.

Subfields: Cancer Research, Cell Biology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/12567efdc6f85b862b3523fc9ece405950cc3b3c

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cancer Research

In Cell Biology

In Molecular Biology

Citations in the corpus

Transcriptional Regulation by Hypoxia Inducible Factors (2013, background): “Of note, PKM2 enzymatic activity was not required for its coactivator function, and others have shown that phosphorylation of Tyr-105, which inhibits its enzymatic activity, is important for Warburg type effects (Hitosugi et al., 2009).”
Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages (2015, positive): “Current data indicates that PKM2, when highly expressed, exists in an equilibrium of enzymatically inactive pyruvate kinase dimers (or monomers) which can translocate into the nucleus(Christofk et al., 2008; Hitosugi et al., 2009), and enzymatically active tetramers Cell Metab.”
The return of metabolism: biochemistry and physiology of the pentose phosphate pathway (2014, background): “Most human tissues are dominated by the expression of one of two mutually exclusive spliceforms of the PKM gene: PKM1 and PKM2 (Mazurek et al., 2005; Bluemlein et al., 2011).”
HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations. (2013, neutral): “First and foremost, PKM2 functions as a pyruvate kinase in glycolysis (Figure 3) but, in contrast to PKM1, its activity is regulated by allosteric interactions with phosphopeptides (67) and intermediary metabolites (68, 69) as well as by phosphorylation, acetylation, and oxidation (70–72).”
Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate (2012, background): “…inputs into PKM2 like tyrosine phosphorylation and ROS destabilize the tetrameric form of PKM2 (Anastasiou et al., 2011; Christofk et al., 2008b; Hitosugi et al., 2009), but other inputs present in glycolytic cancer cells like fructose-1,6-bisphosphate and serine can continually allosterically…”
Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013, background): “Moreover, growthfactor–stimulated tyrosine phosphorylation of PKM2 further decreases its activity (58, 59).”
Aerobic glycolysis: meeting the metabolic requirements of cell proliferation. (2011, positive): “PKM2 is less active than PKM1 both in vitro and in cells (Vander Heiden et al 2010), and inactivation of PKM2 appears to be mediated by phospho-tyrosine catalyzed release of FBP from the enzyme (Christofk et al 2008b, Hitosugi et al 2009).”
Dysregulated pH: a perfect storm for cancer progression (2011, background): “Recent findings suggest that the inhibition of PKM2 activity promotes metabolic adaptation, with oncogene- and growth factor signalling-mediated phosphorylation of Tyr105 of PKM2 suppressing its activit”
Acetylation Targets the M2 Isoform of Pyruvate Kinase for Degradation through Chaperone-Mediated Autophagy and Promotes Tumor Growth (2011, positive): “Acetylation Mimetic Mutant K305Q Accumulates Glycolytic Intermediates Accumulation of glycolytic intermediates resulting from decreased PKM2 activity by cellular signals, such as binding with phosphotyrosine or phosphorylation by FGFR1 (Christofk et al., 2008a; Hitosugi et al., 2009), has been sugge”
Targeting mitochondrial glutaminase activity inhibits oncogenic transformation (2010, positive): “Recently, it was found that phospho-tyrosine signaling impacts the glycolytic pathway by shifting the utilization of glucose metabolites from energy production to anabolic processes through the regulation of the M2 (fetal) isoform of pyruvate kinase, an enzyme that catalyzes the conversion of phosph”
Mitochondrial reactive oxygen species and cancer (2014, background): “In contrast to its constitutively active splice isoform PKM1, PKM2 is preferentially expressed in cancer cells and is unique due to its ability to be inhibited by a variety of stimuli [65,66].”
Pyruvate Kinase M2 Regulates Gene Transcription by Acting as A Protein Kinase (2012, positive): “, 2008b), phosphorylation modifications (Hitosugi et al., 2009), and direct interaction with oncogenic proteins (Mazurek et al.”
Signal transduction in cancer. (2015, positive): “PKM1 remains active undermost physiological conditions, but PKM2 can be turned off by signaling via tyrosine kinases, including the upstream RTKs in the Ras-ERK and PI3K-Akt pathways (Christofk et al. 2008; Hitosugi et al. 2009) and reactive oxygen species (ROS) (Anastasiou et al. 2011).”
Pyruvate Kinase M2 is a PHD3-stimulated Coactivator for Hypoxia-Inducible Factor 1 (2011, positive): “PKM2 promotes the Warburg effect and tumorigenesis (Christofk et al., 2008; Hitosugi et al., 2009).”