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

Abstract

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.

Pyruvate kinase type M2 is upregulated in colorectal cancer and promotes proliferation and migration of colon cancer cells

“…So, inhibition of expression of PKM2 may also affect the proliferation of other cells. The superiority of PKM2 compared with PKM1 might be that it can balance energy supply and glycolytic phospho-metabolite pools by switching between two quaternary conformations (12)(13)(14)(15)(16)(17)(18). As is mentioned above, PKM2 can exist as an active tetrameric and an inactive dimeric form.…”

“…Studies have shown that most PKM2 exists mainly as a dimeric form in tumor cells. Some viral oncoproteins like HPV-16E7 and pp60v-Src kinase (12,13) as well as cellular phosphotyrosine signaling (14,15) can induce the dimerization of PKM2, but the Ras oncogene induces the tetramerization of PKM2 (16,17). Recently, Kosugi et al (18) found that PKM2 activity is also regulated by direct binding of oncoprotein MUC1-C. Another important metabolic regulator of PKM2 is fructose 1,6-bisphosphate.…”

“…High level of this glycolytic intermediate reflects sufficient amounts of phosphor-metabolites and induces reassociation of the dimeric form of PKM2 to the highly active tetrameric form, thus shifting tumor metabolism from synthesis of cell building blocks to energy regeneration (12). So it is believed that PKM2 plays a key role in the channeling of glucose carbons either into catabolic or into anabolic pathways [14,15]. But not all of the tumors express PKM2 only; there might be different expressing patterns and roles of PKM2 in different tumors (19,20).…”

Death-associated protein kinase increases glycolytic rate through binding and activation of pyruvate kinase

“…I Mor et al phosphorylation of tyrosine residues and proteinprotein interactions, are inhibitory (Hitosugi et al, 2009;Mazurek, 2011). The M2 isoform is expressed during embryonic development and is turned off in adult somatic cells (Hitosugi et al, 2009;Mazurek, 2011).…”

“…The M2 isoform is expressed during embryonic development and is turned off in adult somatic cells (Hitosugi et al, 2009;Mazurek, 2011). A switch in the alternative splicing pattern leads to re-expression of the PKM2 during cancerous transformation and as a consequence, this isoform is almost ubiquitously expressed in tumors and proliferating cell lines (Clower et al, 2010;David et al, 2010).…”