Pyruvate kinase M2 promotes de novo serine synthesis to sustain mTORC1 activity and cell proliferation

Abstract

Despite the fact that most cancer cells display high glycolytic activity, cancer cells selectively express the less active M2 isoform of pyruvate kinase (PKM2). Here we demonstrate that PKM2 expression makes a critical regulatory contribution to the serine synthetic pathway. In the absence of serine, an allosteric activator of PKM2, glycolytic efflux to lactate is significantly reduced in PKM2-expressing cells. This inhibition of PKM2 results in the accumulation of glycolytic intermediates that feed into serine synthesis. As a consequence, PKM2-expressing cells can maintain mammalian target of rapamycin complex 1 activity and proliferate in serinedepleted medium, but PKM1-expressing cells cannot. Cellular detection of serine depletion depends on general control nonderepressible 2 kinase-activating transcription factor 4 (GCN2-ATF4) pathway activation and results in increased expression of enzymes required for serine synthesis from the accumulating glycolytic precursors. These findings suggest that tumor cells use serinedependent regulation of PKM2 and GCN2 to modulate the flux of glycolytic intermediates in support of cell proliferation.amino acid synthesis | glucose | metabolism | nucleotide biosynthesis

GCN2 sustains mTORC1 suppression upon amino acid deprivation by inducing Sestrin2

“…2C). The kinetics of Sestrin2 induction resembled those of an established ATF4 target, phosphoserine amino transferase 1 (PSAT1) (Ye et al 2012). In contrast to Sestrin2, the mRNA and/or protein levels of Sestrin1 and Sestrin3 were not induced in response to AAD.…”

“…Among them, ATF4 is critical for increasing nonessential amino acid synthesis (Harding et al 2003). For instance, the GCN2-ATF4 pathway up-regulates all three enzymes in the serine biosynthetic pathway (PHGDH, PSAT1, and PSPH), which are essential for cell proliferation under serine depletion (Ye et al 2012). Additionally, upon glutamine withdrawal, ATF4 up-regulates asparagine synthetase (ASNS), which increases asparagine synthesis to support cell survival (Ye et al 2010).…”

“…However, particular mRNAs that contain an upstream ORF (uORF) cluster in their 5 ′ untranslated region (UTR) are efficiently translated upon eIF2α phosphorylation, including the yeast transcription factor GCN4 (Hinnebusch 1984) and its mammalian ortholog, ATF4 (Harding et al 2000;Vattem and Wek 2004). Once ATF4 is up-regulated, it induces expression of many genes involved in amino acid metabolism, including amino acid synthetases and transporters, amino acyl tRNA synthetases (Harding et al 2003;Bunpo et al 2009;Ye et al 2010Ye et al , 2012, and regulators of autophagy (B'chir et al 2013). Together, these ATF4 targets promote cellular adaptation to the amino acid shortage.…”

cMyc-mediated activation of serine biosynthesis pathway is critical for cancer progression under nutrient deprivation conditions

“…It was reported recently that, upon serine starvation, p53 activates p21 to promote GSH production to combat ROS [25,26]. Additionally, p73, ATF4, G9A, HIF1 and PKCζ were also reported to regulate serine biosynthesis and metabolism [27][28][29][30][31]. However, compared to the profound understanding of glycolysis and glutaminolysis in cancer cells, we are only beginning to appreciate the critical impact of serine synthesis pathway (SSP) on cancer progression.…”

Nutrient stress revamps cancer cell metabolism

“…This has important metabolic implications due to the critical role played by PKM2 in the regulation of the glycolytic flux (Figure 1). Furthermore, Thompson and co-workers presented compelling evidence that PKM2 exerts a regulatory contribution to the serine synthetic pathway [9]. Thus, in the absence of serine, the glycolytic flux to lactate is diminished due to the reduced activity of PKM2, which results in the accumulation of glycolytic intermediates that are diverted to the PHGDH-driven serine biosynthetic pathway [9].…”