The Power of PKM2
In recent years pyruvate kinase isoform M2 (PKM2) has emerged as an increasingly attractive oncogenic target; its unique ability to function as both a pyruvate kinase and a protein kinase make it a key player in both abnormal metabolism and sustained proliferation. However, to date, little light has been shed on the molecular mechanism responsible for PKM2’s dual function. It seems as though the mystery has finally been solved; a new study led by Young-Sam Lee at John Hopkins University highlights the molecular mechanism responsible for inducing PKM2 protein kinase activity and suggests that the two processes, metabolism, and proliferation, are linked.
PKM2’s unique ability to function as a protein kinase was first reported in 2012 (Gao, et al 2012; Yang, et al 2012). (Recall from your intro biochemistry course that pyruvate kinase catalyzes a “reverse” kinase reaction, with the phosphate from PEP transferred to ADP, yielding pyruvate and ATP.) Researchers showed that ADP inhibits the protein kinase reaction with PKM2, and thus, concluded that the same active site normally used to convert PEP (phosphoenolpyruvate) to pyruvate and ATP, is also used by PKM2 to phosphorylate protein substrates using PEP, rather than ATP, as the phosphoryl donor.
The new study, published in last month’s issue of Molecular Cell, builds on existing research in which Lee and his colleagues discovered that the metabolite succinyl-5-aminoimidazole- 4-carboxamide-1-ribose-50-phosphate (SAICAR) binds PKM2. Now they show that SAICAR binding induces robust protein kinase activity from PKM2, in effect switching it from the terminal enzyme in glycolysis to a protein kinase involved in controlling cell proliferation. And, based on in vitro screening of a human protein microarray, Lee and colleagues also report that this PKM2 phosphorylates more than 100 human proteins, mostly protein kinases, among them several proliferative growth factor receptor kinases; e.g., EGFR, FGFR, and PDGFR.
SAICAR-activated PKM2 also phosphorylates ERK1, which (the plot grows thicker) has been previously shown to phosphorylate PKM2. The researchers report that the phosphorylation of PKM2 by ERK1 sensitizes PKM2 for SAICAR binding, creating a positive feedback loop: Erk1-mediated phosphorylation of PKM2 causes the enzyme to be sensitized to the stimulatory effects of SAICAR, causing PKM2 to have enhanced activity as a protein kinase. The SAICAR-activated form of PKM2 can, in turn, phosphorylate many protein kinase enzymes, including Erk1, which phosphorylates PKM2 leading to its activation.
Researchers believe their results provide a detailed molecular mechanism describing how two tumorigenic hallmarks, altered metabolism, and sustained proliferative signaling, are interrelated in highly proliferating cells. Next, Lee and his colleagues hope to determine how SAICAR activates PKM2 and further explore this link between metabolome and proteome.
