Abstract
Abnormal metabolism and sustained proliferation are hallmarks of cancer. Pyruvate kinase M2 (PKM2) is a metabolic enzyme that plays important roles in both processes. Recently, PKM2 was shown to have protein kinase activity phosphorylating histone H3 and promoting cancer cell proliferation. However, the mechanism and extent of this protein kinase in cancer cells remain unclear. Here, we report that binding of succinyl-5-aminoimidazole-4-carboxamide-1-ribose-5'-phosphate (SAICAR), a metabolite abundant in proliferating cells, induces PKM2's protein kinase activity invitro and in cells.Protein microarray experiments revealed that more than 100 human proteins, mostly protein kinases, are phosphorylated by PKM2-SAICAR. In particular, PKM2-SAICAR phosphorylates and activates Erk1/2, which in turn sensitizes PKM2 for SAICAR binding through phosphorylation. Additionally, PKM2-SAICAR was necessary to induce sustained Erk1/2 activation and mitogen-induced cell proliferation. Thus, the ligand-induced protein kinase activity from PKM2 is a mechanism that directly couples cell proliferation with intracellular metabolic status.
Original language | English |
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Pages (from-to) | 700-709 |
Number of pages | 10 |
Journal | Molecular Cell |
Volume | 53 |
Issue number | 5 |
DOIs | |
State | Published - Mar 6 2014 |
Bibliographical note
Funding Information:We thank B. Wendland, G. Bowman, H. Zhao, and members of our department for reagents and for allowing access to their instruments; E. Pryce and J.M. McCaffery for technical assistance with fluorescence microscopy; T. Coupet for preparation of reagents; and W. An (University of Southern California) for plasmids encoding HA-tagged H3.1 and H3.3. We also thank R. Kuruvilla, X. Chen, H. Zhao, G. Bowman, and members of our department for their comments on this manuscript. K.E.K. was supported by an NIH training grant (T32GM007231) to the department. This work was supported in part by an NIH grant (R01CA168658), the Sidney Kimmel Foundation for Cancer Research Kimmel Scholar’s Award (SKF-13-082), and the Johns Hopkins University Krieger School of Arts and Sciences startup package to Y.-S.L.
Funding
We thank B. Wendland, G. Bowman, H. Zhao, and members of our department for reagents and for allowing access to their instruments; E. Pryce and J.M. McCaffery for technical assistance with fluorescence microscopy; T. Coupet for preparation of reagents; and W. An (University of Southern California) for plasmids encoding HA-tagged H3.1 and H3.3. We also thank R. Kuruvilla, X. Chen, H. Zhao, G. Bowman, and members of our department for their comments on this manuscript. K.E.K. was supported by an NIH training grant (T32GM007231) to the department. This work was supported in part by an NIH grant (R01CA168658), the Sidney Kimmel Foundation for Cancer Research Kimmel Scholar’s Award (SKF-13-082), and the Johns Hopkins University Krieger School of Arts and Sciences startup package to Y.-S.L.
Funders | Funder number |
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Johns Hopkins University Krieger School of Arts and Sciences | |
Sidney Kimmel Foundation for Cancer Research Kimmel Scholar | SKF-13-082 |
National Institutes of Health (NIH) | R01CA168658 |
National Institute of General Medical Sciences | T32GM007231 |
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology