SAICAR induces protein kinase activity of PKM2 that is necessary for sustained proliferative signaling of cancer cells

Kirstie E. Keller; Zainab M. Doctor; Zachary W. Dwyer; Young Sam Lee

doi:10.1016/j.molcel.2014.02.015

SAICAR induces protein kinase activity of PKM2 that is necessary for sustained proliferative signaling of cancer cells

Kirstie E. Keller
, Zainab M. Doctor
, Zachary W. Dwyer
, Young Sam Lee

Molecular and Cellular Biochemistry

Producción científica: Article › revisión exhaustiva

153 Citas (Scopus)

Resumen

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.

Idioma original	English
Páginas (desde-hasta)	700-709
Número de páginas	10
Publicación	Molecular Cell
Volumen	53
N.º	5
DOI	https://doi.org/10.1016/j.molcel.2014.02.015
Estado	Published - mar 6 2014

Nota bibliográfica

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.

Financiación

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.

Financiadores	Número del financiador
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 Institutes of Health (NIH)
National Institute of General Medical Sciences	T32GM007231
National Institute of General Medical Sciences

ODS de las Naciones Unidas

Este resultado contribuye a los siguientes Objetivos de Desarrollo Sostenible

Good health and well being

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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10.1016/j.molcel.2014.02.015

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title = "SAICAR induces protein kinase activity of PKM2 that is necessary for sustained proliferative signaling of cancer cells",

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.",

author = "Keller, \{Kirstie E.\} and Doctor, \{Zainab M.\} and Dwyer, \{Zachary W.\} and Lee, \{Young Sam\}",

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{\textquoteright}s Award (SKF-13-082), and the Johns Hopkins University Krieger School of Arts and Sciences startup package to Y.-S.L. ",

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AU - Doctor, Zainab M.

AU - Dwyer, Zachary W.

AU - Lee, Young Sam

N1 - 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.

PY - 2014/3/6

Y1 - 2014/3/6

N2 - 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.

AB - 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.

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JO - Molecular Cell

JF - Molecular Cell

IS - 5

ER -

SAICAR induces protein kinase activity of PKM2 that is necessary for sustained proliferative signaling of cancer cells

Resumen

Nota bibliográfica

Financiación

ODS de las Naciones Unidas

ASJC Scopus subject areas

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