ERK2 Phosphorylates PFAS to Mediate Posttranslational Control of De Novo Purine Synthesis

Eunus S. Ali; Umakant Sahu; Elodie Villa; Brendan P. O'Hara; Peng Gao; Cynthia Beaudet; Antony W. Wood; John M. Asara; Issam Ben-Sahra

doi:10.1016/j.molcel.2020.05.001

ERK2 Phosphorylates PFAS to Mediate Posttranslational Control of De Novo Purine Synthesis

Eunus S. Ali
, Umakant Sahu
, Elodie Villa
, Brendan P. O'Hara
, Peng Gao
, Cynthia Beaudet
, Antony W. Wood
, John M. Asara
, Issam Ben-Sahra

Research output: Contribution to journal › Article › peer-review

65 Scopus citations

Abstract

The RAS-ERK/MAPK (RAS-extracellular signal-regulated kinase/mitogen-activated protein kinase) pathway integrates growth-promoting signals to stimulate cell growth and proliferation, at least in part, through alterations in metabolic gene expression. However, examples of direct and rapid regulation of the metabolic pathways by the RAS-ERK pathway remain elusive. We find that physiological and oncogenic ERK signaling activation leads to acute metabolic flux stimulation through the de novo purine synthesis pathway, thereby increasing building block availability for RNA and DNA synthesis, which is required for cell growth and proliferation. We demonstrate that ERK2, but not ERK1, phosphorylates the purine synthesis enzyme PFAS (phosphoribosylformylglycinamidine synthase) at T619 in cells to stimulate de novo purine synthesis. The expression of nonphosphorylatable PFAS (T619A) decreases purine synthesis, RAS-dependent cancer cell-colony formation, and tumor growth. Thus, ERK2-mediated PFAS phosphorylation facilitates the increase in nucleic acid synthesis required for anabolic cell growth and proliferation.

Original language	English
Pages (from-to)	1178-1191.e6
Journal	Molecular Cell
Volume	78
Issue number	6
DOIs	https://doi.org/10.1016/j.molcel.2020.05.001
State	Published - Jun 18 2020

Bibliographical note

Publisher Copyright:
© 2020 Elsevier Inc.

Funding

The authors thank B.D. Manning and G. Hoxhaj for helpful discussion and comments and Z. Djabari and M. Yuan for technical assistance. This work was supported by the Lynn Sage (to I.B.-S.) and LAM Foundations (grant LAM0127C01-18 to I.B.-S.), and by the National Institutes of Health (NIH) (grants R00CA194192 and R01GM135587 to I.B.-S. and grants 5P01CA120964 and 5P30CA006516 to J.M.A.). The authors thank B.D. Manning and G. Hoxhaj for helpful discussion and comments and Z. Djabari and M. Yuan for technical assistance. This work was supported by the Lynn Sage (to I.B.-S.) and LAM Foundations (grant LAM0127C01-18 to I.B.-S.), and by the National Institutes of Health (NIH) (grants R00CA194192 and R01GM135587 to I.B.-S. and grants 5P01CA120964 and 5P30CA006516 to J.M.A.). E.S.A. and U.S. performed and analyzed all experiments and prepared the manuscript. E.V. performed the qPCR experiments. B.P.O. provided assistance to E.S.A. U.S. and E.V. P.G. and J.M.A. performed the LC-MS/MS experiments. C.B. and A.W.W. produced the phospho-specific PFAS antibody. I.B.-S. supervised the project, reviewed all experimental data, and prepared the manuscript. All the authors have reviewed, commented on, and edited the manuscript. The authors declare no competing interests.

Funders	Funder number
National Institutes of Health (NIH)	R01GM135587, 5P01CA120964, R00CA194192
National Institutes of Health (NIH)
National Childhood Cancer Registry – National Cancer Institute	P30CA006516
National Childhood Cancer Registry – National Cancer Institute

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

ERK
FGAM
MAPK
PFAS
RAS
cancer
nucleotide synthesis
posttranslational modification
purine metabolism
tumor growth

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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10.1016/j.molcel.2020.05.001

Cite this

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title = "ERK2 Phosphorylates PFAS to Mediate Posttranslational Control of De Novo Purine Synthesis",

abstract = "The RAS-ERK/MAPK (RAS-extracellular signal-regulated kinase/mitogen-activated protein kinase) pathway integrates growth-promoting signals to stimulate cell growth and proliferation, at least in part, through alterations in metabolic gene expression. However, examples of direct and rapid regulation of the metabolic pathways by the RAS-ERK pathway remain elusive. We find that physiological and oncogenic ERK signaling activation leads to acute metabolic flux stimulation through the de novo purine synthesis pathway, thereby increasing building block availability for RNA and DNA synthesis, which is required for cell growth and proliferation. We demonstrate that ERK2, but not ERK1, phosphorylates the purine synthesis enzyme PFAS (phosphoribosylformylglycinamidine synthase) at T619 in cells to stimulate de novo purine synthesis. The expression of nonphosphorylatable PFAS (T619A) decreases purine synthesis, RAS-dependent cancer cell-colony formation, and tumor growth. Thus, ERK2-mediated PFAS phosphorylation facilitates the increase in nucleic acid synthesis required for anabolic cell growth and proliferation.",

keywords = "ERK, FGAM, MAPK, PFAS, RAS, cancer, nucleotide synthesis, posttranslational modification, purine metabolism, tumor growth",

author = "Ali, \{Eunus S.\} and Umakant Sahu and Elodie Villa and O'Hara, \{Brendan P.\} and Peng Gao and Cynthia Beaudet and Wood, \{Antony W.\} and Asara, \{John M.\} and Issam Ben-Sahra",

note = "Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",

year = "2020",

month = jun,

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doi = "10.1016/j.molcel.2020.05.001",

language = "English",

volume = "78",

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AU - Ali, Eunus S.

AU - Sahu, Umakant

AU - Villa, Elodie

AU - O'Hara, Brendan P.

AU - Gao, Peng

AU - Beaudet, Cynthia

AU - Wood, Antony W.

AU - Asara, John M.

AU - Ben-Sahra, Issam

PY - 2020/6/18

Y1 - 2020/6/18

N2 - The RAS-ERK/MAPK (RAS-extracellular signal-regulated kinase/mitogen-activated protein kinase) pathway integrates growth-promoting signals to stimulate cell growth and proliferation, at least in part, through alterations in metabolic gene expression. However, examples of direct and rapid regulation of the metabolic pathways by the RAS-ERK pathway remain elusive. We find that physiological and oncogenic ERK signaling activation leads to acute metabolic flux stimulation through the de novo purine synthesis pathway, thereby increasing building block availability for RNA and DNA synthesis, which is required for cell growth and proliferation. We demonstrate that ERK2, but not ERK1, phosphorylates the purine synthesis enzyme PFAS (phosphoribosylformylglycinamidine synthase) at T619 in cells to stimulate de novo purine synthesis. The expression of nonphosphorylatable PFAS (T619A) decreases purine synthesis, RAS-dependent cancer cell-colony formation, and tumor growth. Thus, ERK2-mediated PFAS phosphorylation facilitates the increase in nucleic acid synthesis required for anabolic cell growth and proliferation.

AB - The RAS-ERK/MAPK (RAS-extracellular signal-regulated kinase/mitogen-activated protein kinase) pathway integrates growth-promoting signals to stimulate cell growth and proliferation, at least in part, through alterations in metabolic gene expression. However, examples of direct and rapid regulation of the metabolic pathways by the RAS-ERK pathway remain elusive. We find that physiological and oncogenic ERK signaling activation leads to acute metabolic flux stimulation through the de novo purine synthesis pathway, thereby increasing building block availability for RNA and DNA synthesis, which is required for cell growth and proliferation. We demonstrate that ERK2, but not ERK1, phosphorylates the purine synthesis enzyme PFAS (phosphoribosylformylglycinamidine synthase) at T619 in cells to stimulate de novo purine synthesis. The expression of nonphosphorylatable PFAS (T619A) decreases purine synthesis, RAS-dependent cancer cell-colony formation, and tumor growth. Thus, ERK2-mediated PFAS phosphorylation facilitates the increase in nucleic acid synthesis required for anabolic cell growth and proliferation.

KW - ERK

KW - FGAM

KW - MAPK

KW - PFAS

KW - RAS

KW - cancer

KW - nucleotide synthesis

KW - posttranslational modification

KW - purine metabolism

KW - tumor growth

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M3 - Article

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AN - SCOPUS:85086362989

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SP - 1178-1191.e6

JO - Molecular Cell

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IS - 6

ER -

ERK2 Phosphorylates PFAS to Mediate Posttranslational Control of De Novo Purine Synthesis

Abstract

Bibliographical note

Funding

UN SDGs

Keywords

ASJC Scopus subject areas

Access to Document

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