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A cellular threshold for active ERK1/2 levels determines Raf/MEK/ERK-mediated growth arrest versus death responses. Cell Signal 2018 Jan;42:11-20



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Scopus ID

2-s2.0-85031106212   5 Citations


In addition to its conventional role for cell proliferation and survival, the Raf/MEK/Extracellular signal-regulated kinase (ERK) pathway can also induce growth arrest and death responses, if aberrantly activated. Here, we determined a molecular basis of ERK1/2 signaling that underlies these growth inhibitory physiological outputs. We found that overexpression of ERK1 or ERK2 switches ΔRaf-1:ER-induced growth arrest responses to caspase-dependent apoptotic death responses in different cell types. These death responses, however, were reverted to growth arrest responses upon titration of cellular phospho-ERK1/2 levels by the MEK1/2 inhibitor AZD6244. These data suggest that a cellular threshold for active ERK1/2 levels exists and affects the cell fate between death and growth arrest. We also found that death-mediating ability of ERK2 is abolished by the catalytic site-disabling Lys52Arg replacement or significantly attenuated by the F-site recruitment site-disabling Tyr261Asn replacement, although unaffected by the mutations that disable the common docking groove or the dimerization interface. Therefore, ERK1/2 mediates death signaling dependently of kinase activity and specific physical interactions. Intriguingly, Tyr261Asn-replaced ERK2 could still mediate growth arrest signaling, further contrasting the molecular basis of ERK1/2-mediated growth arrest and death signaling. These data reveal a mechanism underlying the role of ERK1/2 as a focal point of Raf/MEK/ERK-mediated growth arrest and death signaling.

Author List

Hong SK, Wu PK, Park JI


Jong-In Park PhD Professor in the Biochemistry department at Medical College of Wisconsin
Pui Kei Wu PhD Instructor in the Biochemistry department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Amino Acid Substitution
Cell Cycle Checkpoints
Cell Differentiation
Cell Line, Tumor
Cell Proliferation
Gene Expression Regulation
HEK293 Cells
MAP Kinase Kinase Kinases
MAP Kinase Signaling System
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
Transduction, Genetic
raf Kinases
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a