DUSP7 regulates the activity of ERK2 to promote proper chromosome alignment during cell division

Xiao Guo; Ivan Ramirez; Yenni A Garcia; Erick F Velasquez; Ankur A Gholkar; Whitaker Cohn; Julian P Whitelegge; Bobby Tofig; Robert Damoiseaux; Jorge Z Torres

doi:10.1016/j.jbc.2021.100676

DUSP7 regulates the activity of ERK2 to promote proper chromosome alignment during cell division

J Biol Chem. 2021 Jan-Jun:296:100676. doi: 10.1016/j.jbc.2021.100676. Epub 2021 Apr 16.

Authors

Affiliations

¹ Department of Chemistry and Biochemistry, University of California, Los Angeles, California, USA.
² Pasarow Mass Spectrometry Laboratory, The Jane and Terry Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, California, USA.
³ Pasarow Mass Spectrometry Laboratory, The Jane and Terry Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, California, USA; Molecular Biology Institute, University of California, Los Angeles, California, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California, USA.
⁴ California NanoSystems Institute, University of California, Los Angeles, California, USA.
⁵ California NanoSystems Institute, University of California, Los Angeles, California, USA; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, California, USA.
⁶ Department of Chemistry and Biochemistry, University of California, Los Angeles, California, USA; Molecular Biology Institute, University of California, Los Angeles, California, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California, USA. Electronic address: torres@chem.ucla.edu.

Abstract

Human cell division is a highly regulated process that relies on the accurate capture and movement of chromosomes to the metaphase plate. Errors in the fidelity of chromosome congression and alignment can lead to improper chromosome segregation, which is correlated with aneuploidy and tumorigenesis. These processes are known to be regulated by extracellular signal-regulated kinase 2 (ERK2) in other species, but the role of ERK2 in mitosis in mammals remains unclear. Here, we have identified the dual-specificity phosphatase 7 (DUSP7), known to display selectivity for ERK2, as important in regulating chromosome alignment. During mitosis, DUSP7 bound to ERK2 and regulated the abundance of active phospho-ERK2 through its phosphatase activity. Overexpression of DUSP7, but not catalytically inactive mutants, led to a decrease in the levels of phospho-ERK2 and mitotic chromosome misalignment, while knockdown of DUSP7 also led to defective chromosome congression that resulted in a prolonged mitosis. Consistently, knockdown or chemical inhibition of ERK2 or chemical inhibition of the MEK kinase that phosphorylates ERK2 led to chromosome alignment defects. Our results support a model wherein MEK-mediated phosphorylation and DUSP7-mediated dephosphorylation regulate the levels of active phospho-ERK2 to promote proper cell division.

Keywords: cell division; chromosome alignment; dual-specificity phosphatase 7 (DUSP7); extracellular signal-regulated kinase 2 (ERK2); mitogen-activated protein kinases (MAPK); mitosis.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Chromosomes, Human / genetics
Chromosomes, Human / metabolism*
Dual-Specificity Phosphatases / genetics
Dual-Specificity Phosphatases / metabolism*
HCT116 Cells
HeLa Cells
Humans
MAP Kinase Kinase Kinases / genetics
MAP Kinase Kinase Kinases / metabolism
Mitogen-Activated Protein Kinase 1 / genetics
Mitogen-Activated Protein Kinase 1 / metabolism*
Mitosis*
Mutation
Phosphorylation / genetics

Substances

MAPK1 protein, human
Mitogen-Activated Protein Kinase 1
MAP Kinase Kinase Kinases
DUSP7 protein, human
Dual-Specificity Phosphatases

Abstract

Publication types

MeSH terms

Substances

Grants and funding