Department of Chemistry and Biochemistry, University of California, Los Angeles, California, USA.
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.
J Biol Chem. 2021 Jan-Jun;296:100676. doi: 10.1016/j.jbc.2021.100676. Epub 2021 Apr 16.
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.
人类细胞分裂是一个高度受调控的过程，依赖于染色体准确地捕获和移动到中期板。染色体向心和排列的保真度错误会导致染色体分离不当，这与非整倍体和肿瘤发生有关。这些过程在其他物种中已知受细胞外信号调节激酶 2（ERK2）调控，但 ERK2 在哺乳动物有丝分裂中的作用仍不清楚。在这里，我们鉴定了双特异性磷酸酶 7（DUSP7），已知其对 ERK2 具有选择性，是调节染色体排列的重要因素。在有丝分裂过程中，DUSP7 与 ERK2 结合，并通过其磷酸酶活性调节活性磷酸化 ERK2 的丰度。DUSP7 的过表达，但不是催化失活突变体，导致磷酸化 ERK2 水平降低和有丝分裂染色体排列不当，而 DUSP7 的敲低也导致染色体向心缺陷，导致有丝分裂延长。一致地，ERK2 的敲低或化学抑制或磷酸化 ERK2 的 MEK 激酶的化学抑制导致染色体排列缺陷。我们的结果支持这样一种模型，即 MEK 介导的磷酸化和 DUSP7 介导的去磷酸化调节活性磷酸化 ERK2 的水平，以促进适当的细胞分裂。
