Reduced levels of Dusp3/Vhr phosphatase impair normal spindle bipolarity in an Erk1/2 activity‐dependent manner

Abstract

Dual specificity phosphatase-3 (Dusp3/Vhr) regulates cell cycle progression by counteracting the effects of mitogen-activated protein kinases (Mapk) Erk1/2 and Jnk. Despite the known upregulation of Dusp3 at M phase in mammalian cells, its mitotic functions are poorly characterized. Here, we report that loss of Dusp3 by RNAi leads to the formation of multipolar spindles in human mitotic cancer cells in an Erk1/2-dependent manner. In the phosphatase-silenced cells, the normal bipolar spindle structure was restored by chemical inhibition of Erk1/2 and ectopic overexpression of Dusp3. We propose that at M phase Dusp3 keeps Erk1/2 activity in check to facilitate normal mitosis.

Revisiting the roles of VHR/DUSP3 phosphatase in human diseases

“…In terms of MAPK signaling, with MAPKs the best characterized substrates of VHR, over-activating ERK1/2 induced multipolar spindles and aneuploidy in cells, while inhibiting ERK1/2 did not cause defects during chromosomal events such as the spindle assembly checkpoint (SAC) and mitotic exit 49 . The role of this phosphatase in the formation of multipolar spindles in cancer cells was recently investigated 50 . In early mitotic mammalian cells, both VHR and ERK1/2 localized to the spindle apparatus 17 , 51 , and transient VHR inhibition promoted the formation of multipolar spindles in human mitotic cells 50 .…”

“…The role of this phosphatase in the formation of multipolar spindles in cancer cells was recently investigated 50 . In early mitotic mammalian cells, both VHR and ERK1/2 localized to the spindle apparatus 17 , 51 , and transient VHR inhibition promoted the formation of multipolar spindles in human mitotic cells 50 . These studies also demonstrated that depleting ERK1/2 activity but not JNK restored the multipolarity induced by a lack of VHR and that overexpressing VHR reduced ERK1/2 phosphorylation by reversing multipolar spindles.…”

Neighbours of cancer-related proteins have key influence on pathogenesis and could increase the drug target space for anticancer therapies

“…The cancer-related DUSP4 overexpression blocks ERK1/2 signalling, and this leads to increased cell proliferation in colorectal cells 45. Expression of DUSP3 is needed during intensive cell proliferation to inhibit the active MAPK signal, and blocking DUSP3 by compounds leads to cell cycle arrest 46,47. Therefore, DUSP3 could be a potential drug target in colon cancer, similarly as it was proven in cervical cancer, where targeting DUSP3 by small molecules led to decreased proliferation 48.…”

“…Interestingly, DUSP4 alone can still limit the ERK1/2 over activation leading to cancer stem cell formation and epithelial mesenchymal transition (EMT) instead of cell-cycle arrest 50. The inhibition of DUSP4 could prevent the EMT in breast cancer,50 as well as causing cell cycle arrest, similarly as the inhibition of DUSP3 in colorectal cancer 46. Therefore, DUSP4 inhibitors (such as the CHEMBL 2146956 compound, which inhibits DUSP4 with an IC50 of 2.29 μm) are under intensive experimental investigations.…”

Transcriptome stability profiling using 5’-bromouridine IP chase (BRIC-seq) identifies novel and functional microRNA targets in human melanoma cells

“…DUSP3 is a dual activity phosphatase that regulates signaling pathways by dephosphorylating target tyrosine and/or serine/threonine residues [59]. While DUSP3 has been shown to specifically target ERK1/2 and JNK MAP kinase (MAPK) pathways in multiple cancers [58,60,55,56], its role in melanoma is unknown. To investigate the specific kinase pathway(s) regulated by DUSP3 in A375 cells, we assessed phosphorylation of various MAPK pathway members using a MAPK array upon DUSP3 knockdown ( Fig.…”