Dual-specificity phosphatase 6 (DUSP6): a review of its molecular characteristics and clinical relevance in cancer

Abstract

Mitogen-activated protein kinases (MAPKs) are the main regulators of cellular proliferation, growth, and survival in physiological or pathological conditions. Aberrant MAPK signaling plays a pivotal role in carcinogenesis, which leads to development and progression of human cancer. Dual-specificity phosphatase 6 (DUSP6), a member of the MAPK phosphatase family, interacts with specifically targeted extracellular signal-regulated kinase 1/2 via negative feedback regulation in the MAPK pathway of mammalian cells. This phosphatase functions in a dual manner, pro-oncogenic or tumor-suppressive, depending on the type of cancer. To date, the tumor-suppressive role of DUSP6 has been demonstrated in pancreatic cancer, non-small cell lung cancer, esophageal squamous cell and nasopharyngeal carcinoma, and ovarian cancer. Its pro-oncogenic role has been observed in human glioblastoma, thyroid carcinoma, breast cancer, and acute myeloid carcinoma. Both roles of DUSP6 have been documented in malignant melanoma depending on the histological subtype of the cancer. Loss- or gain-of-function effects of DUSP6 in these cancers highlights the significance of this phosphatase in carcinogenesis. Development of methods that use the DUSP6 gene as a therapeutic target for cancer treatment or as a prognostic factor for diagnosis and evaluation of cancer treatment outcome has great potential. This review focuses on molecular characteristics of the DUSP6 gene and its role in cancers in the purview of development, progression, and cancer treatment outcome.

Keywords: Dual-specificity phosphatase 6; MAPK signaling; cancer; chemoresistance; chemoresponsiveness.

1

Phylogenetic tree of DUSP sequences. Vector NTI software was used to derive the phylogenetic tree of the mouse DUSP amino acid sequence alignment. Sequence differences between proteins in each DUSP protein are proportionate to the length of the branches of the phylogenetic tree.

2

The domain structure of MKP-3/DUSP6 is made up of the C-terminal catalytic domain and N-terminal non-catalytic domain consisting of the Cdc25/rhodanese-homology domain, kinase interaction motif (KIM), and nuclear export signal (NES). Domains in the encoded proteins are indicated by the shaded shapes, and the three exons of DUSP6 denoted by roman numerals (rectangles) are connected through lines representing introns^,,,.

3

Inactivation of ERK1/2 by DUSP6. Binding of activated ERK1/2 to the ERK binding (EB) domain of DUSP6 results in conformational change, prompting phosphatase activation of the DUSP6 catalytic domain, leading to dephosphorylation of ERK1/2.

4

A schematic diagram of DUSP6 regulation and interaction with other associated genes. The diagram shows the multiple effects of these interactions, including synthesis of various functional proteins, mitochondrial damage and cell death, cell cycle and growth arrest, and proteasomal degradation of DUSP6 due to phosphorylation and ubiquitination. These interactions also propagate signalling for cellular proliferation and differentiation.