Role of DUSP2 in cancer cell signaling in hematological malignancies
Dual-specificity phosphatases (DUSPs) are a subclass of protein tyrosine phosphatases (PTPs) and they play key roles in dephosphorylation and inactivation of MAP kinase (MAPK) isoforms that are key components of signaling pathways regulating cell proliferation, differentiation, and stress response in mammalian cells. DUSPs comprise a subfamily of 10 catalytically active enzymes and they are divided into three subgroups based on protein sequence homology, subcellular localization and substrate specificity. These are the inducible nuclear DUSPs (DUSP1, DUSP2, DUSP4, DUSP5), cytoplasmic DUSPs (DUSP6, DUSP7, DUSP9), and cytoplasmic and nuclear DUSPs (DUSP8, DUSP10, DUSP16).
The nuclear inducible DUSP2 also known as PAC-1 was first identified in human T-cells and it is mainly expressed in hematopoietic tissues and hematological cancers (Figure 1). DUSP2 is mitogen inducible gene and when expressed in mammalian cells it favors dephosphorylation of ERK1/2 and p38 MAPKs, being less able to inactivate JNK (Fig.2). Recently, our lab found that DUSP2 is unique amongst the 10 mammalian DUSPs in being able to dephosphorylate the “atypical” MAP kinases ERK3 and ERK4. In some types of solid and liquid cancers, down-regulation of DUSP2 has been reported suggesting a tumor suppressive role for DUSP2 in both forms of cancers. So far, few studies demonstrated a role for DUSP2 as a positive mediator of inflammation. In contrast, some reports described DUSP2 as a negative regulator of inflammation or T cell function. Moreover, Diffuse Large B cell lymphoma (DLBCL) sequencing results from our collaborators and literature showed that DUSP2 is one of the most frequently mutated genes in DLBCL patients. Despite the fact that DUSP2 is mainly expressed and frequently mutated in some hematological cancers, a little attention has been invested to study the possible role of DUSP2 and its mutations in cancer causing signaling in hematological malignancies such as leukemias and lymphomas.
Therefore, the main goal of this project is to study in detail how DUSP2 and other DUSPs contribute to MAPK signaling and cancer in hematological malignancies such as Acute T cell leukemia and DLBCL. We are also interested to study the impact of DUSP2 mutations on the magnitude of MAPK signaling pathways in our aforementioned cancer models. We use CRISPR-Cas-9 gene editing technology, Phospho flow cytometry, lentiviral vectors, and standard molecular biological techniques to generate engineered cell lines needed to accomplish our goals. DUSP2 project team is equipped with researchers experienced in cell signaling, CRISPR-Cas-9 technology, immunology, molecular biology, and cell biology. Ultimately, the knowledge gained from this study will be used to develop novel approaches to target respective cancers.
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This study is supported by the Norwegian Cancer Society.