Abstract 2360: Regulation of the MAPK phosphatase MKP-1 by the E3 ligase GP78 in cancer cells

Mitogen-activated protein kinase (MAPK) phosphatase 1 (DUSP1/MKP-1) is a member of the threonine-tyrosine dual-specificity phosphatase family that is endogenous inhibitor for extracellular signal-regulated protein kinases (ERKs), p38 MAPKs, and JNKs signaling. MKP-1 plays a key role in determining the magnitude and duration of MAPK activation in response to extracellular stimuli. In human cancers, abnormal expression of DUSP1 is associated with tumor development, chemoresistance and prognosis. However, the mechanism by which MKP-1 is regulated is not fully understood. Here, we show that GP78, an E3 ligase, plays an important role in regulation of MKP-1 protein levels. Specifically, we found that MKP-1 interacts with GP78 both in vitro and in vivo. Their interaction occurs between the N-terminal, Rhodanese domain of MKP-1 and C-terminal E3 ligase domain of GP78. We also found that K230, 280, and 289 residues on MKP-1 are responsible for its ubiquitination. Importantly, this interaction causes MKP-1 ubiquitination and subsequent degradation. Furthermore, we showed by overexpression and knockdown studies that GP78 downregulates the level of MKP-1 protein in cancer cells. Therefore, we identify a novel mechanism by which GP78 controls MKP-1 protein levels and suggest that this regulatory mechanism may play an important in cancer. Citation Format: Dhonghyo Kho, Gen Sheng Wu. Regulation of the MAPK phosphatase MKP-1 by the E3 ligase GP78 in cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2360. doi:10.1158/1538-7445.AM2017-2360