DUSP9, a Dual-Specificity Phosphatase with a Key Role in Cell Biology and Human Diseases

Abstract

Mitogen-activated protein kinases (MAPKs) are essential for proper cell functioning as they regulate many molecular effectors. Careful regulation of MAPKs is therefore required to avoid MAPK pathway dysfunctions and pathologies. The mammalian genome encodes about 200 phosphatases, many of which dephosphorylate the MAPKs and bring them back to an inactive state. In this review, we focus on the normal and pathological functions of dual-specificity phosphatase 9 (DUSP9)/MAP kinase phosphatases-4 (MKP-4). This cytoplasmic phosphatase, which belongs to the threonine/tyrosine dual-specific phosphatase family and was first described in 1997, is known to dephosphorylate ERK1/2, p38, JNK and ASK1, and thereby to control various MAPK pathway cascades. As a consequence, DUSP9 plays a major role in human pathologies and more specifically in cardiac dysfunction, liver metabolic syndromes, diabetes, obesity and cancer including drug response and cell stemness. Here, we recapitulate the mechanism of action of DUSP9 in the cell, its levels of regulation and its roles in the most frequent human diseases, and discuss its potential as a therapeutic target.

Multi-layered proteomics identifies insulin-induced upregulation of the EphA2 receptor via the ERK pathway and dependent on low IGF1R level

“…Furthermore, understanding the mechanisms behind sustained MAPK signaling in insulin resistance is important and adds relevance to our observation of the down-regulated phosphorylation levels of the ERK phosphatase, DUSP9. Increased levels of this phosphatase have been shown to protect against insulin resistance [65], [66], [82]. The potential regulatory role of the significantly regulated C-terminal phosphorylation sites of DUSP9 identified in this study is unknown.…”

“…Noteworthy, only insulin-resistant cells showed upregulated phosphorylation levels of DUSP9 Ser368 and Thr384 upon insulin stimulation (>1.5-fold at 3 nM and >2-fold at 100 nM, p<0.05) (Figure S4.C). DUSP9 dephosphorylates MAPKs, including ERK1/2 [65], and several studies have shown its involvement in insulin resistance [66]- [68]. Thus, it was speculated whether the lowered phosphorylation levels of DUSP9 at Ser368 and Thr384 under unstimulated insulin-resistant conditions, potentially impact the activity or stability of the protein, leading to sustained ERK phosphorylation and signaling.…”

Sinomenine attenuates pulmonary fibrosis by downregulating TGF-β1/Smad3, PI3K/Akt and NF-κB signaling pathways

“…The PD-1/PD-L1 pathway is currently one of the main targets of immunologic drugs for the treatment of lung cancer, and some studies have shown that IPF patients with concurrent enlarged lymph nodes have higher PD-1 expression and CD4/CD8 ratios, whereas pembrolizumab shows antifibrotic effects in the bleomycin model in mice [33,34]. In addition, the dualspecificity protein phosphatase protein family (DUSP10/ MKP-5, DUSP9/ MKP-4) shows antagonistic effects in cancer and fibrosis [35,36]. This reminds us that for this easily overlooked population, they urgently need to find a common target of anti-cancer and anti-fibrosis, and also need a consensus statement of unified standard methods.…”

Exogenous expression of protein phosphatase DUSP9 reduces the rate of migration of kidney carcinoma cells

“…DUSP9 принадлежит к семейству протеинфосфатаз, негативно регулирующих ERK1/2, p38 и JNK MAP-киназы, дефосфорилируя их как по тирозиновым, так и по серин/треониновым остаткам. На 2021 г. в человеческом геноме выявлена 61 протеинфосфатаза такого типа [3].…”

“…Мы также выя-вили связь транскрипционной активности DUSP9 c определенными модификациями гистона H3 в локусе гена, что свидетельствует о возможном вовлечении процесса модификации гистонов в регулирование активности гена DUSP9 [14]. Кроме эпигенетических, активность DUSP9 в опухолях человека может регулироваться на транскрипционном и пост-транскрипционном уровнях [3].…”