Regulation of Dual-Specificity Phosphatase (DUSP) Ubiquitination and Protein Stability

Chen, Hsueh‐Fen; Chuang, Huai‐Chia; Tan, Tse‐Hua

doi:10.3390/ijms20112668

Cited by 140 publications

(130 citation statements)

References 102 publications

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“…DUSPs are classified primarily based on the presence of a kinase-interacting motif (KIM). If a DUSP contains a KIM, then it is classified as a typical MAP kinase phosphatase (MKP) or typical DUSP [55]. An atypical DUSP or MKP does not have a KIM [55].…”

Section: Dual-specificity Phosphatases (Dusps): Regulators Of the Jnkmentioning

confidence: 99%

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Phosphorylation Dynamics of JNK Signaling: Effects of Dual-Specificity Phosphatases (DUSPs) on the JNK Pathway

Kang

Seo

et al. 2019

IJMS

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Protein phosphorylation affects conformational change, interaction, catalytic activity, and subcellular localization of proteins. Because the post-modification of proteins regulates diverse cellular signaling pathways, the precise control of phosphorylation states is essential for maintaining cellular homeostasis. Kinases function as phosphorylating enzymes, and phosphatases dephosphorylate their target substrates, typically in a much shorter time. The c-Jun N-terminal kinase (JNK) signaling pathway, a mitogen-activated protein kinase pathway, is regulated by a cascade of kinases and in turn regulates other physiological processes, such as cell differentiation, apoptosis, neuronal functions, and embryonic development. However, the activation of the JNK pathway is also implicated in human pathologies such as cancer, neurodegenerative diseases, and inflammatory diseases. Therefore, the proper balance between activation and inactivation of the JNK pathway needs to be tightly regulated. Dual specificity phosphatases (DUSPs) regulate the magnitude and duration of signal transduction of the JNK pathway by dephosphorylating their substrates. In this review, we will discuss the dynamics of phosphorylation/dephosphorylation, the mechanism of JNK pathway regulation by DUSPs, and the new possibilities of targeting DUSPs in JNK-related diseases elucidated in recent studies.

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Section: Dual-specificity Phosphatases (Dusps): Regulators Of the Jnkmentioning

confidence: 99%

“…If a DUSP contains a KIM, then it is classified as a typical MAP kinase phosphatase (MKP) or typical DUSP [55]. An atypical DUSP or MKP does not have a KIM [55]. With the type and domain of DUSPs, a phylogenetic tree was constructed in Figure 4.…”

Section: Dual-specificity Phosphatases (Dusps): Regulators Of the Jnkmentioning

confidence: 99%

Phosphorylation Dynamics of JNK Signaling: Effects of Dual-Specificity Phosphatases (DUSPs) on the JNK Pathway

Kang

Seo

et al. 2019

IJMS

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“…KLF4 increases the susceptibility of GCs to apoptosis by downregulating Bcl2 expression and promotes LH induced luteal transition of GCs (Choi and Roh, 2018). Dual-specific phosphatases (DUSPs) dephosphorylate MAPKs and thereby inhibiting their activities (Chen et al, 2019). We speculate that PMSG-induced Dusp9 suppresses ERK activation to allow proper development of preantral follicles in wildtype ovaries.…”

Section: Discussionmentioning

confidence: 94%

Granulosa cell genes that regulate ovarian follicle development beyond the antral stage: the role of estrogen receptor β

Chakravarthi

Borosha

Ghosh

et al. 2020

Preprint

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Follicle development beyond the preantral stage is dependent on gonadotropins. FSH signaling is crucial for the advancement of preantral follicles to the antral stage, and LH signaling is essential for further maturation of preovulatory follicles. Estrogen is intricately tied to gonadotropin signaling during the advanced stages of folliculogenesis. We observed that Erβnull ovarian follicles fail to develop beyond the antral stage, even after exogenous gonadotropin stimulation. As ERβ is primarily expressed in the granulosa cells (GCs), we explored the gonadotropin-regulated GC genes that induce maturation of antral follicles. Synchronized follicle development was induced by administration of exogenous gonadotropins to wildtype 4-wk-old female rats. The GC transcriptome was analyzed via RNA-sequencing before and after gonadotropin stimulation. An Erβnull mutant model that fails to show follicle maturation was also included in order to identify the ERβ-regulated genes involved at this step. We observed that specific groups of genes were differentially expressed in response to PMSG or hCG administration in wildtype rats. While some of the PMSG or hCG-induced genes showed a similar expression pattern in Erβnull GCs, a subset of PMSG- or hCG-induced genes showed a differential expression in Erβnull GCs. These latter ERβ-regulated genes included previously known FSH or LH target genes including Lhcgr, Cyp11a1, Cyp19a1, Pgr, Runx2, Egfr, Kiss1, and Ptgs2, which are involved in follicle development, oocyte maturation, and ovulation. We also identified novel ERβ-regulated genes including Jaml, Galnt6, Znf750, Dusp9, Wnt16, and Mageb16 that failed to respond to gonadotropin stimulation in Erβnull GCs. Our findings indicate that the gonadotropin-induced spatiotemporal pattern of gene expression is essential for ovarian follicle maturation beyond the antral stage. However, expression of a subset of those gonadotropin-induced genes is dependent on transcriptional regulation by ERβ.

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“…In previous study, the allosteric sites in DUSP3 (VHR) and DUSP10 (MKP5) are reported, and these allosteric sites are surrounded by the N-loop and can affect the phosphatase activity [ 30 , 31 ]. Whether the mutations shown in Tables S1 and S2 participate in the process of cancer development is worth studying because N-loop-containing PTPs regulate several signaling pathways, and the deficiency or downregulation of these PTPs is frequently observed in cancer development [ 32 , 33 ]. Drug development to stabilize the DPN–triloop interaction is a possible strategy to benefit cancer treatment.…”

Section: Discussionmentioning

confidence: 99%

Structural Insights into the Active Site Formation of DUSP22 in N-loop-containing Protein Tyrosine Phosphatases

Lai

Chang

Chuang

et al. 2020

IJMS

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Cysteine-based protein tyrosine phosphatases (Cys-based PTPs) perform dephosphorylation to regulate signaling pathways in cellular responses. The hydrogen bonding network in their active site plays an important conformational role and supports the phosphatase activity. Nearly half of dual-specificity phosphatases (DUSPs) use three conserved residues, including aspartate in the D-loop, serine in the P-loop, and asparagine in the N-loop, to form the hydrogen bonding network, the D-, P-, N-triloop interaction (DPN–triloop interaction). In this study, DUSP22 is used to investigate the importance of the DPN–triloop interaction in active site formation. Alanine mutations and somatic mutations of the conserved residues, D57, S93, and N128 substantially decrease catalytic efficiency (kcat/KM) by more than 102-fold. Structural studies by NMR and crystallography reveal that each residue can perturb the three loops and induce conformational changes, indicating that the hydrogen bonding network aligns the residues in the correct positions for substrate interaction and catalysis. Studying the DPN–triloop interaction reveals the mechanism maintaining phosphatase activity in N-loop-containing PTPs and provides a foundation for further investigation of active site formation in different members of this protein class.

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Regulation of Dual-Specificity Phosphatase (DUSP) Ubiquitination and Protein Stability

Cited by 140 publications

References 102 publications

Phosphorylation Dynamics of JNK Signaling: Effects of Dual-Specificity Phosphatases (DUSPs) on the JNK Pathway

Phosphorylation Dynamics of JNK Signaling: Effects of Dual-Specificity Phosphatases (DUSPs) on the JNK Pathway

Granulosa cell genes that regulate ovarian follicle development beyond the antral stage: the role of estrogen receptor β

Structural Insights into the Active Site Formation of DUSP22 in N-loop-containing Protein Tyrosine Phosphatases

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