Phosphorylation Dynamics of JNK Signaling: Effects of Dual-Specificity Phosphatases (DUSPs) on the JNK Pathway
Abstract
:1. Phosphorylation-Dephosphorylation: The Scope of Thermodynamics
2. The c-Jun N-terminal Kinase (JNK) Pathway
3. Phosphatases in Mitogen-Activated Protein Kinase (MAPK) Pathways
4. Dual-Specificity Phosphatases (DUSPs): Regulators of the JNK Pathway
4.1. Negative Regulation of JNK by DUSPs
4.2. DUSPs Acting on other JNK Signaling Kinases
4.3. DUSPs as Scaffolds of JNK Signaling
5. Effects of DUSPs in JNK-Associated Diseases
6. Possibilities for DUSP inhibitors
7. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Name | Alternative Names | Target Signaling | Cellular Effects Related to the JNK Pathway | Ref. |
---|---|---|---|---|
DUSP1 | MKP1, CL100, VH1, PTPN10, HVH1 | JNK, p38 > ERK1/2 | ■ Inhibits the activation of JNK in COS-7 cells ■ Leads cancer cell death in liver cancer cell line ■ c-Jun and ATF2 mediate DUSP1 | [56,57,58,59,60,61] |
DUSP2 | PAC-1 | ERK1/2, p38 > JNK1 | ■ Functions as a negative regulator of JNK in DUSP2−/− mice ■ Interacts with JNK1 | [62] |
DUSP3 | VHR | JNK | ■ Functions as a negative regulator of JNK ■ DUSP3 C124S, catalytically inactive mutant, acts as a substrate trap in vivo ■ Phosphorylation sites of DUSP3 are specifically blocked from c-Jun complexed with JNK in vitro ■ Deletion of DUSP3 leads the cell cycle arrest | [63,64,65] |
DUSP4 | MKP2, VH2, VHV2, TYP | JNK, ERK1/2 > p38 | ■ Affects the cellular proliferation in embryonic fibroblasts from KO mice | [66,67] |
DUSP6 | MKP3, PYST1 | ERK1/2, ERK5 > JNK | ■ Functions as a negative regulator of ERK and interacts with ERK2 ■ Could not bind to JNK2/3 in vitro ■ Increases the level of TCR-mediated p-JNK when DUSP6 is suppressed ■ Reduces the level of p-JNK in primary rat neonatal brain cortex astrocytes cells | [49,68,69,70,71,72] |
DUSP7 | MKP-X, PYST2 | ERK1/2 > JNK1/2 | ■ Binds to JNK and leads inactivation | [73] |
DUSP8 | VH5, HVH8, HVH-5 (M3/6 in mouse) | JNK3 > ERK, p38 | ■ A highly specific inactivator of JNK ■ Inactivates JNK3 when expressed in COS-7 cells ■ Binds to JIP1 in ND7 and N1E-115 cells ■ Regulated by JNK | [74,75,76,77,78,79] |
DUSP9 | MKP4 | ERK > p38 > JNK | ■ Dephosphorylates ASK1 | [80] |
DUSP10 | MKP5 | JNK, p38 > ERK | ■ Inactivates JNK in vitro ■ Enhances JNK when deleted in T- cells | [81,82] |
DUSP12 | YVH1 | JNK | ■ Binds directly to ASK1 and dephosphorylates in L02 cells ■ Dephosphorylates and inactivates JNK | [81,82] |
DUSP13 | DUSP13A, DUSP13B, BEDP, MOSP, SKRP4, TMDP | JNK, p38 > ERK | ■ DUSP13B dephosphorylates JNK ■ DUSP13A acts as a scaffold protein that binds to ASK1 to activate JNK | [83,84] |
DUSP14 | MKP6, MKP-L | JNK > ERK > p38 | ■ Inactivates JNK in vitro ■ Dephosphorylates TAB1 ■ Directly interacts with TAK1 | [85,86,87,88,89] |
DUSP16 | MKP7 | JNK3, p38 > ERK | ■ Dephosphorylates JNK directly in COS-7 cells ■ Phosphorylated by ERK ■ Binds to JIP-1 | [77,90,91,92,93,94] |
DUSP18 | DUSP20, LNW-DSP20 | JNK | ■ Dephosphorylates and inactivates the pathway of JNK signaling | [95] |
DUSP19 | SKRP1, DUSP17, LMW-DSP3, TS-DSP1 | JNK | ■ Binds directly to MKK7 in COS-7 cells ■ Functions as a scaffold of JNK pathways ■ Increases ATF-2 dependent on the expression level of DUSP19 | [96,97] |
DUSP22 | JSP-1, JKAPVHX, LMW-DSP2, MKPX | JNK | ■ Activates MKK4 in COS-7 and MKK7 in HEK293 cells ■ Dephosphorylates and inactivates JNK signaling in COS-7 cells ■ Binds to ASK1, MKK7, and JNK to function as a scaffold protein | [98,99,100,101] |
DUSP23 | DUSP25, VHZ, LDP-3, MOSP | JNK, p38 | ■ Induces MKK4 and 6 activations in COS-7 cells | [102] |
Name | Target Inhibition DUSPs | Reference |
---|---|---|
Arsenite | DUSP8 | [74,79] |
Rosiglitazone | DUSP8 | [125,126,127] |
PTP inhibitor IV | DUSP14 | [128] |
NSC95397 | DUSP1, DUSP6, DUSP14 | [129,130] |
Sanguinarine | DUSP1, DUSP6 | [131] |
Adociaquinone B & Naphthoquinone | DUSP1, DUSP6, CDC25B | [132] |
TPI-3 | DUSP1 | [133] |
BCI | DUSP1, DUSP6 | [70,134] |
RK-682 | DUSP3 | [135,136] |
AS077234-4 | DUSP10 | [137] |
Quinoxalinylurea | DUSP22 | [138] |
Rhodanine | DUSP22 | [139] |
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Ha, J.; Kang, E.; Seo, J.; Cho, S. Phosphorylation Dynamics of JNK Signaling: Effects of Dual-Specificity Phosphatases (DUSPs) on the JNK Pathway. Int. J. Mol. Sci. 2019, 20, 6157. https://doi.org/10.3390/ijms20246157
Ha J, Kang E, Seo J, Cho S. Phosphorylation Dynamics of JNK Signaling: Effects of Dual-Specificity Phosphatases (DUSPs) on the JNK Pathway. International Journal of Molecular Sciences. 2019; 20(24):6157. https://doi.org/10.3390/ijms20246157
Chicago/Turabian StyleHa, Jain, Eunjeong Kang, Jihye Seo, and Sayeon Cho. 2019. "Phosphorylation Dynamics of JNK Signaling: Effects of Dual-Specificity Phosphatases (DUSPs) on the JNK Pathway" International Journal of Molecular Sciences 20, no. 24: 6157. https://doi.org/10.3390/ijms20246157