Pseudophosphatases as Regulators of MAPK Signaling
Abstract
:1. Introduction
1.1. Mitogen-Activated Protein Kinase (MAPK) Signaling
1.2. Pseudophosphatases as Signaling Molecules
2. MAPK Phosphatases (MKPs) Role in MAPK Signaling
Atypical MKP: MK-STYX
3. STYX
4. TAB1
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
ERK | Extracellular signal-regulated kinases 1/2 |
CH2 | Cell division cycle 25 phosphatase homology 2 |
DYRK | Dual-specificity tyrosine-phosphorylated and-regulated kinase |
I-TASSER | Iterative Threading ASSEmbly Refinement |
FBXW7 | F-box protein WD40 (tryptophan and aspartic acid repeats) domain |
G3BP-1 | Ras-GTPase-activating protein SH3 domain-binding protein-1 |
JNK | c-JUN NH2-terminus kinase |
KIM | Kinase interaction motif |
MAPK | Mitogen-activated protein kinase |
MAP2K/MEK | MAPK kinase |
MAP3K | MAPK kinase kinase |
MBK-2 | Mini brain kinase 2 |
MKP | MAP kinase phosphatase |
MK-STYX | Mitogen-activated protein kinase Phosphoserine/threonine/tyrosine-binding protein |
MTM | Myotubularins |
POCASA | Pocket Cavity Search Application |
PTMs | Post-translational modifications |
PTPM1 | PTP localized to the mitochondrion 1 |
PTP | Protein tyrosine phosphatase |
RTKs | Receptor tyrosine kinases |
RhoGAP | Rho GTPase-activating protein |
SCF | SKP/CUL1-F-box |
STYX | Phosphoserine/threonine/tyrosine-interacting protein |
TAB 1 | TAK1-binding protein |
TAK1 | TGF-beta-activated kinase 1 |
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Pseudophosphatase | Critical Mutation(s) | Implications in MAPK Signaling | Implications in Other Pathways | Links to Diseases |
---|---|---|---|---|
MK-STYX (STYXL1/DUSP-24) | Contains the active site sequence FSX5R instead of HCX5R which results in the loss of catalytic activity. The KIM of MK-STYX lacks consecutive arginines (R53V), which may be the reason that MK-STYX does not bind MAPK/ERK. | Does not function like the other MKPs in that MK-STYX does not impact MAPK/ERK signaling. | The overexpression of MK-STYX decreases stress granule formation through interaction with G3BP1 and alters the localization of HDAC6. MK-STYX modulates the activity of PTPM1 in order to induce stress-activated mitochondrial-dependent apoptosis. In PC12 cells, the overexpression of MK-STYX induces neurite formation by affecting cofilin and decreasing RhoA activation. | MK-STYX has a potential oncogenic role in Ewing’s sarcoma family tumors (ESFT) linked to the EWS-FLI1-driven overexpression of MK-STYX in these tumors [38]. Potential oncogenic role in glioblastoma (GBM) as MK-STYX was found to be upregulated and promoted aggressive phenotypes in gliomas [86]. Increased expression of MK-STYX implicated in the proliferation of hepatocellular carcinoma (HCC) by inhibiting apoptosis [87]. Increased expression of MK-STYX noted in breast cancer and prostate cancer [88]. |
STYX | The essential active site cysteine (C) is replaced by a glycine (G) and results in the loss of catalytic activity. | Competes with MKP-2 to serve as a spatiotemporal regulator of ERK1/2 and reduce downstream MAPK activation. Downregulation of STYX inhibits Golgi polarization in an ERK-dependent manner. | STYX associates with CRHSP-24 (calcium-regulated heat-stable protein of 24 kDa) to serve as a critical regulator of spermatogenesis in mice and the deletion of STYX results in male sterility [89]. STYX regulates ubiquitination by interacting with F-box proteins and inhibiting the associated SCF complex. | The ability of STYX to bind and inhibit the F-box protein FBXW7, along with imbalances in the relative expression of these two proteins, has been implicated in breast cancer, colorectal cancer, and endometrial cancer [72,90,91]. |
TAB1 (MAP3K7IP1) | The N-terminal of TAB1 lacks the three catalytic residues of PP2C (protein phosphatase 2C): -Asp282 (substituted with Glu356 in TAB1), -His62 (substituted with Tyr71 in TAB1), and -Arg33 (missing in TAB1) [76,92]. Four of the active site aspartic acid residues that co-ordinate the metal ions required for catalytic function in PP2C have been substituted: -Asp60 (substituted with Asn69 in TAB1), -Asp239 (substituted with Glu290 in TAB1), -Asp 282 (substituted with Glu356) this is also a catalytic residue, and -Asn283 (substituted with Asp357 in TAB1) [76,92]. | Downstream regulator of the MAP3K TAK1 by activating and changing the localization of p38 MAPK in order to recruit p38 MAPK to the TAK1 complex in order to activate TAK1. | Blocks inhibition of p53 by inhibiting the negative regulator MDM2. | TAB1 as part of the TAK1 complex is linked with the outcome of viral infection with enterovirus 71 (EV71), the pathogen responsible for hand, foot, and mouth disease via inhibition of NF-κB activation [93]. TAB1 is implicated as a potential tumor suppressor and lower levels of TAB1 are associated with cancerous ovarian tumors [81]. Implicated in rheumatoid arthritis and other pro-inflammatory diseases [77,78,79]. |
EGG4/EGG5 | Catalytic cysteine (C) residue replaced by aspartic acid (D) in the active site motif [35,36]. | Does not regulate MAPK signaling. However, EGG4/5 do regulate dual-specificity tyrosine-regulated kinase (DYRK) signaling. EGG4/5 regulates the oocyte-to-zygote transition in Caenorhabditis elegans via competition with mini brain kinase 2 (MBK-2). | EGG4/5 regulates the localization of EGG3 and CHS-1 during meiotic progression and EGG4/5 localize to the cortex in developing oocytes independently of MBK-2. | Loss of function of both EGG4/5 results in maternal-effect lethality in the nematode C. elegans. |
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Hepworth, E.M.W.; Hinton, S.D. Pseudophosphatases as Regulators of MAPK Signaling. Int. J. Mol. Sci. 2021, 22, 12595. https://doi.org/10.3390/ijms222212595
Hepworth EMW, Hinton SD. Pseudophosphatases as Regulators of MAPK Signaling. International Journal of Molecular Sciences. 2021; 22(22):12595. https://doi.org/10.3390/ijms222212595
Chicago/Turabian StyleHepworth, Emma Marie Wilber, and Shantá D. Hinton. 2021. "Pseudophosphatases as Regulators of MAPK Signaling" International Journal of Molecular Sciences 22, no. 22: 12595. https://doi.org/10.3390/ijms222212595