The Post-Translational Regulation of Epithelial–Mesenchymal Transition-Inducing Transcription Factors in Cancer Metastasis
Abstract
:1. Introduction
2. Regulation of the Snail Family
2.1. Snail
2.1.1. Phosphorylation of Snail
2.1.2. Ubiquitination of Snail
2.1.3. Acetylation of Snail
2.1.4. Glycosylation of Snail
2.2. Slug
2.2.1. Phosphorylation of Slug
2.2.2. Ubiquitination of Slug
2.2.3. Sumoylation of Slug
2.2.4. Acetylation of Slug
2.3. Smuc
3. Regulation of the Twist Family
3.1. Twist1
3.1.1. Phosphorylation of Twist1
3.1.2. Ubiquitination of Twist1
3.1.3. Acetylation of Twist1
3.1.4. Methylation of Twist1
4. Regulation of the ZEB Family
4.1. ZEB1 and ZEB2
4.1.1. Phosphorylation of ZEB1 and ZEB2
4.1.2. Ubiquitination of ZEB1 and ZEB2
4.1.3. Sumoylation of ZEB1 and ZEB2
4.1.4. Acetylation of ZEB1 and ZEB2
5. Concluding Remarks
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
ATM | Ataxia–telangiectasia mutated kinase |
BLBCs | Basal-like breast cancer cells |
β-TrCP | Beta-transducin repeat-containing protein |
CBP | CREB-binding protein |
CDK2 | Cyclin-dependent kinase 2 |
CSN5 | COP9 signalosome subunit 5 |
CtBP | C-terminal binding protein |
CZF | C-terminal zinc finger |
DUBs | Deubiquitinating enzymes |
ECM | Extracellular matrix |
EMT | Epithelial–mesenchymal transition |
EMT-TFs | EMT-transcription factors |
EndoMT | Endothelial-to-mesenchymal transition |
ERK | Extracellular signal-regulated kinases |
FBXL14 | F-Box and leucine-rich repeat protein 14 |
FBXL5 | F-box and leucine-rich repeat protein 5 |
FBXO11 | F-box only protein 11 |
FBXO45 | F-box only protein 45 |
FBXW7 | F-box/WD repeat-containing protein 7 |
GSK3β | Glycogen synthase kinase 3 |
HAT | Histone acetyltransferase |
HCC | Hepatocellular carcinoma |
HDAC1/2 | Histone deacetylase 1/2 |
HNSCC | Head and neck squamous cell carcinoma |
IGF-1 | Insulin-like growth factor-1 |
IL-6 | Interleukin 6 |
Lats2 | Large tumor suppressor kinase 2 |
MAPK | Mitogen-activated protein kinase |
MDM2 | Mouse double minute 2 homolog |
MET | Mesenchymal–epithelial transition |
MMPs | Matrix metalloproteinases |
NF-κB | Nuclear factor-kappa B |
NSCLC | Non-small cell lung cancer |
NuRD | Nucleosome remodeling and deacetylation |
NZF | N-terminal zinc finger |
O-GlcNAc | O-linked β-N-acetylglucosamine |
Pc2 | Polycomb protein 2 |
PCAF | p300/CBP-associated factor |
PI3K | Phosphoinositide 3-kinase |
PKA | Protein kinase A |
PKC | Protein kinase C |
PKCα | Protein kinase C alpha |
PKD1 | Protein kinase D1 |
PRMTs | Protein arginine methyl transferases |
PTM | Post-translational modification |
SBD | SMAD-binding domain |
SCP | Small C-terminal domain phosphatase |
SRD | Serine-rich domain |
TGF-β | Transforming growth factor beta |
Tip60 | Tat-interacting protein of 60 kDa |
USP51 | Ubiquitin specific peptidase 51 |
ZnF | Zinc finger |
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Transcription Factor | Function | Effects on EMT-TFs | Regulation Factor | Role or Mechanism | Reference |
---|---|---|---|---|---|
Snail | Phosphorylation | Stabilization | Lats2 | Phosphorylation at Thr203 | [52] |
PTK6 | Phosphorylation at Tyr342 | [53] | |||
ATM | Phosphorylation at Ser100 | [54] | |||
Degradation | PKD1 | Phosphorylation at Ser11 | [55] | ||
Nuclear accumulation | GROα | Phosphorylation at Ser246 | [56] | ||
ERK | Phosphorylation at Ser82 and Ser104 | [57] | |||
PAK1 | Phosphorylation at Ser246 | [58] | |||
Ubiquitination | Degradation | β-TrCP | Ubiquitination at pSer96 and pSer100 | [59] | |
FBXO11 | Ubiquitination at pSer11 | [60] | |||
FBXL14 | Ubiquitination at Lys98, Lys137, and Lys146 | [61] | |||
FBXL5 | Ubiquitination at Lys85, Lys146, and Lys234 | [62] | |||
Dephosphorylation | Stabilization | SCP | Dephosphorylation at Ser96 and Ser100 | [63,64] | |
Acetylation | Increasing transcriptional activity | CBP | Acetylation at Lys126 and Lys187 | [65] | |
Glycosylation | Stabilization | O-GlcNAc | O-GlcNAc at Ser112 | [66] | |
Slug | Phosphorylation | Nuclear translocation | ERK-vimentin complex | Phosphorylation at Ser87 | [67] |
Degradation | GSK3β | Phosphorylation at Ser92, Ser96, Ser100, and Ser104 | [48] | ||
CDK2 | Phosphorylation at Ser54 and Ser104 | [68] | |||
Stabilization | PAK4 | Phosphorylation at Ser158 and Ser254 | [69] | ||
Ubiquitination | Degradation | FBXL14 | Ubiquitination depends on Leu33, Tyr34, Val58, and Trp59 | [70] | |
β-TrCP | GSK3β-mediated ubiquitination | [71] | |||
CHIP | GSK3β-mediated ubiquitination | [72] | |||
p53 | MDM2-mediated ubiquitination | [73] | |||
Stabilization | pellino-1 | Ubiquitination at Lys63 | [74] | ||
Sumoylation | Stabilization | p14Arf | Sumoylation at Lys192 | [75] | |
Acetylation | Stabilization | Sirtuin 2 | Deacetylation at Lys116 | [51] | |
CBP | Acetylation at Lys166 and Lys211 | [76] |
Transcription Factor | Function | Effects on EMT-TFs | Regulation Factor | Role or Mechanism | Reference |
---|---|---|---|---|---|
Twist1 | Phosphorylation | Stabilization | MAPK | Phosphorylation at Ser68 | [133] |
Akt2 | Phosphorylation at Ser42 | [134,135] | |||
CK2α | Phosphorylation at Ser18 and Ser20 | [136] | |||
PKCα | Phosphorylation at Ser144 | [137] | |||
Aurora A | Phosphorylation at Ser123, Thr148, and Ser184 | [138] | |||
Nuclear translocation | CD44 | c-Src-dependent phosphorylation at tyrosine | [139] | ||
Degradation | Akt1 | Phosphorylation at Ser42, Thr121, and Ser123 | [140] | ||
IKKβ | Phosphorylation at Thr125 and Ser127 | [141] | |||
Dephosphorylation | Degradation | SCP1 | Dephosphorylation at Ser68 | [142] | |
Ubiquitination | Degradation | β-TrCP | Ubiquitination at Thr121 and Ser123 | [140] | |
FBXL14 | C-terminal Twist box-dependent ubiquitination | [143] | |||
Acetylation | Nuclear translocation | PCAF | Acetylation at Lys73, Lys76, and Lys77 | [144] | |
Nuclear translocation | Tip60 | Acetylation at Lys73 and Lys76 | [145,146] | ||
Methylation | PRMT1 | Methylation at Arg34 | [147] |
Transcription Factor | Function | Effects on EMT-TFs | Regulation Factor | Role or Mechanism | Reference |
---|---|---|---|---|---|
ZEB1 | Phosphorylation | Stabilization | ATM | Phosphorylation at Ser585 | [168,169] |
Inhibition of transcriptional activity | PKC | Phosphorylation at Thr851, Ser852, and Ser853 | [170] | ||
ERK | Phosphorylation at Thr867 | [170] | |||
Deubiquitination | Stabilization | USP51 | Binding to N-terminal of ZEB1 | [171] | |
CSN5 | Binding to ZEB1 | [172] | |||
Sumoylation | Inhibition of transcriptional activity | Pc2 | Sumoylation at Lys347 and Lys774 | [173] | |
Acetylation | Inhibition of transcriptional activity | p300 and PCAF | Acetylation at Lys741, Lys774, and Lys775 | [174] | |
Tip60 | Binding to N-terminal of ZEB1 | [175] | |||
Deacetylation | Increasing transcriptional activity | HDAC1/2 | Binding to ZEB1 | [176,177] | |
ZEB2 | Phosphorylation | Degradation | GSK3β | Phosphorylation at Ser705 and Tyr802 | [178] |
Ubiquitination | Degradation | FBXL14 | Binding to ZEB2 | [143] | |
FBXO45 | Ubiquitination at Lys48 | [179] | |||
FBXW7 | GSK3β-mediated ubiquitination | [178] | |||
Sumoylation | Inhibition of transcriptional activity | Pc2 | Sumoylation at Lys391 and Lys866 | [173] |
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Kang, E.; Seo, J.; Yoon, H.; Cho, S. The Post-Translational Regulation of Epithelial–Mesenchymal Transition-Inducing Transcription Factors in Cancer Metastasis. Int. J. Mol. Sci. 2021, 22, 3591. https://doi.org/10.3390/ijms22073591
Kang E, Seo J, Yoon H, Cho S. The Post-Translational Regulation of Epithelial–Mesenchymal Transition-Inducing Transcription Factors in Cancer Metastasis. International Journal of Molecular Sciences. 2021; 22(7):3591. https://doi.org/10.3390/ijms22073591
Chicago/Turabian StyleKang, Eunjeong, Jihye Seo, Haelim Yoon, and Sayeon Cho. 2021. "The Post-Translational Regulation of Epithelial–Mesenchymal Transition-Inducing Transcription Factors in Cancer Metastasis" International Journal of Molecular Sciences 22, no. 7: 3591. https://doi.org/10.3390/ijms22073591
APA StyleKang, E., Seo, J., Yoon, H., & Cho, S. (2021). The Post-Translational Regulation of Epithelial–Mesenchymal Transition-Inducing Transcription Factors in Cancer Metastasis. International Journal of Molecular Sciences, 22(7), 3591. https://doi.org/10.3390/ijms22073591