Table 2.
Regulation of Smad2/3 by posttranslational modification
| Modification | Site | Enzyme | Outcome | Ref |
|---|---|---|---|---|
| acetylation | Smad2 (K19)/Smad3 (K19) | p300/CBP (Smad2/3), P/CAF (Smad2) | enhancement of DNA binding | (198) |
| Smad3 (K378) | p300/CBP | enhancement of Smad2/3 signaling | (199) | |
| ADP-ribosylation | Smad3 | PARP-1 | inhibition of DNA binding | (200) |
| de-ADP-ribosylation | Smad3 | PARG | (counteracting PARP-1) | (201) |
| methylation | Smad3 (K53/K333) | EZH2 | required to interact with SARA | (202) |
| palmitoylation | Smad3 (C421) | ZDHHC19 | enhancement of the association with the plasma membrane and activation of signaling | (203) |
| ubiquitylation (mono) | Smad3 | (not specified) | inhibition of DNA binding | (204) |
| Smad3 (T179 phosphorylated) | Smurf2 | inhibition of trimer formation | (205) | |
| ubiquitylation (poly) | Smad3 | CHIP | degradation (independently of signaling) | (352) |
| Smad2 | ITCH | enhancement of Smad2 phosphorylation | (353) | |
| Smad2 | NEDD4-2 | degradation of activated Smad2 | (354) | |
| Smad3 (K378) | pVHL | degradation | (355) | |
| Smad3 | ROC1-SCFFbw1a | degradation of activated Smad3 | (356) | |
| Smad2 | Smurf2 | degradation of activated Smad2 | (357) | |
| Smad2 | WWP1 | degradation of activated Smad2 | (358) | |
| Smad2/3 | WWP2 | degradation of unstimulated Smad2/3 | (359) | |
| deubiquitylation | Smad2/3 | USP15 | facilitation of DNA binding | (204) |
| Smad3 | USP7 | facilitation of DNA binding | (360) | |
| SUMOylation | Smad3 | E3 SUMO-protein ligase PIAS4 | inhibition of DNA binding | (361) |
| phosphorylation | Smad2 (Ser-465, Ser-467) Smad3 (Ser-423, Ser-425) |
ALK-5, ALK-4, ALK-7 | activation as a transcriptional regulator | (226, 227) |
| Smad2 (Thr-252) | Araf | negative regulation (degradation) | (362) | |
| Smad2 (Ser-465, Ser-467) | ATM (inhibited by KU55933) | pSmad2 foci formation at DNA double strand break | (193) | |
| Smad2 (Ser-240) | CAM kinase | negative regulation | (363) | |
| Smad3 (Ser-418) | casein kinase 1γ2 | negative regulation (degradation) | (364) | |
| Smad2 (Thr-8) | CDK2 | negative regulation (inhibition of Smad2-Smad4 interaction) | (221) | |
| Smad3 (Thr-8, Thr-179, Ser-213) | CDK2/4 | negative regulation of transcriptional activity | (220) | |
| Smad2 (Ser-255) | CDK4 (inhibited by palbociclib) | inhibition of the Smad complex to bind to the genome. | (365) | |
| Smad2 (Thr-220) Smad3 (Thr-179, Ser-208, Ser-213) |
CDK8/9 | negative regulation (degradation) | (208) | |
| Smad2 (Thr-220, Ser-245, Ser-250) Smad3 (Ser-208, Ser-213) |
ERK | negative regulation (inhibition of nuclear localizaion of Smad2/3) | (206) | |
| Smad3 (Thr-179, Ser-204, Ser-208) | ERK | enhancement of ARE-dependent reporter activity | (366) | |
| Smad3 (Ser-204) | ERK | enhancement of COL1A2 in mesenchymal cells | (367) | |
| Smad2 (Thr-197) | GRK2 | negative regulation (inhibition of Smad2 C-terminal phosphorylation) | (368) | |
| Smad3 (Thr-66) | GSK-3β | negative regulation (degradation) | (369) | |
| Smad3 (Ser-204) | GSK-3β | negative regulation (inhibition of CBP binding) | (370) | |
| Smad2 (Ser-250, Ser-255) Smad3 (Ser-208, Ser-213) |
JNK | enhancement of invasive capacity and negative regulation of p15ink4b promoter activity | (209) | |
| Smad2 (Ser-245) Smad3 (Ser-204) |
MPK38 | enhancement of TGF-β signaling | (371) | |
| Smad2 (Ser-465, Ser-467) Smad3 (Ser-423, Ser-425) |
Mps | not examined | (229) | |
| Smad2 (Ser-250) Smad3 (Ser-208) |
NEMO-like kinase (NLK) | negative regulation (degradation) | (372) | |
| Smad2 (Thr-220) Smad3 (Thr-179) |
OSR1 (oxidative stress-responsive kinase) | enhancement of Smad2/3 signaling | (373) | |
| Smad2 (Ser-417) | PAK2 | negative regulation (inhibition of ALK5-Smad2 interaction) | (374) | |
| Smad2 (Ser-465) | PAK4 | negative regulation (degradation) | (228) | |
| Smad2 (Ser-465, Ser-467) Smad3 (Ser-423, Ser-425) |
PIM1 | activation as a transcriptional regulator | (230) | |
| Smad3 (Ser-37, Ser-70) | Protein kinase C | inhibition of DNA binding | (375) | |
| Smad3 (Ser-309, Thr-388) | PKG | negative regulation (inhibition of nuclear translocation of phosphorylated Smad2/3) | (222) | |
| Smad3 (Ser-204, Ser-208) | ROCK (inhibited by Y27632) | up-regulation of p21waf1 protein, down-regulation of c-Myc protein | (376) | |
| Smad2 (Ser-465) | WNK1 | negative regulation of Smad2 C-terminal phosphorylation | (377) | |
| de-phosphorylation | Smad2 (Ser-465, Ser-467) Smad3 (Ser-423, Ser-425) |
MTMR4 | attenuation of TGFβ signaling by reducing the phosphorylation of R-Smads in early endosome | (52) |
| Smad3 (Ser-423, Ser-425) | PP2A | attenuation of nuclear accumulation of TGF-β-induced Smad3 | (378) | |
| Smad2 (Ser-465, Ser-467) Smad3 (Ser-423, Ser-425) |
PP5 | negative regulation of TGF-β signaling by decreasing the levels of Smad3 protein | (379) | |
| Smad2 (Ser-465, Ser-467) Smad3 (Ser-423, Ser-425) |
PPM1A/PP2Cα | promotion of nuclear export of TGFβ-activated Smad2/3 | (51) | |
| Smad2 (Ser-245, Ser-250, Ser-255) | SCP1/2/3 | enhancement of TGFβ signaling | (218) | |
| Smad2 (Thr-8, Ser-245, Ser-250, Ser-255) Smas3 (Thr-8, Ser-204, Ser-208, Ser-213) |
SCP1/2/3 | increase of TGF-β-induced transcriptional activity | (219) | |
| Smad2 (Ser-465, Ser-467) Smad3 (Ser-423, Ser-425) |
TNAP | negative regulation | (380) |