From: Regulation of Wnt/β-catenin signaling by posttranslational modifications
Protein | PTM | Sites | Domains | Involved enzymes | Function | References |
---|---|---|---|---|---|---|
Frizzled | Phosphorylation | S576 (Xenopus Fz3) | - | - | Reduces Fz3 activity | [25] |
S554/S560 (Drosophila Fz1) | KTxxxW motif | aPKC | Inhibits Fz1 activity | [26] | ||
Ubiquitination | - | - | ZNRF3/RNF43 | Targets for degradation | ||
- | - | UBPY/USP8 (deubiquitinase) | Targets for degradation | [29] | ||
Glycosylation | - | - | - | Important for Fz maturation | [30] | |
LRP6 | Phosphorylation | T1479 | Intracellular domain (ICD) | CK1γ | Recruits Axin and promotes Wnt/β-catenin signaling | [31] |
S1490 | ICD | GSK3/Grk5/6/MAPKs | Recruits Axin and promotes Wnt/β-catenin signaling | |||
T1493 | ICD | CK1α,γ,ϵ,δ | Recruits Axin and promotes Wnt/β-catenin signaling | |||
S1420/S1430 | ICD | CK1ϵ | Suppresses LRP6-Axin interaction and β-catenin accumulation | [36] | ||
S1490 | ICD | PKA | Essential for PT-induced β-catenin stabilization | [37] | ||
S1490 | ICD | PFTK1/Cyclin Y | Promots Wnt/β-catenin signaling | [38] | ||
Palmitoylation | C1394/C1399 | ICD | - | ER exit | [39] | |
Ubiquitination | K1403 | ICD | - | ER retention | [39] | |
- | - | ZNRF3/RNF43 | Targets for degradation | [28] | ||
LRP5 | Phosphorylation | PPPSPxS motifs | ICD | GSK3/CK1 | Required for Axin binding | [40] |
Axin | Phosphorylation | S322/S326/S330/S333/T337/ S339/T341/S343 (Rat Axin) | - | GSK3 | - | [41] |
S322/S326/S330 (Rat Axin) | - | GSK3 | Increases stability | [42] | ||
T609/S614 (Mouse Axin) | β-catenin binding domain | GSK3 | Required for Axin binding to β-catenin | [43] | ||
S497/S500 (Mouse Axin1 isoform 2) | β-catenin binding domain | GSK3/PP1cγ (phosphatase) | Essential for Axin-β-catenin interaction | [17] | ||
Ubiquitination | - (K48-linked chain) | - | RNF146 | Targets for degradation | ||
K789/K821 (K29-linked chain) | DIX domain | Smurf1 | Disrupts Axin interaction with LRP5/6 | [46] | ||
K505 (Mouse Axin1 isoform 1) | - | Smurf2 | Targets for degradation | [47] | ||
Sumoylation | C-terminal KVEKVD (Mouse Axin) | DIX domain | Likely PIAS family | No effect on Wnt pathway | [48] | |
ADP-ribosylation | - | - | TNKS1/TNKS2 | Facilitates ubiquitin E3 binding; Promotes Wnt/β-catenin signaling | [49] | |
GSK3 | Phosphorylation | S27 (GSK3α)/S9 (GSK3β) | - | AKT/S6K1/RSK/PKA/PKC | Suppresses kinase activity towards certain substrates | |
Y279 (GSK3α)/Y216 (GSK3β) | Kinase domain | PYK2/GSK3 | May have impact on GSK3 activity | |||
T43 (GSK3β) | - | ERK | Required for phosphorylation at Ser9 which inactivates GSK3β | [58] | ||
T390 (GSK3β) | - | P38 MAPK | Inactivates GSK3β | [59] | ||
Ubiquitination | - | - | - | Targets for degradation | [60] | |
Sumoylation | K292 | Kinase domain | - | Critical for kinase activity, protein stability and nuclear localization | [61] | |
ADP-ribosylation | - | - | ARTD10 | Inhibits activity | [62] | |
APC | Phosphorylation | - | - | GSK3 | Increases APC binding to β-catenin | |
S1279/S1392 | - | CK1ϵ | Essential for the regulatory activity of APC towards β-catenin | [66] | ||
Ubiquitination | - | - | USP15 (deubiquitinase) | Targets for degradation | ||
- (K63-linked chain) | Trabid (deubiquitinase) | - | [69] | |||
- (K63-linked chain) | - | HectD1 | Enhances APC-Axin interaction | [70] | ||
Dvl | Phosphorylation | S139/S142 (mouse Dvl1) | - | CK1ϵ | Promotes Wnt signaling | [71] |
- | - | CK1ϵ | May enhance interaction between Dvl1 and Frat-1 | [72] | ||
S298/S480 (Dvl2) | PDZ domain (S298)/DEP domain (S480) | RIPK4 | Essential for Wnt-induced β-catenin accumulation; promotes Dvl2 signalosome assembly | [73] | ||
S236 (Drosophila DSH) | - | CK1ϵ | - | [74] | ||
- | - | PAR-1/CK2 | - | |||
- | - | DDX3 | May promote signalosome formation | [77] | ||
Ubiquitination | K413/K444/K451/K461 (Dvl1) | DEP domain | USP14 (deubiquitinase) | Suppresses Fz-Dvl interaction | [78] | |
K5/K20/K34/K46/K50/K60/K69 (K63-linked chain) (Dvl1) | DIX domain | CYLD (deubiquitinase) | May enhance DVL signaling activity | [79] | ||
- | - | KLHL12-Cullin-3/ITCH/NEDD4L/pVHL/Malin/NEDL1 | Targets for degradation | |||
β-catenin | Phosphorylation | S45 | - | CK1 | Primes phosphorylation by GSK3 | [12] |
S33/S37/T41 | - | GSK3 | Required for β-TrCP recognition | |||
S675 | - | PKA | Increases stability | [88] | ||
S552 | Armadillo (ARM) repeats domain | AKT | Promotes β-catenin disassociation from cell-cell contact and accumulation in both the cytosol and nucleus | [89] | ||
S191/S605 | ARM repeats domain | JNK2 | Critical for β-catenin nuclear localization | [90] | ||
T120 | - | PKD1 | May suppress β-catenin transcription activity | [91] | ||
Ubiquitination | K19/K49 (K48-linked chain) | - | β-TrCP | Targets for degradation | ||
- (K11/K29-linked chain) | - | EDD | Increases stability | [97] | ||
K394 (K63-linked chain) | - | Rad6B (ubiquitin conjugating enzyme) | Increases stability | |||
- (K11/K63-linked chain) | - | FANCL | May increase β-catenin expression and activity | [100] | ||
- | - | Jade-1 | Targets for degradation | [101] | ||
Acetylation | K49 | - | CBP | Inhibits β-catenin ability to activate c-myc gene | [102] | |
K345 | ARM repeats domain | P300 | Enhances β-catenin interaction with TCF-4 | [103] | ||
K19/K49 | - | PCAF | Increases stability | [104] | ||
TCF/LEF | Phosphorylation | T155/S166 (LEF-1) | - | Nemo-like kinase | Inhibits DNA binding of TCF/β-catenin complex | |
T178/T189 (TCF4) | ||||||
S154 (TCF4) | - | TNIK | Required for TCF4 transcriptional activity | |||
- | - | GSK3/CK1ϵ | Inhibits/enhances TCF3 interaction with β-catenin | [109] | ||
S42/S61 (LEF-1) | β-catenin binding domain | CK2 | Enhances LEF-1 binding to β-catenin and transactivation | [110] | ||
S40 (murine LEF-1) | β-catenin binding domain | CKIδ | Disrupts LEF-1/β-catenin complex | [111] | ||
S147/S149/T170/S181/ T184/S190 (Xenopus TCF3) | - | HIPK2 | Promotes dissociation of TCF/LEF from promoter DNA | |||
S130/T153/S164 (mouse LEF-1) | ||||||
Acetylation | K25 (Drosophila TCF) | β-catenin binding domain | CBP | Decreases the affinity of β-catenin to TCF | [114] | |
K185/K187/K188 (POP1) | - | CBP/p300 | Required for POP1 nuclear localization and biological activity | [115] | ||
Lys150 (TCF4E2) | - | CBP | Releases inhibition by HBP1 repressor | [116] | ||
- | - | CBP/p300 | - | [116] | ||
Sumoylation | K25/K267 (Mouse LEF-1) | β-catenin binding domain (K25) | PIASy | May repress LEF-1 activity by targeting LEF-1 to nuclear bodies | [117] | |
K297 (TCF4) | - | PIASy, Axam | Activates β-catenin-dependent transcriptional activity of TCF4 | [118] | ||
Ubiquitination | - | - | NARF | Targets for degradation |