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Table 1 Summary of PTMs of Wnt/β-catenin pathway components

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 [27, 28]
- - 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 [3235]
T1493 ICD CK1α,γ,ϵ,δ Recruits Axin and promotes Wnt/β-catenin signaling [31, 32]
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 [44, 45]
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 [5054]
Y279 (GSK3α)/Y216 (GSK3β) Kinase domain PYK2/GSK3 May have impact on GSK3 activity [5557]
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 [6365]
S1279/S1392 - CK1ϵ Essential for the regulatory activity of APC towards β-catenin [66]
Ubiquitination - - USP15 (deubiquitinase) Targets for degradation [67, 68]
- (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 - [75, 76]
- - 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 [8085]
β-catenin Phosphorylation S45 - CK1 Primes phosphorylation by GSK3 [12]
S33/S37/T41 - GSK3 Required for β-TrCP recognition [12, 86, 87]
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 [14, 9296]
- (K11/K29-linked chain) - EDD Increases stability [97]
K394 (K63-linked chain) - Rad6B (ubiquitin conjugating enzyme) Increases stability [98, 99]
- (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 [105, 106]
T178/T189 (TCF4)
S154 (TCF4) - TNIK Required for TCF4 transcriptional activity [107, 108]
- - 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 [112, 113]
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 [119, 120]