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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]