Fatty acid modification of Wnt1 and Wnt3a at serine is prerequisite for lipidation at cysteine and is essential for Wnt signalling.
The Wnt family of proteins is a group of extracellular signalling molecules that regulate cell-fate decisions in developing and adult tissues. It is presumed that all 19 mammalian Wnt family members contain two types of post-translational modification: the covalent attachment of fatty acids at two distinct positions, and the N-glycosylation of multiple asparagines. We examined how these modifications contribute to the secretion, extracellular movement and signalling activity of mouse Wnt1 and Wnt3a ligands. We revealed that O-linked acylation of serine is required for the subsequent S-palmitoylation of cysteine. As such, mutant proteins that lack the crucial serine residue are not lipidated. Interestingly, although double-acylation of Wnt1 was indispensable for signalling in mammalian cells, in Xenopus embryos the S-palmitoyl-deficient form retained the signalling activity. In the case of Wnt3a, the functional duality of the attached acyls was less prominent, since the ligand lacking S-linked palmitate was still capable of signalling in various cellular contexts. Finally, we show that the signalling competency of both Wnt1 and Wnt3a is related to their ability to associate with the extracellular matrix.
Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Videnska 1083, 142 20 Prague 4, Czech Republic.
Lenka
L
Doubravska
Michaela
M
Krausova
Dietmar
D
Gradl
Martina
M
Vojtechova
Lucie
L
Tumova
Jan
J
Lukas
Tomas
T
Valenta
Vendula
V
Pospichalova
Bohumil
B
Fafilek
Jiri
J
Plachy
Ondrej
O
Sebesta
Vladimir
V
Korinek
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D002460:Cell Line; D003545:Cysteine / Q000378:metabolism*; D047108:Embryonic Development; D006801:Humans; D054878:Lipoylation; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D051381:Rats; D012694:Serine / Q000378:metabolism*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D051155:Wnt1 Protein / Q000235:genetics / Q000378:metabolism*; D060508:Wnt3 Protein; D060509:Wnt3A Protein; D014981:Xenopus / Q000196:embryology / Q000378:metabolism; D029867:Xenopus Proteins
C555506:WNT3A protein, Xenopus; C555510:WNT3A protein, human; D051153:Wnt Proteins; D051155:Wnt1 Protein; C495246:Wnt1 protein, mouse; D060508:Wnt3 Protein; D060509:Wnt3A Protein; C555511:Wnt3a protein, mouse; D029867:Xenopus Proteins; D012694:Serine; D003545:Cysteine