PMID- 36484635
OWN - NLM
STAT- MEDLINE
DCOM- 20221220
LR  - 20221222
IS  - 1470-8752 (Electronic)
IS  - 0300-5127 (Linking)
VI  - 50
IP  - 6
DP  - 2022 Dec 16
TI  - Functional regulation of Wnt protein through post-translational modifications.
PG  - 1797-1808
LID - 10.1042/BST20220735 [doi]
AB  - Wnts are lipid-modified signaling glycoproteins present in all metazoans that 
      play key roles in development and homeostasis. Post-translational modifications 
      of Wnts regulate their function. Wnts have a unique post-translational 
      modification, O-linked palmitoleation, that is absolutely required for their 
      function. This Wnt-specific modification occurs during Wnt biosynthesis in the 
      endoplasmic reticulum (ER), catalyzed by the O-acyltransferase Porcupine (PORCN). 
      Palmitoleation is required for Wnt to bind to its transporter Wntless (WLS/Evi) 
      as well as to its receptor Frizzled (FZD). Recent structural studies have 
      illustrated how PORCN recognizes its substrates, and how drugs inhibit this. The 
      abundance of WLS is tightly regulated by intracellular recycling and 
      ubiquitylation-mediated degradation in the ER. The function of Wnt glycosylation 
      is less well understood, and the sites and types of glycosylation are not largely 
      conserved among different Wnts. In polarized tissues, the type of glycans can 
      determine whether the route of trafficking is apical or basolateral. In addition, 
      pairing of the 24 highly conserved cysteines in Wnts to form disulfide bonds is 
      critical in maintaining proper structure and activities. Extracellularly, the 
      amino terminus of a subset of Wnts can be cleaved by a dedicated 
      glycosylphosphatidylinositol (GPI)-anchored metalloprotease TIKI, resulting in 
      the inactivation of these Wnt proteins. Additionally, NOTUM is a secreted 
      extracellular carboxylesterase that removes the palmitoleate moiety from Wnt, 
      antagonizing its activity. In summary, Wnt signaling activity is controlled at 
      multiple layers by post-translational modifications.
CI  - (c) 2022 The Author(s). Published by Portland Press Limited on behalf of the 
      Biochemical Society.
FAU - Yu, Jia
AU  - Yu J
AD  - Programme in Cancer and Stem Cell Biology, Duke-NUS Medical School, 169857 
      Singapore.
FAU - Virshup, David M
AU  - Virshup DM
AUID- ORCID: 0000-0001-6976-850X
AD  - Programme in Cancer and Stem Cell Biology, Duke-NUS Medical School, 169857 
      Singapore.
AD  - Department of Pediatrics, Duke University School of Medicine, Durham, NC 27710, 
      U.S.A.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Biochem Soc Trans
JT  - Biochemical Society transactions
JID - 7506897
RN  - 0 (Wnt Proteins)
RN  - EC 2.3.- (Acyltransferases)
SB  - IM
MH  - *Wnt Proteins/metabolism
MH  - *Protein Processing, Post-Translational
MH  - Wnt Signaling Pathway
MH  - Acyltransferases/metabolism
MH  - Endoplasmic Reticulum/metabolism
OTO - NOTNLM
OT  - NOTUM
OT  - PORCN
OT  - TIKI
OT  - WLS
OT  - Wnt secretion
OT  - Wnt signaling
EDAT- 2022/12/10 06:00
MHDA- 2022/12/21 06:00
CRDT- 2022/12/09 09:32
PHST- 2022/09/05 00:00 [received]
PHST- 2022/11/10 00:00 [revised]
PHST- 2022/11/21 00:00 [accepted]
PHST- 2022/12/10 06:00 [pubmed]
PHST- 2022/12/21 06:00 [medline]
PHST- 2022/12/09 09:32 [entrez]
AID - 232228 [pii]
AID - 10.1042/BST20220735 [doi]
PST - ppublish
SO  - Biochem Soc Trans. 2022 Dec 16;50(6):1797-1808. doi: 10.1042/BST20220735.