PMID- 31061124
OWN - NLM
STAT- MEDLINE
DCOM- 20200326
LR  - 20221017
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 116
IP  - 21
DP  - 2019 May 21
TI  - Wnt canonical pathway activates macropinocytosis and lysosomal degradation of 
      extracellular proteins.
PG  - 10402-10411
LID - 10.1073/pnas.1903506116 [doi]
AB  - Canonical Wnt signaling is emerging as a major regulator of endocytosis. Wnt 
      treatment markedly increased the endocytosis and degradation in lysosomes of BSA. 
      In this study, we report that in addition to receptor-mediated endocytosis, Wnt 
      also triggers the intake of large amounts of extracellular fluid by 
      macropinocytosis, a nonreceptor-mediated actin-driven process. Macropinocytosis 
      induction is rapid and independent of protein synthesis. In the presence of Wnt, 
      large amounts of nutrient-rich packages such as proteins and glycoproteins were 
      channeled into lysosomes after fusing with smaller receptor-mediated vesicles 
      containing glycogen synthase kinase 3 (GSK3) and protein arginine 
      ethyltransferase 1 (PRMT1), an enzyme required for canonical Wnt signaling. 
      Addition of Wnt3a, as well as overexpression of Disheveled (Dvl), Frizzled (Fz8), 
      or dominant-negative Axin induced endocytosis. Depletion of the tumor suppressors 
      adenomatous polyposis coli (APC) or Axin dramatically increased macropinocytosis, 
      defined by incorporation of the high molecular weight marker tetramethylrhodamine 
      (TMR)-dextran and its blockage by the Na(+)/H(+) exchanger ethylisopropyl 
      amiloride (EIPA). Macropinocytosis was blocked by dominant-negative vacuolar 
      protein sorting 4 (Vps4), indicating that the Wnt pathway is dependent on 
      multivesicular body formation, a process called microautophagy. SW480 colorectal 
      cancer cells displayed constitutive macropinocytosis and increased extracellular 
      protein degradation in lysosomes, which were suppressed by restoring full-length 
      APC. Accumulation of the transcriptional activator beta-catenin in the nucleus of 
      SW480 cells was inhibited by methyltransferase inhibition, EIPA, or the diuretic 
      amiloride. The results indicate that Wnt signaling switches metabolism toward 
      nutrient acquisition by engulfment of extracellular fluids and suggest possible 
      treatments for Wnt-driven cancer progression.
CI  - Copyright (c) 2019 the Author(s). Published by PNAS.
FAU - Tejeda-Munoz, Nydia
AU  - Tejeda-Munoz N
AD  - Howard Hughes Medical Institute, University of California, Los Angeles, CA 
      90095-1662.
AD  - Department of Biological Chemistry, University of California, Los Angeles, CA 
      90095-1662.
FAU - Albrecht, Lauren V
AU  - Albrecht LV
AD  - Howard Hughes Medical Institute, University of California, Los Angeles, CA 
      90095-1662.
AD  - Department of Biological Chemistry, University of California, Los Angeles, CA 
      90095-1662.
FAU - Bui, Maggie H
AU  - Bui MH
AD  - Howard Hughes Medical Institute, University of California, Los Angeles, CA 
      90095-1662.
AD  - Department of Biological Chemistry, University of California, Los Angeles, CA 
      90095-1662.
FAU - De Robertis, Edward M
AU  - De Robertis EM
AD  - Howard Hughes Medical Institute, University of California, Los Angeles, CA 
      90095-1662; ederobertis@mednet.ucla.edu.
AD  - Department of Biological Chemistry, University of California, Los Angeles, CA 
      90095-1662.
LA  - eng
GR  - F32 GM123622/GM/NIGMS NIH HHS/United States
GR  - UL1 TR000124/TR/NCATS NIH HHS/United States
GR  - HHMI/Howard Hughes Medical Institute/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20190506
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Axin Protein)
RN  - 0 (Glycoproteins)
RN  - 0 (Trans-Activators)
RN  - 0 (Wnt Proteins)
RN  - 0 (beta Catenin)
RN  - EC 2.1.1.319 (Protein-Arginine N-Methyltransferases)
RN  - EC 2.7.11.26 (Glycogen Synthase Kinase 3)
SB  - IM
MH  - Animals
MH  - Axin Protein/metabolism
MH  - Cell Line
MH  - Cell Line, Tumor
MH  - Endocytosis/physiology
MH  - Glycogen Synthase Kinase 3/metabolism
MH  - Glycoproteins/metabolism
MH  - HeLa Cells
MH  - Humans
MH  - Lysosomes/*metabolism
MH  - Mice
MH  - NIH 3T3 Cells
MH  - Neoplasms/metabolism
MH  - Pinocytosis/*physiology
MH  - Protein-Arginine N-Methyltransferases/metabolism
MH  - Trans-Activators/metabolism
MH  - Wnt Proteins/*metabolism
MH  - Wnt Signaling Pathway/*physiology
MH  - beta Catenin/metabolism
PMC - PMC6534993
OTO - NOTNLM
OT  - ESCRT
OT  - Wnt-STOP
OT  - adenomatous polyposis coli
OT  - arginine methylation
OT  - macropinocytosis
COIS- The authors declare no conflict of interest.
EDAT- 2019/05/08 06:00
MHDA- 2020/03/27 06:00
PMCR- 2019/05/06
CRDT- 2019/05/08 06:00
PHST- 2019/05/08 06:00 [pubmed]
PHST- 2020/03/27 06:00 [medline]
PHST- 2019/05/08 06:00 [entrez]
PHST- 2019/05/06 00:00 [pmc-release]
AID - 1903506116 [pii]
AID - 201903506 [pii]
AID - 10.1073/pnas.1903506116 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2019 May 21;116(21):10402-10411. doi: 
      10.1073/pnas.1903506116. Epub 2019 May 6.