PMID- 24752894
OWN - NLM
STAT- MEDLINE
DCOM- 20140731
LR  - 20211021
IS  - 1098-5549 (Electronic)
IS  - 0270-7306 (Print)
IS  - 0270-7306 (Linking)
VI  - 34
IP  - 13
DP  - 2014 Jul
TI  - The canonical wnt signal restricts the glycogen synthase kinase 3/fbw7-dependent 
      ubiquitination and degradation of eya1 phosphatase.
PG  - 2409-17
LID - 10.1128/MCB.00104-14 [doi]
AB  - Haploinsufficiency of Eya1 causes the branchio-oto-renal (BOR) syndrome, and 
      abnormally high levels of Eya1 are linked to breast cancer progression and poor 
      prognosis. Therefore, regulation of Eya1 activity is key to its tissue-specific 
      functions and oncogenic activities. Here, we show that Eya1 is 
      posttranslationally modified by ubiquitin and that its ubiquitination level is 
      self-limited to prevent premature degradation. Eya1 has an evolutionarily 
      conserved CDC4 phosphodegron (CPD) signal, a target site of glycogen synthase 
      kinase 3 (GSK3) kinase and Fbw7 ubiquitin ligase, which is required for Eya1 
      ubiquitination. Genetic deletion of Fbw7 and pharmacological inhibition of GSK3 
      significantly decrease Eya1 ubiquitination. Conversely, activation of the 
      phosphatidylinositol 3-kinase (PI3K)/Akt and the canonical Wnt signal suppresses 
      Eya1 ubiquitination. Compound Eya1(+/-); Wnt9b(+/-) mutants exhibit an increased 
      penetrance of renal defect, indicating that they function in the same genetic 
      pathway in vivo. Together, these findings reveal that the canonical Wnt and 
      PI3K/Akt signal pathways restrain the GSK3/Fbw7-dependent Eya1 ubiquitination, 
      and they further suggest that dysregulation of this novel axis contributes to 
      tumorigenesis.
CI  - Copyright (c) 2014, American Society for Microbiology. All Rights Reserved.
FAU - Sun, Ye
AU  - Sun Y
AD  - Urological Diseases Research Center, Boston Children's Hospital, and Departments 
      of Surgery and Pathology, Harvard Medical School, Boston, Massachusetts, USA.
FAU - Li, Xue
AU  - Li X
AD  - Urological Diseases Research Center, Boston Children's Hospital, and Departments 
      of Surgery and Pathology, Harvard Medical School, Boston, Massachusetts, USA 
      sean.li@childrens.harvard.edu.
LA  - eng
GR  - P50DK65298/DK/NIDDK NIH HHS/United States
GR  - R01 DE019823/DE/NIDCR NIH HHS/United States
GR  - P30 HD018655/HD/NICHD NIH HHS/United States
GR  - R01DK916451/DK/NIDDK NIH HHS/United States
GR  - R01 DK091645/DK/NIDDK NIH HHS/United States
GR  - P50 DK065298/DK/NIDDK NIH HHS/United States
GR  - 1R01DE019823/DE/NIDCR NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20140421
PL  - United States
TA  - Mol Cell Biol
JT  - Molecular and cellular biology
JID - 8109087
RN  - 0 (F-Box Proteins)
RN  - 0 (F-Box-WD Repeat-Containing Protein 7)
RN  - 0 (Fbxw7 protein, mouse)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Ubiquitin)
RN  - EC 2.3.2.27 (Ubiquitin-Protein Ligases)
RN  - EC 2.7.1.137 (Phosphatidylinositol 3-Kinase)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.26 (Glycogen Synthase Kinase 3)
RN  - EC 3.1.3.48 (Eya1 protein, mouse)
RN  - EC 3.1.3.48 (Protein Tyrosine Phosphatases)
SB  - IM
MH  - Animals
MH  - Branchio-Oto-Renal Syndrome/genetics
MH  - Cell Line
MH  - Cell Transformation, Neoplastic/*genetics
MH  - Enzyme Activation
MH  - F-Box Proteins/*antagonists & inhibitors/genetics
MH  - F-Box-WD Repeat-Containing Protein 7
MH  - Glycogen Synthase Kinase 3/*antagonists & inhibitors/genetics
MH  - HCT116 Cells
MH  - Humans
MH  - Intracellular Signaling Peptides and Proteins/genetics/*metabolism
MH  - Mice
MH  - Nuclear Proteins/genetics/*metabolism
MH  - Phosphatidylinositol 3-Kinase/metabolism
MH  - Protein Processing, Post-Translational
MH  - Protein Tyrosine Phosphatases/genetics/*metabolism
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Ubiquitin
MH  - Ubiquitin-Protein Ligases/*antagonists & inhibitors/genetics
MH  - *Ubiquitination
MH  - Wnt Signaling Pathway/*genetics
PMC - PMC4054306
EDAT- 2014/04/23 06:00
MHDA- 2014/08/01 06:00
PMCR- 2015/01/01
CRDT- 2014/04/23 06:00
PHST- 2014/04/23 06:00 [entrez]
PHST- 2014/04/23 06:00 [pubmed]
PHST- 2014/08/01 06:00 [medline]
PHST- 2015/01/01 00:00 [pmc-release]
AID - MCB.00104-14 [pii]
AID - 00104-14 [pii]
AID - 10.1128/MCB.00104-14 [doi]
PST - ppublish
SO  - Mol Cell Biol. 2014 Jul;34(13):2409-17. doi: 10.1128/MCB.00104-14. Epub 2014 Apr 
      21.