PMID- 23555187
OWN - NLM
STAT- MEDLINE
DCOM- 20130918
LR  - 20211021
IS  - 1476-5586 (Electronic)
IS  - 1522-8002 (Print)
IS  - 1476-5586 (Linking)
VI  - 15
IP  - 4
DP  - 2013 Apr
TI  - gamma-Catenin at adherens junctions: mechanism and biologic implications in 
      hepatocellular cancer after beta-catenin knockdown.
PG  - 421-34
AB  - beta-Catenin is important in liver homeostasis as a part of Wnt signaling and 
      adherens junctions (AJs), while its aberrant activation is observed in 
      hepatocellular carcinoma (HCC). We have reported hepatocyte-specific beta-catenin 
      knockout (KO) mice to lack adhesive defects as gamma-catenin compensated at AJ. 
      Because gamma-catenin is a desmosomal protein, we asked if its increase in KO might 
      deregulate desmosomes. No changes in desmosomal proteins or ultrastructure other 
      than increased plakophilin-3 were observed. To further elucidate the role and 
      regulation of gamma-catenin, we contemplate an in vitro model and show gamma-catenin 
      increase in HCC cells upon beta-catenin knockdown (KD). Here, gamma-catenin is unable to 
      rescue beta-catenin/T cell factor (TCF) reporter activity; however, it sufficiently 
      compensates at AJs as assessed by scratch wound assay, centrifugal assay for cell 
      adhesion (CAFCA), and hanging drop assays. gamma-Catenin increase is observed only 
      after beta-catenin protein decrease and not after blockade of its transactivation. 
      gamma-Catenin increase is associated with enhanced serine/threonine phosphorylation 
      and abrogated by protein kinase A (PKA) inhibition. In fact, several PKA-binding 
      sites were detected in gamma-catenin by in silico analysis. Intriguingly gamma-catenin KD 
      led to increased beta-catenin levels and transactivation. Thus, gamma-catenin 
      compensates for beta-catenin loss at AJ without affecting desmosomes but is unable 
      to fulfill functions in Wnt signaling. gamma-Catenin stabilization after beta-catenin 
      loss is brought about by PKA. Catenin-sensing mechanism may depend on absolute 
      beta-catenin levels and not its activity. Anti-beta-catenin therapies for HCC affecting 
      total beta-catenin may target aberrant Wnt signaling without negatively impacting 
      intercellular adhesion, provided mechanisms leading to gamma-catenin stabilization 
      are spared.
FAU - Wickline, Emily Diane
AU  - Wickline ED
AD  - Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, 
      PA, USA.
FAU - Du, Yu
AU  - Du Y
FAU - Stolz, Donna B
AU  - Stolz DB
FAU - Kahn, Michael
AU  - Kahn M
FAU - Monga, Satdarshan P S
AU  - Monga SP
LA  - eng
GR  - 1R01CA124414/CA/NCI NIH HHS/United States
GR  - R01 DK100287/DK/NIDDK NIH HHS/United States
GR  - 1R01DK62277/DK/NIDDK NIH HHS/United States
GR  - R01 CA124414/CA/NCI NIH HHS/United States
GR  - R01 DK062277/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Neoplasia
JT  - Neoplasia (New York, N.Y.)
JID - 100886622
RN  - 0 (Desmogleins)
RN  - 0 (Desmoplakins)
RN  - 0 (JUP protein, human)
RN  - 0 (PKP3 protein, human)
RN  - 0 (Plakophilins)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (beta Catenin)
RN  - 0 (gamma Catenin)
RN  - EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases)
RN  - EC 2.7.11.12 (Cyclic GMP-Dependent Protein Kinases)
SB  - IM
MH  - Adherens Junctions/*metabolism
MH  - Animals
MH  - Cell Adhesion
MH  - Cell Membrane/metabolism
MH  - Cell Movement
MH  - Cyclic AMP-Dependent Protein Kinases/metabolism
MH  - Cyclic GMP-Dependent Protein Kinases/metabolism
MH  - Desmogleins/metabolism
MH  - Desmoplakins/genetics/*metabolism
MH  - Desmosomes/metabolism
MH  - Gene Expression
MH  - Gene Knockdown Techniques
MH  - Hep G2 Cells
MH  - Humans
MH  - Liver Neoplasms
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Phosphorylation
MH  - Plakophilins/metabolism
MH  - Protein Processing, Post-Translational
MH  - Protein Stability
MH  - RNA, Small Interfering/genetics
MH  - Wnt Signaling Pathway
MH  - beta Catenin/*genetics/metabolism
MH  - gamma Catenin
PMC - PMC3612914
EDAT- 2013/04/05 06:00
MHDA- 2013/09/21 06:00
PMCR- 2013/04/01
CRDT- 2013/04/05 06:00
PHST- 2012/12/11 00:00 [received]
PHST- 2013/01/29 00:00 [revised]
PHST- 2013/01/30 00:00 [accepted]
PHST- 2013/04/05 06:00 [entrez]
PHST- 2013/04/05 06:00 [pubmed]
PHST- 2013/09/21 06:00 [medline]
PHST- 2013/04/01 00:00 [pmc-release]
AID - 122098 [pii]
AID - 10.1593/neo.122098 [doi]
PST - ppublish
SO  - Neoplasia. 2013 Apr;15(4):421-34. doi: 10.1593/neo.122098.