The RNA-Binding Protein KSRP Promotes Decay of
b-Catenin mRNA and Is Inactivated by PI3K-AKT Signaling
Roberto Gherzi et al. PLoS Biol. (2006)
Decay of ARE-containing mRNA
AU-rich element (AREs), located in the 3’untranslated region (3’UTR) of
many short-lived transcripts, promote mRNA degradation.
The process of mRNA decay is integral to the posttranscriptional
control of gene expression.
Carol J. Wilusz and Jeffrey Wilusz. Trends Genet. (2004)
What is KSRP?
FBP2 was identified as an ARE-BP in Jurkat cell extracts that could be
UV cross-linked to the IL-2 3’UTR.
FBP2 is also known as KH-type splicing regulatory protein (KSRP).
Dean JL. et al. Cell Signal. (2004 )
Function of KSRP
KSRP, a KH domain-containing ARE-BP, is an essential factor for
ARE-directed mRNA decay.
Gherzi R. et al. Mol Cell. (2004)
Hall MP. et al. Mol Biol Cell. (2004)
KSRP targets c-fos, NOSII, TNF-a, IL-2 mRNA for rapid degradation by binding to an
AU-rich element (ARE).
Barreau C. et al. Nucleic Acids Res. (2006)
p38-dependent phosphorylation of the mRNA decay-promoting factor KSRP
controls the stability of select myogenic transcripts
Briata P. et al. Mol Cell. (2005)
Scheme of PI3K-AKT signaling
http://www.cellsignal.com/reference/pathway/pdfs/Akt_PKB.pdf
Cross-talks between Wnt and PI3K-AKT pathway
Activated Akt by Wnt bound to the Axin-GSK3b complex in the presence of Dvl,
phosphorylated GSK3b and increased free b-catenin levels.
Fukumoto S. et al. J Biol Chem. (2001)
Insulin and IGF-1 to activate the b-catenin pathway through GSK-3b inhibition
by PI3K-AKT pathway.
Desbois-Mouthon C. et al. Oncogene. (2001)
Akt phosphorylates b-catenin, which results in 14-3-3z binding and
stabilization of b-catenin.
Tian Q. et al. Proc Natl Acad Sci U S A. (2004)
Wnt proteins prolong the survival of osteoblasts and uncommitted osteoblast
progenitors via activation of the Src/ERK and PI3K/Akt signaling cascades.
Almeida M. et al. J Biol Chem. (2005)
The phosphatidyl inositol 3 kinases (PI3K)-Akt pathway is also involved in
the Wnt3a-induced proliferation.
Kim SE. et al. Cell Signal. (2006)
mRNA Encoding b-Catenin Is Labile and Is Stabilized by LiCl and Wnt-3A
PI3K-AKT Signaling Stabilizes b-Catenin mRNA and Increases Its Expression
PI3K-AKT Signaling Stabilizes b-Catenin mRNA and Increases Its Expression
Insulin Stabilizes b-Catenin mRNA and Increases Its Expression
KSRP Is Phosphorylated by AKT in Serine 193
KSRP Is Required for b-Catenin mRNA Degradation
KSRP Phosphorylation by AKT Promotes Its Interaction with 14-3-3 and
Affects Its mRNA-Destabilizing Function
AKT Activation Affects KSRP-Exosome Interaction
GST-KH1-4
Summary
AKT
KSRP
P
KSRP
14-3-3
P
KSRP
14-3-3
14-3-3
P
KSRP
P
KSRP
14-3-3
P
KSRP PARN
ARE
AAAAAAAAAAAA
AKT phosphorylates KSRP, induces its interaction with 14-3-3,
and prevents KSRP interaction with the exosome.
Decay of b-catenin mRNA by KSRP is inactivated.