The RNA-Binding Protein KSRP Promotes Decay of

-Catenin mRNA and Is Inactivated by PI3K-AKT Signaling

Roberto Gherzi et al. PLoS Biol. (2006)

Carol J. Wilusz and Jeffrey Wilusz. Trends Genet. (2004)

Decay of ARE-containing mRNA

The process of mRNA decay is integral to the posttranscriptionalcontrol of gene expression.

AU-rich element (AREs), located in the 3’untranslated region (3’UTR) of many short-lived transcripts, promote mRNA degradation.

FBP2 is also known as KH-type splicing regulatory protein (KSRP).

FBP2 was identified as an ARE-BP in Jurkat cell extracts that could be

UV cross-linked to the IL-2 3’UTR.

What is KSRP?

Dean JL. et al. Cell Signal. (2004 )

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)

KSRP targets c-fos, NOSII, TNF-, IL-2 mRNA for rapid degradation by binding to anAU-rich element (ARE).

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)

Function of KSRP

http://www.cellsignal.com/reference/pathway/pdfs/Akt_PKB.pdf

Scheme of PI3K-AKT signaling

Cross-talks between Wnt and PI3K-AKT pathway

Akt phosphorylates -catenin, which results in 14-3-3 binding and stabilization of -catenin.

Tian Q. et al. Proc Natl Acad Sci U S A. (2004)

Activated Akt by Wnt bound to the Axin-GSK3 complex in the presence of Dvl, phosphorylated GSK3 and increased free -catenin levels.

Fukumoto S. et al. J Biol Chem. (2001)

Insulin and IGF-1 to activate the -catenin pathway through GSK-3 inhibition by PI3K-AKT pathway.

Desbois-Mouthon C. et al. Oncogene. (2001)

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 -Catenin Is Labile and Is Stabilized by LiCl and Wnt-3A

PI3K-AKT Signaling Stabilizes -Catenin mRNA and Increases Its Expression

PI3K-AKT Signaling Stabilizes -Catenin mRNA and Increases Its Expression

Insulin Stabilizes -Catenin mRNA and Increases Its Expression

KSRP Is Phosphorylated by AKT in Serine 193

KSRP Is Required for -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

KSRP KSRPP

KSRP

14-3-3P

KSRP

14-3-3P

KSRP

14-3-3P

PARNKSRP

14-3-3P

AAAAAAAAAAAAARE

AKT

Summary

AKT phosphorylates KSRP, induces its interaction with 14-3-3, and prevents KSRP interaction with the exosome.

Decay of -catenin mRNA by KSRP is inactivated.