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 posttranscriptional control 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 an AU-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

Scheme of PI3K-AKT signaling

Cross-talks between Wnt and PI3K-AKT pathway Akt phosphorylates  -catenin, which results in  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

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 and Affects Its mRNA-Destabilizing Function

AKT Activation Affects KSRP-Exosome Interaction GST-KH1-4

KSRP P P KSRP P KSRP P PARN KSRP P AAAAAAAAAAAA ARE AKT Summary AKT phosphorylates KSRP, induces its interaction with , and prevents KSRP interaction with the exosome. Decay of  -catenin mRNA by KSRP is inactivated.