FRAT proteins bind GSK3beta

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Homo sapiens
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The FRAT genes, which were initially identified as a target of Frequent Rearrangement in Advanced T-cell lymphoma, encode potent activators of canonical WNT signaling and are highly conserved in vertebrates. Xenopus and zebrafish each have one FRAT gene, while the human and mouse genomes contains two and three, respectively (Jonkers et al, 1997; reviewed in van Amerongen and Berns, 2005). Frat proteins activate WNT signaling by binding to GSK3beta and inhibiting its phosphorylation of beta-catenin (Yost et al, 1998; van Amerongen et al, 2004). The interaction with GSK3beta is mediated by a highly conserved IKEA box in the C-terminal domain of FRAT (Yost et al, 1998; van Amerongen et al, 2004; Thomas et al, 1999). This region of FRAT is able to compete with AXIN for binding to GSK3beta, suggesting a model where FRAT is able to destabilize the destruction complex by abrogating the GSK3beta-AXIN interaction (Farr et al, 2000; Thomas et al, 1999; Fraser at el, 2002; Ferkey et al, 2002). This model is supported by structural studies showing that AXIN and FRAT bind to the same region on the surface of GSK3beta (Bax et al, 2001; Dajani et al, 2003). Endogenous FRAT1 has also been shown to interact with DVL3, and this reaction persists in a FRAT1 mutant lacking the GSK3beta-interacting domain (Li et al, 1999). FRAT proteins may thus help bridge between GSK3beta’s role in the destruction complex and its role in activating signaling in response to WNT.

Despite the apparent importance of FRAT proteins in beta-catenin-dependent signaling, a triple FRAT knockout mouse shows no readily evident defects in canonical signaling and, unlike the GBP knockout in Xenopus, no overt phenotypic defects (van Amerongen et al, 2005; Yost et al, 1989). The in vivo role and significance of the FRAT proteins in WNT signaling remains to be resolved; it is worth noting, however, that FRAT proteins have also recently been shown to be involved in non-canonical WNT signaling in a GSK3beta-independent manner. It is possible that it is through this non-canonical role that FRAT proteins contribute to oncogenesis (van Amerongen et al, 2010; Walf-Vorderwülbecke et al, 2012).

Literature References
PubMed ID Title Journal Year
10481074 A GSK3-binding peptide from FRAT1 selectively inhibits the GSK3-catalysed phosphorylation of axin and beta-catenin

Polakis, P, Thomas, GM, Nathke, I, Goedert, M, Cohen, P, Frame, S

FEBS Lett. 1999
10684251 Interaction among GSK-3, GBP, axin, and APC in Xenopus axis specification

Farr, GH, Weaver, C, Pierce, SB, Kimelman, D, Yost, C, Ferkey, DM

J. Cell Biol. 2000
12554650 Structural basis for recruitment of glycogen synthase kinase 3beta to the axin-APC scaffold complex

Roe, SM, Pearl, LH, Yeo, M, Fraser, E, Dajani, R, Dale, TC, Good, VM, Thompson, V

EMBO J 2003
11707456 Identification of the Axin and Frat binding region of glycogen synthase kinase-3

Webster, MT, Smalley, MJ, Dale, TC, Harwood, A, Franca-Koh, J, Ryves, J, Richardson, C, Yeo, M, Dajani, R, Pearl, LH, Williams, RS, Fraser, E, Young, N

J. Biol. Chem. 2002
11861647 Glycogen synthase kinase-3 beta mutagenesis identifies a common binding domain for GBP and Axin

Kimelman, D, Ferkey, DM

J. Biol. Chem. 2002
11738041 The structure of phosphorylated GSK-3beta complexed with a peptide, FRATtide, that inhibits beta-catenin phosphorylation

Reith, AD, Pettman, G, Bax, B, Culbert, AA, Tanner, R, Bridges, A, Lewis, C, Guy, AR, Mannix, C, Carter, PS, Brown, MJ, Smith, DG

Structure 2001
9635432 GBP, an inhibitor of GSK-3, is implicated in Xenopus development and oncogenesis

Farr, GH, Chen, MM, Pierce, SB, Kimelman, D, Ferkey, DM, Yost, C

Cell 1998
23074275 Frat2 mediates the oncogenic activation of Rac by MLL fusions

Horton, SJ, Proost, N, Walf-Vorderwülbecke, V, de Boer, J, van Amerongen, R, Williams, O, Berns, A

Blood 2012
19802005 Frat oncoproteins act at the crossroad of canonical and noncanonical Wnt-signaling pathways

Proost, N, Lambooij, JP, van Amerongen, R, Jonkers, J, Berns, A, Nawijn, MC

Oncogene 2010
15681612 Frat is dispensable for canonical Wnt signaling in mammals

van der Gulden, H, Zevenhoven, J, van Amerongen, R, Jonkers, J, Franca-Koh, J, Nawijn, M, Berns, A

Genes Dev. 2005
16082208 Re-evaluating the role of Frat in Wnt-signal transduction

van Amerongen, R, Berns, A

Cell Cycle 2005
15073180 Characterization and functional analysis of the murine Frat2 gene

van der Gulden, H, van Amerongen, R, Jonkers, J, Bleeker, F, Berns, A

J. Biol. Chem. 2004
10428961 Axin and Frat1 interact with dvl and GSK, bridging Dvl to GSK in Wnt-mediated regulation of LEF-1

Farr, GH, Weaver, CD, Li, L, Sussman, DJ, Mao, J, Jonkers, J, Yuan, H, Wu, D, Kimelman, D

EMBO J. 1999
9034327 Activation of a novel proto-oncogene, Frat1, contributes to progression of mouse T-cell lymphomas

Korswagen, HC, Breuer, M, Acton, D, Jonkers, J, Berns, A

EMBO J. 1997
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