Reactome | FRAT proteins bind GSK3beta

FRAT proteins bind GSK3beta

Stable Identifier

R-HSA-5323526

Type

Reaction

Species

Homo sapiens

Compartment

cytosol

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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