The Structure of Phosphorylated GSK-3β Complexed with a Peptide, FRATtide, that Inhibits β-Catenin Phosphorylation

Bax, Benjamin; Carter, Paul S.; Lewis, Ceri; Guy, A.R.; Bridges, Angela; Tanner, Robert D.; Pettman, Gary; Mannix, C.J.; Culbert, Ainsley A.; Brown, Murray J. B.; Smith, David George Emslie; Reith, Alastair D.

doi:10.1016/s0969-2126(01)00679-7

Cited by 196 publications

(179 citation statements)

References 44 publications

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“…A short peptide (FRATtide) comprising amino-acids 188-226 from human FRAT1 is sufficient to inhibit GSK3 (Thomas et al, 1999;Bax et al, 2001). Mutation of the IKEA-box to IAQA has been shown to disrupt Gsk3b binding in Xenopus GBP (Yost et al, 1998) Frat2, but not Frat1, is expressed at sites of Frizzled/PCP-pathway activity Our in vitro experiments suggested a Gsk3b-independent activity that was more prominent for Frat2 than for (Figure 4).…”

Section: Ap-1 Activation By Frat2 Is Gsk3b Independentmentioning

confidence: 82%

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

et al. 2009

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Wnt-signal transduction is critical for development and tissue homeostasis in a wide range of animal species and is frequently deregulated in human cancers. Members of the Frat/GBP family of glycogen synthase kinase 3b (Gsk3b)-binding oncoproteins are recognized as potent activators of the Wnt/b-catenin pathway in vertebrates. Here, we reveal a novel, Gsk3b-independent function of Frat converging on the activation of JNK and AP-1. Both these have been used as readouts for the noncanonical Frizzled/PCP pathway, which controls polarized cell movements and the establishment of tissue polarity. We find that Frat synergizes with Diversin, the mammalian homolog of the Drosophila PCP protein diego, in the activation of JNK/ AP-1 signaling. Importantly, Frat mutants deficient for binding to Gsk3b retain oncogenic activity in vivo, suggesting that Wnt/b-catenin-independent events contribute to Frat-induced malignant transformation. The observed activities of Frat are reminiscent of the dual function of Dishevelled in the Wnt/b-catenin and Frizzled/ PCP pathways and suggest that Frat may also function to bridge canonical and noncanonical Wnt pathways.

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Section: Ap-1 Activation By Frat2 Is Gsk3b Independentmentioning

confidence: 82%

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

et al. 2009

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“…In addition to MAPKs, insertions in the kinase core between subdomains X and XI are found in the cyclin-dependent kinases and glycogen synthase kinase-3. Xray crystal structures of cyclin-dependent kinase 2 and glycogen synthase kinase-3 in complex with their regulatory factors have also recently demonstrated the functional importance of this region for these kinase families (33)(34)(35). Thus, the insertion in MAPKs and other structurally related serine/threonine kinases may act as a common docking site for a variety of regulatory proteins.…”

Section: Discussionmentioning

confidence: 99%

PEA-15 Binding to ERK1/2 MAPKs Is Required for Its Modulation of Integrin Activation

Chou

Hill

Hsieh

et al. 2003

Journal of Biological Chemistry

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Activation of Raf-1 suppresses integrin activation, potentially through the activation of extracellular signalregulated kinases 1 and 2 (ERK1/2). However, bulk ERK1/2 activation does not correlate with suppression. PEA-15 reverses suppression of integrin activation and binds ERK1/2. Here we report that PEA-15 reversal of integrin suppression depends on its capacity to bind ERK1/2, indicating that ERK1/2 function is indeed required for suppression. Mutations in either the death effector domain or C-terminal tail of PEA-15 that block ERK1/2 binding abrogated the reversal of integrin suppression. Furthermore, we used ERK/p38 chimeras and site-directed mutagenesis to identify ERK1/2 residues required for binding PEA-15. Mutations of residues that precede the ␣G helix and within the mitogenactivated protein kinase insert blocked ERK2 binding to PEA-15, but not activation of ERK2. These ERK2 mutants blocked the ability of PEA-15 to reverse suppression of integrin activation. Thus, PEA-15 regulation of integrin activation depends on its binding to ERK1/2. To directly test the role of ERK1/2 localization in suppression, we enforced membrane association of ERK1 and 2 by joining a membrane-targeting CAAX box sequence to them. Both ERK1-CAAX and ERK2-CAAX were membrane-localized and suppressed integrin activation. In contrast to suppression by membrane-targeted Raf-CAAX, suppression by ERK1/2-CAAX was not reversed by PEA-15. Thus, ERK1/2 are the Raf effectors for suppression of integrin activation, and PEA-15 reverses suppression by binding ERK1/2.

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“…[22][23][24][25] Recent studies revealed that intrinsic disorder is an abundant phenomenon and many proteins lack rigid 3-D structure under physiological conditions in vitro, existing instead as dynamic ensembles of interconverting structures. [26][27][28][29][30] In contrast to ordered proteins whose 3-D structures are relatively stable and whose Ramachandran angles vary slightly around their equilibrium positions with occasional cooperative conformational switches, intrinsically disordered proteins or regions exist as dynamic ensembles in which the atom positions and backbone Ramachandran angles vary significantly over time with no specific equilibrium values and typically undergo non-cooperative conformational changes. 23 Statistical analysis shows that amino acid sequences encoding for the disordered proteins or regions are significantly different from those characteristic for the ordered proteins on the basis of local amino acid composition, flexibility, hydropathy, charge, coordination number and several other factors.…”

Section: Introductionmentioning

confidence: 99%

Conservation of Intrinsic Disorder in Protein Domains and Families: I. A Database of Conserved Predicted Disordered Regions

et al. 2006

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Many protein regions have been shown to be intrinsically disordered, lacking unique structure under physiological conditions. These intrinsically disordered regions are not only very common in proteomes, they are also crucial to the function of many proteins, especially those involved in signaling, recognition, and regulation. The goal of this work was to identify the prevalence, characteristics, and functions of conserved disordered regions within protein domains and families.A database was created to store the amino acid sequences of nearly one million proteins and their domain matches from the InterPro database, a resource integrating eight different protein family and domain databases. Disorder prediction was performed on these protein sequences. Regions of sequence corresponding to domains were aligned using a multiple sequence alignment tool. From this initial information, regions of conserved predicted disorder were found within the domains. The methodology for this search consisted of finding regions of consecutive positions in the multiple sequence alignments in which a 90% or more of the sequences were predicted to be disordered. This procedure was constrained to find such regions of conserved disorder prediction that were at least 20 amino acids in length.The results of this work were 3,653 regions of conserved disorder prediction, found within 2,898 distinct InterPro entries. Most regions of conserved predicted disorder detected were short, with less than 10% of those found exceeding 30 residues in length.

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The Structure of Phosphorylated GSK-3β Complexed with a Peptide, FRATtide, that Inhibits β-Catenin Phosphorylation

Cited by 196 publications

References 44 publications

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

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

PEA-15 Binding to ERK1/2 MAPKs Is Required for Its Modulation of Integrin Activation

Conservation of Intrinsic Disorder in Protein Domains and Families: I. A Database of Conserved Predicted Disordered Regions

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