A GSK3‐binding peptide from FRAT1 selectively inhibits the GSK3‐catalysed phosphorylation of Axin and β‐catenin

Thomas, Gareth M.; Frame, Sheelagh; Goedert, Michel; Näthke, Inke; Polakis, Paul; Cohen, Philip

doi:10.1016/s0014-5793(99)01161-8

Cited by 219 publications

(205 citation statements)

References 35 publications

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“…While the majority of GSK-3β substrates are primed by prior phosphorylation at n + 4 (where n is the site of GSK-3β phosphorylation) (Wang and Roach, 1993;Welsh et al, 1997), GSK-3β can also phosphorylate certain substrates in the absence of a priming event. This is exemplified by the ability of GSK-3β to catalyze phosphorylation of unprimed β-catenin in vitro (Thomas et al, 1999), or phosphorylate cyclin D1 (Diehl et al, 1998), or cyclin D3, as shown in this study, at a location in which the n+4 residue is Val. However, GSK-3β has been shown to have 400-to 1000-fold less activity against unprimed substrates than primed proteins, leading to the suggestion that phosphorylation of unprimed substrates by GSK-3β is an in vitro phenomenon that is brought about by high concentrations of enzyme and substrate used in reactions in vitro (Frame et al, 2001;Thomas et al, 1999).…”

Section: Discussionmentioning

confidence: 69%

“…This is exemplified by the ability of GSK-3β to catalyze phosphorylation of unprimed β-catenin in vitro (Thomas et al, 1999), or phosphorylate cyclin D1 (Diehl et al, 1998), or cyclin D3, as shown in this study, at a location in which the n+4 residue is Val. However, GSK-3β has been shown to have 400-to 1000-fold less activity against unprimed substrates than primed proteins, leading to the suggestion that phosphorylation of unprimed substrates by GSK-3β is an in vitro phenomenon that is brought about by high concentrations of enzyme and substrate used in reactions in vitro (Frame et al, 2001;Thomas et al, 1999). However, through formation of protein complexes in vivo, bringing GSK-3β and its unprimed substrate into close proximity could be assumed to facilitate the phosphorylation of the unprimed substrate by GSK-3β.…”

Section: Discussionmentioning

confidence: 69%

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cAMP-induced degradation of cyclin D3 through association with GSK-3β

Naderi

Gützkow

Låhne

et al. 2004

Journal of Cell Science

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In this study we report a new mechanism whereby cyclic AMP (cAMP) regulates the cell-cycle machinery. We demonstrate that elevation of intracellular levels of cAMP promotes degradation of cyclin D3 in proteasomes, and that this occurs via glycogen synthase kinase-3β (GSK-3β)-mediated phosphorylation of cyclin D3 at Thr-283. Elevation of cAMP did not change the subcellular distribution of either cyclin D3 or GSK-3β. However, cAMP promoted the interaction between cyclin D3 and GSK-3β both in vitro and in vivo, indicating that GSK-3β-mediated phosphorylation of cyclin D3 might require the association between the two proteins. These results demonstrate how cAMP enhances degradation of cyclin D3. Furthermore, we provide evidence for a novel mechanism by which GSK-3β might phosphorylate unprimed substrates in vivo.

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Section: Discussionmentioning

confidence: 69%

Section: Discussionmentioning

confidence: 69%

cAMP-induced degradation of cyclin D3 through association with GSK-3β

Naderi

Gützkow

Låhne

et al. 2004

Journal of Cell Science

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“…This suggests that Dvl may decrease tau phosphorylation by inhibiting the activity of some other protein kinase(s) and/or by increasing the activity of protein phosphatases, in concert with its effects on GSK3b mediated phosphorylation events. Interestingly, Thomas et al (1999) demonstrated that FRATtide (a small fragment from the GSK3b-binding protein FRAT1 that binds GSK3b) decreased tau phosphorylation by GSK3b at nonprimed sites, but not at primed sites. Similar results were obtained when PC12 cells were infected with full-length FRAT1; decreases in tau phosphorylation at unprimed sites were observed (Culbert et al 2001).…”

Section: Discussionmentioning

confidence: 99%

Axin negatively affects tau phosphorylation by glycogen synthase kinase 3β

Stoothoff¹,

Bailey²,

Mi³

et al. 2002

Journal of Neurochemistry

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Glycogen synthase kinase 3b (GSK3b) is an essential protein kinase that regulates numerous functions within the cell. One critically important substrate of GSK3b is the microtubuleassociated protein tau. Phosphorylation of tau by GSK3b decreases tau-microtubule interactions. In addition to phosphorylating tau, GSK3b is a downstream regulator of the wnt signaling pathway, which maintains the levels of b-catenin. Axin plays a central role in regulating b-catenin levels by bringing together GSK3b and b-catenin and facilitating the phosphorylation of b-catenin, targeting it for ubiquitination and degradation by the proteasome. Although axin clearly facilitates the phosphorylation of b-catenin, its effects on the phosphorylation of other GSK3b substrates are unclear.Therefore in this study the effects of axin on GSK3b-mediated tau phosphorylation were examined. The results clearly demonstrate that axin is a negative regulator of tau phosphorylation by GSK3b. This negative regulation of GSK3b-mediated tau phosphorylation is due to the fact that axin efficiently binds GSK3b but not tau and thus sequesters GSK3b away from tau, as an axin mutant that does not bind GSK3b did not inhibit tau phosphorylation by GSK3b. This is the first demonstration that axin negatively affects the phosphorylation of a GSK3b substrate, and provides a novel mechanism by which tau phosphorylation and function can be regulated within the cell.

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“…Such a conclusion is further strengthened by an inhibition experiment using a synthetic peptide (FRATide), which was derived from a vertebrate GSK3-binding protein (Yost et al, 1998) and was shown to inhibit the phosphorylation of non-primed substrates by GSK3 kinases (Thomas et al, 1999;Farr et al, 2000). As indicated in Figure 3C, the FRATide had little effect on the phosphorylation of BES1 or BZR1 by BIN2 at the concentrations known to be inhibitory to animal GSK3 kinases.…”

Section: Bin2 Phosphorylates Bes1 and Bzr1 Via A Novel Mechanismmentioning

confidence: 93%

Two Putative BIN2 Substrates Are Nuclear Components of Brassinosteroid Signaling

et al. 2002

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GSK3 is a highly conserved kinase that negatively regulates many cellular processes by phosphorylating a variety of protein substrates. BIN2 is a GSK3-like kinase in Arabidopsis that functions as a negative regulator of brassinosteroid (BR) signaling. It was proposed that BR signals, perceived by a membrane BR receptor complex that contains the leucine (Leu)-rich repeat receptor-like kinase BRI1, inactivate BIN2 to relieve its inhibitory effect on unknown downstream BR-signaling components. Using a yeast (Saccharomyces cerevisiae) two-hybrid approach, we discovered a potential BIN2 substrate that is identical to a recently identified BR-signaling protein, BES1. BES1 and its closest homolog, BZR1, which was also uncovered as a potential BR-signaling protein, display specific interactions with BIN2 in yeast. Both BES1 and BZR1 contain many copies of a conserved GSK3 phosphorylation site and can be phosphorylated by BIN2 in vitro via a novel GSK3 phosphorylation mechanism that is independent of a priming phosphorylation or a scaffold protein. Five independent bes1 alleles containing the same proline-233-Leu mutation were identified as semidominant suppressors of two different bri1 mutations. Overexpression of the wild-type BZR1 gene partially complemented bin2/ϩ mutants and resulted in a BRI1 overexpression phenotype in a BIN2 ؉ background, whereas overexpression of a mutated BZR1 gene containing the corresponding proline-234-Leu mutation rescued a weak bri1 mutation and led to a bes1-like phenotype. Confocal microscopic analysis indicated that both BES1 and BZR1 proteins were mainly localized in the nucleus. We propose that BES1/BZR1 are two nuclear components of BR signaling that are negatively regulated by BIN2 through a phosphorylation-initiated process.BRs are a special class of plant polyhydroxysteroids that have wide distribution throughout the plant kingdom and play many important roles throughout plant development that include seed germination, stem elongation, pollen tube growth, vascular differentiation, skotomorphogenesis, and stress resistance (Clouse and Sasse, 1998;Steber and McCourt, 2001). It was well documented that gene regulation is critical for many BR-elicited physiological responses (Clouse and Feldmann, 1999), however, the signaling mechanism from BR perception to gene regulation remains largely unknown. Extensive genetic screens for BR-insensitive-signaling mutants in Arabidopsis have so far identified only two genes, BRI1 and BIN2 (Clouse et al., 1996;Kauschmann et al., 1996;Li and Chory, 1997;Noguchi et al., 1999;Li et al., 2001;Li and Nam, 2002).BRI1 encodes a Leu-rich repeat receptor-like kinase that is composed of an extracellular domain, a singlepass transmembrane segment, and an intracellular kinase domain (Li and Chory, 1997). BRI1 is a plasma membrane-localized protein and can function as a Ser/Thr kinase when expressed in Escherichia coli or animal cell culture (Friedrichsen et al., 2000;Oh et al., 2000). The extracellular domain of BRI1 can confer BR responsiveness to the kinase ...

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A GSK3‐binding peptide from FRAT1 selectively inhibits the GSK3‐catalysed phosphorylation of Axin and β‐catenin

Cited by 219 publications

References 35 publications

cAMP-induced degradation of cyclin D3 through association with GSK-3β

cAMP-induced degradation of cyclin D3 through association with GSK-3β

Axin negatively affects tau phosphorylation by glycogen synthase kinase 3β

Two Putative BIN2 Substrates Are Nuclear Components of Brassinosteroid Signaling

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