Complex Formation of Adenomatous Polyposis Coli Gene Product and Axin Facilitates Glycogen Synthase Kinase-3β-dependent Phosphorylation of β-Catenin and Down-regulates β-Catenin

Hinoi, Toshihide; Yamamoto, Hideki; Kishida, Michiko; Takada, Shinji; Kishida, Shosei; Kikuchi, Akira

doi:10.1074/jbc.m003997200

Cited by 119 publications

(98 citation statements)

References 57 publications

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“…The reasons for these differences are unknown, but may be due to different regulatory factors present in Xenopus oocytes and cultured mammalian cells. Further complicating the interpretation of these data is the fact that the RGS domain of axin, which binds APC , has been reported to both contribute to (Zeng et al 1997;Hinoi et al 2000) and inhibit axin-facilitated GSK3b-mediated b-catenin phosphorylation (de Hart et al 1998).…”

Section: Discussionmentioning

confidence: 99%

“…Axin is required for efficient GSK3b-mediated phosphorylation of cytosolic b-catenin, both in vivo and in vitro Farr et al 2000;Hinoi et al 2000). To demonstrate that axin is a positive regulator of GSK3b-mediated b-catenin phosphorylation in our paradigm, the phosphorylation of GST-b-catenin in an in vitro assay was measured (Fig.…”

Section: Axin Facilitates the Phosphorylation Of Gst-b-catenin In Vitromentioning

confidence: 99%

“…The wnt pathway is ultimately responsible for controlling b-catenin-mediated transcriptional activity. Within the wnt pathway, axin interacts with GSK3b, the adenomatous polyposis coli gene product (APC), and b-catenin (Hinoi et al 2000). This complex is stable in the absence of wnt signal and results in the efficient phosphorylation of b-catenin by GSK3b, which targets b-catenin for degradation by the proteasome.…”

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confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Axin Facilitates the Phosphorylation Of Gst-b-catenin In Vitromentioning

confidence: 99%

mentioning

confidence: 99%

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Axin negatively affects tau phosphorylation by glycogen synthase kinase 3β

Stoothoff¹,

Bailey²,

Mi³

et al. 2002

Journal of Neurochemistry

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“…This suggests that GSK3 inhibitors could exert a therapeutically negative, pro-survival effect on tumor cells. In addition, some studies found that GSK3 is part of a tumor suppressor complex consisting of axin and APC that phosphorylates the oncoprotein -catenin and that, when GSK3 is inactivated, could possibly lead to tumor promotion (Hinoi et al, 2000;Rask et al, 2003). Available evidence indicates that GSK3 may function as a "tumor suppressor" for certain types of tumors such as skin and mammary tumors (Farago et al, 2005;Ma et al, 2007).…”

Section: Pathological Functionmentioning

confidence: 99%

The Pivotal Roles of GSK3β in Glioma Biology

Nakada¹,

Minamoto²,

Pyko³

et al. 2011

Molecular Targets of CNS Tumors

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“…The locus of the familial adenomatous polyposi encodes the tumor suppressor gene APC (Adenomatous Polyposis Coli), which is mutated and is found to be inactivated in both patients with familial adenomatous polyposis and in many sporadic cases of colorectal cancer (Powell et al, 1992;Kinzler and Vogelstein, 1996;Clements et al, 2003;Clevers, 2004;Aguilera et al, 2006). Under quiescent conditions, Axin, glycogen synthase kinase-3b (GSK-3b), casein kinase-Ia and APC form a complex with b-catenin (b-cat) that facilitates b-cat phosphorylation at Ser33, Ser37 and Thr41 by GSK-3b and casein kinase-Ia at Ser45, as well as its subsequent degradation by the ubiquitin-proteasome pathway (Aberle et al, 1997;Hinoi et al, 2000;Liu et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

P-21-activated protein kinase-1 functions as a linker between insulin and Wnt signaling pathways in the intestine

et al. 2009

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Hyperinsulinemia and type II diabetes are associated with an increased risk of developing colorectal tumors. We found previously that in intestinal cells, insulin or insulinlike growth factor-1 stimulates c-Myc and cyclin D1 protein expression through both Akt-dependent and Aktindependent mechanisms. The effect of Akt is attributed to the stimulation of c-Myc translation by mammalian target of rapamycin. However, Akt-independent stimulation was, associated with an increase in b-catenin (b-cat) in the nucleus and an increased association between b-cat and T-cell factor binding sites on the c-Myc promoter, detected by chromatin immunoprecipitation. In this study, we show that insulin stimulated the phosphorylation/ activation of p-21-activated protein kinase-1 (PAK-1) in an Akt-independent manner in vitro and in an in vivo hyperinsulinemic mouse model. Significantly, shRNA (small hairpin RNA)-mediated PAK-1 knockdown attenuated both basal and insulin-stimulated c-Myc and cyclin D1 expression, associated with a marked reduction in extracellular signal-regulated kinase activation and b-cat phosphorylation at Ser675. Furthermore, PAK-1 silencing led to a complete blockade of insulin-stimulated b-cat binding to the c-Myc promoter and cellular growth. Finally, inhibition of MEK, a downstream target of PAK-1, blocked insulin-stimulated nuclear b-cat accumulation and c-Myc expression. Our observations suggest that PAK-1 serves as an important linker between insulin and Wnt signaling pathways.

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Complex Formation of Adenomatous Polyposis Coli Gene Product and Axin Facilitates Glycogen Synthase Kinase-3β-dependent Phosphorylation of β-Catenin and Down-regulates β-Catenin

Cited by 119 publications

References 57 publications

Axin negatively affects tau phosphorylation by glycogen synthase kinase 3β

Axin negatively affects tau phosphorylation by glycogen synthase kinase 3β

The Pivotal Roles of GSK3β in Glioma Biology

P-21-activated protein kinase-1 functions as a linker between insulin and Wnt signaling pathways in the intestine

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