Phosphatidylinositol 3-Kinase Signaling Does Not Activate the Wnt Cascade

Abstract

Mutational activation of the phosphatidylinositol 3-kinase (PI3K) pathway occurs in a wide variety of tumors, whereas activating Wnt pathway mutants are predominantly found in colon cancer. Because GSK3 is a key component of both pathways, it is widely assumed that active PI3K signaling feeds positively into the Wnt pathway by protein kinase B (PKB)-mediatefd inhibition of GSK3. In addition, PKB has been proposed to modulate the canonical Wnt signaling through direct stabilization and nuclear localization of ␤-catenin. Here, we show that compartmentalization by Axin of GSK3 prohibits cross-talk between the PI3K and Wnt pathways and that Wnt-mediated transcriptional activity is not modulated by activation of the PI3K/PKB pathway.Developmental signaling cascades typically transduce signals from the cell surface onto regulatory sequences of nuclear target genes. In the simplest model, signals transduced through different pathways are integrated at the level of the regulatory elements of individual genes. Such regulatory elements may be viewed as assemblies of cis-acting response elements that are tailored to create the unique expression pattern for each gene. However, numerous studies propose that signaling pathways may interact at any stage between the plasma membrane and the nucleus. One mechanism by which such cross-talk may occur involves the sharing of a common component between two different pathways. It is often tacitly assumed that such shared components are equally accessible to all pertinent pathways.Glycogen synthase kinase 3-␣ and -␤, collectively termed GSK3, are constitutively active serine/threonine kinases (1). GSK3 features in two signaling pathways that are of particular importance in cancer. GSK3 is a downstream component of the phosphoinositide 3-OH kinase (PI3K) 2 pathway (2, 3). Growth signals, activated Ras proteins, or loss of the phosphatase and tensin homolog (PTEN) all activate PI3K, which in turn phosphorylates and activates protein kinase B (PKB) (3). Active PKB phosphorylates GSK3␣ on Ser-21 (4) and GSK3␤ on Ser-9 (5), in both cases leading to inhibition of the constitutive kinase activity. GSK3 is also a component of the Wnt cascade (6). GSK3 is bound by Axin (Axis inhibition protein) (7) and phosphorylates ␤-catenin, thus targeting it for ubiquitination and degradation by the proteasome. Wnt signaling is assumed to block GSK3-mediated ␤-catenin phosphorylation, leading to the accumulation and nuclear translocation of ␤-catenin (6). It remains unclear how the Wnt cascade controls the activity of the dedicated Axin1-bound GSK3 pool. A recent genetic experiment has demonstrated that removal of the inhibitory serines from the two GSK3 proteins has no effect on Wnt signaling (8).Although an early study proposed that the two pathways do not cross-talk at the level of GSK3 (9), a multitude of papers have since appeared that are based on the premise that a single pool of GSK3 is targeted by both signals (see supplemental Table S1). Moreover, direct stabilization of ␤-catenin by the PI3K/PKB...

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“…The notion that active Akt increases free and nuclear ␤-catenin levels, either indirectly via inhibitory phosphorylation of GSK3␤ or directly via stabilizing phosphorylation of ␤-catenin, has been proposed or accepted by many groups (31)(32)(33)(34)(35)(36)(37)(38)(39)(40). However, it has also been argued that inside the cells, GSK3 kinases exist in different pools; thus, their actions in PI3K/Akt and Wnt/␤-catenin pathways are spatially separate (95,96). We observed a tight correlation between Akt activation and Pygo2 level but not ␤-catenin level in transformed MECs.…”

Targeting mediators of Wnt signalling pathways by GnRH in gonadotropes

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