Bridging the BMP and Wnt pathways by PI3 kinase/Akt and 14-3-3zeta.

BMP, PTEN and Wnt/beta-catenin pathways are the three signaling pathways that control normal development and regeneration of the intestine, and contribute to intestinal polyposis when aberrant inactivation or activation occurs in each of these pathways. Using genetic targeting of BMPR1A in mice, we show that inactivation of BMP signaling results in multiple polyps due to an increased number of crypts and stem cells, accompanied by enhanced Wnt signaling in all proliferating intestine cells. However the increased transcriptional activity of Wnt effecter protein, beta-catenin, is found primarily in intestine stem cells (ISCs). Concurrently, PTEN, an inhibitor of PI3K/Akt pathway, is also primarily inactivated in the ISCs, leading to activation of Akt. Thus, Akt may contribute to activation of beta-catenin in ISCs in coordination with Wnt signaling. By conducting a proteomic analysis of the beta-catenin complex, we show that 14-3-3zeta exists in the beta-catenin complex and facilitates activation of beta-catenin by Akt, which, intriguingly, appears to be predominantly in ISCs. Thus, we propose that BMP signaling plays a role in inhibition of ISC self-renewal through suppression of Wnt/beta-catenin signaling in ISC, and this cross-talk is bridged, at least in part, through the PTEN/Akt pathway and further enforced by 14-3-3zeta.