👤 Nydia Tejeda-Muñoz

Here we review the regulation of macropinocytosis by Wnt growth factor signaling. Canonical Wnt signaling is normally thought of as a regulator of nuclear β-catenin, but emerging results indicate that there is much more than β-catenin to the Wnt pathway. Macropinocytosis is transiently regulated by EGF-RTK-Ras-PI3K signaling. Recent studies show that Wnt signaling provides for sustained acquisition of nutrients by macropinocytosis. Endocytosis of Wnt-Lrp6-Fz receptor complexes triggers the sequestration of GSK3 and components of the cytosolic destruction complex such as Axin1 inside multivesicular bodies (MVBs) through the action of the ESCRT machinery. Wnt macropinocytosis can be induced both by the transcriptional loop of stabilized β-catenin, and by the inhibition of GSK3 even in the absence of new protein synthesis. The cell is poised for macropinocytosis, and all it requires for triggering of Pak1 and the actin machinery is the inhibition of GSK3. Striking lysosomal acidification, which requires macropinocytosis, is induced by GSK3 chemical inhibitors or Wnt protein. Wnt-induced macropinocytosis requires the ESCRT machinery that forms MVBs. In cancer cells, mutations in the tumor suppressors APC and Axin1 result in extensive macropinocytosis, which can be reversed by restoring wild-type protein. In basal cellular conditions, GSK3 functions to constitutively repress macropinocytosis. Show less

Wnt signaling has multiple functions beyond the transcriptional effects of β-catenin stabilization. We review recent investigations that uncover new cell physiological effects through the regulation of Wnt receptor endocytosis, Wnt-induced stabilization of proteins (Wnt-STOP), macropinocytosis, increase in lysosomal activity, and metabolic changes. Many of these growth-promoting effects of canonical Wnt occur within minutes and are independent of new protein synthesis. A key element is the sequestration of glycogen synthase kinase 3 (GSK3) inside multivesicular bodies and lysosomes. Twenty percent of human proteins contain consecutive GSK3 phosphorylation motifs, which in the absence of Wnt can form phosphodegrons for polyubiquitination and proteasomal degradation. Wnt signaling by either the pharmacological inhibition of GSK3 or the loss of tumor-suppressor proteins, such as adenomatous polyposis coli (APC) and Axin1, increases lysosomal acidification, anabolic metabolites, and macropinocytosis, which is normally repressed by the GSK3-Axin1-APC destruction complex. The combination of these cell physiological effects drives cell growth. Show less

Canonical Wnt signaling is emerging as a major regulator of endocytosis. Here, we report that Wnt-induced macropinocytosis is regulated through glycogen synthase kinase 3 (GSK3) and the β-catenin destruction complex. We find that mutation of Axin1, a tumor suppressor and component of the destruction complex, results in the activation of macropinocytosis. Surprisingly, inhibition of GSK3 by lithium chloride (LiCl), CHIR99021, or dominant-negative GSK3 triggers macropinocytosis. GSK3 inhibition causes a rapid increase in acidic endolysosomes that is independent of new protein synthesis. GSK3 inhibition or Axin1 mutation increases lysosomal activity, which can be followed with tracers of active cathepsin D, β-glucosidase, and ovalbumin degradation. Microinjection of LiCl into the blastula cavity of Xenopus embryos causes a striking increase in dextran macropinocytosis. The effects of GSK3 inhibition on protein degradation in endolysosomes are blocked by the macropinocytosis inhibitors EIPA or IPA-3, suggesting that increases in membrane trafficking drive lysosomal activity. Show less