Abstract

New research published in the Proceedings of the National Academy of Sciences of the United States of America (PNAS) reveals a startling function of the canonical Wnt signaling pathway: its crucial role in macropinocytosis and the subsequent lysosomal degradation of extracellular proteins. This finding could have significant implications for our understanding of cellular nutrition and the role of Wnt signaling in diseases like cancer. (DOI: 10.1073/pnas.1903506116)

Introduction

The Wnt signaling pathway has been extensively studied for its part in cell development, proliferation, and differentiation. Its anomalous activation has been implicated in a variety of diseases, including cancer. In a groundbreaking study by Tejeda-Muñoz et al., published in the May 2019 edition of PNAS, it was demonstrated that Wnt signaling plays a previously unrecognized role in regulating endocytosis, particularly macropinocytosis. This discovery adds a new layer of complexity to the functions performed by the Wnt pathway.

Macropinocytosis: The New Facet of Wnt Signaling

Macropinocytosis is an actin-driven endocytic process where cells engulf extracellular fluids, capturing nutrients in the form of large vesicular bodies known as macropinosomes. Usually, it is a non-receptor-mediated process that is prominent in certain cancers as a nutrient acquisition strategy. Tejeda-Muñoz et al.’s study revealed that canonical Wnt signaling massively increases the cellular uptake of extracellular fluids via macropinocytosis, funneling nutrient-rich packages into lysosomes – a concept entirely novel to the understanding of Wnt’s biological activities.

Methodology and Key Findings

The study employed cell lines such as HeLa, NIH 3T3, and mouse embryo fibroblasts to study the effect of Wnt signaling on endocytosis and lysosomal activity. Addition of Wnt3a, overexpression of Disheveled (Dvl), and manipulation of the Frizzled (Fz8) receptors induced macropinocytosis.

Analyses revealed that significant incorporation of the fluid phase marker tetramethylrhodamine (TMR)-dextran occurred upon Wnt treatment, indicating stimulation of macropinocytosis. Furthermore, by depleting tumor suppressors like adenomatous polyposis coli (APC) or Axin, the research team observed an even greater increase in macropinocytosis rates. This marked effect of Wnt on macropinocytosis was rapid and independent of new protein synthesis.

Additionally, the study found that extracellular proteins, specifically bovine serum albumin (BSA), underwent enhanced lysosomal degradation upon Wnt activation. This degradation involved smaller vesicles containing the key signaling molecule glycogen synthase kinase 3 (GSK3) and protein arginine ethyltransferase 1 (PRMT1), an enzyme required for canonical Wnt signaling.

Implications and Future Research

This work by Tejeda-Muñoz et al. opens new avenues for understanding how Wnt signaling impacts nutrition at a cellular level and its consequences for disease pathology, notably in cancer, where abnormal signaling and metabolic requirements are prevalent. The findings intimate that interventions in the Wnt pathway could modulate nutrient uptake and potentially thwart the progression of neoplastic cells.

Conclusion

The novel insight into Wnt signaling as a regulator of cellular endocytosis and metabolism prompts a reevaluation of Wnt’s role within cellular physiology and pathology. Given the canonical Wnt pathway’s newfound significance in macropinocytosis, further exploration into this complex signaling cascade could yield transformative strategies for disease treatment.

Keywords

1. Wnt signaling pathway
2. Macropinocytosis in cancer
3. Lysosomal degradation
4. Endocytosis and Wnt activation
5. Wnt pathway and cell nutrition

References

1. Tejeda-Muñoz, N., Albrecht, L.V., Bui, M.H., & De Robertis, E.M. (2019). Wnt canonical pathway activates macropinocytosis and lysosomal degradation of extracellular proteins. Proc Natl Acad Sci U S A, 116(21), 10402-10411. doi:10.1073/pnas.1903506116.
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DOI: 10.1073/pnas.1903506116