Wnt/β-catenin signaling within multiple cell types dependent upon regulates intestinal stem cell proliferation.

The gut epithelium is subject to constant renewal, a process reliant upon intestinal stem cell (ISC) proliferation that is driven by Wnt/β-catenin signaling. Despite the importance of Wnt signaling within ISCs, the relevance of Wnt signaling within other gut cell types and the underlying mechanisms that modulate Wnt signaling in these contexts remain incompletely understood. Using challenge of the midgut with a non-lethal enteric pathogen, we examine the cellular determinants of ISC proliferation, harnessing , a recently identified regulator of Wnt signaling pathways, as a mechanistic tool.

Advances in extracellular vesicle isolation methods: a path towards cell-type specific EV isolation.

Extracellular vesicles are small, heterogenous, phospholipid-rich vesicles that are secreted by all cells into the extracellular space. They play a key role in intercellular communication because they can transport a variety of biomolecules such as proteins, lipids, and nucleic acids between cells. As categorized by the International Society of Extracellular Vesicles (ISEV), the term EV encompasses different sub-types, including exosomes, microvesicles, and apoptotic bodies, which differ in their size, origin, and cargo.

Ultrasensitive Protein Detection Technologies for Extracellular Vesicle Measurements.

Extracellular vesicles (EVs) are nanoscopic, heterogenous, lipid-rich particles that carry a multitude of cargo biomolecules including proteins, nucleic acids, and metabolites. Although historically EVs were regarded as cellular debris with no intrinsic value, growing understanding of EV biogenesis has led to the realization that EVs facilitate intercellular communication and are sources of liquid biomarkers. EVs can be isolated and analyzed from a wide variety of accessible biofluids for biomarker discovery and diagnostic applications.

Wnt/β-catenin signaling within multiple cell types dependent upon regulates intestinal stem cell proliferation.

The gut epithelium is subject to constant renewal, a process reliant upon intestinal stem cell (ISC) proliferation that is driven by Wnt/β-catenin signaling. Despite the importance of Wnt signaling within ISCs, the relevance of Wnt signaling within other gut cell types and the underlying mechanisms that modulate Wnt signaling in these contexts remain incompletely understood. Using challenge of the midgut with a non-lethal enteric pathogen, we examine the cellular determinants of ISC proliferation, harnessing , a recently identified regulator of Wnt signaling pathways, as a mechanistic tool.

Proximity Labeling Reveals Spatial Regulation of the Anaphase-Promoting Complex/Cyclosome by a Microtubule Adaptor.

The anaphase-promoting complex/cyclosome (APC/C) coordinates advancement through mitosis via temporally controlled polyubiquitination events. Despite the long-appreciated spatial organization of key events in mitosis mediated largely by cytoskeletal networks, the spatial regulation of APC/C, the major mitotic E3 ligase, is poorly understood. We describe a microtubule-resident protein, PLEKHA5, as an interactor of APC/C and spatial regulator of its activity in mitosis.

PLEKHA4 Promotes Wnt/β-Catenin Signaling-Mediated G-S Transition and Proliferation in Melanoma.

Despite recent promising advances in targeted therapies and immunotherapies, patients with melanoma incur substantial mortality. In particular, inhibitors targeting BRAF-mutant melanoma can lead to resistance, and no targeted therapies exist for NRAS-mutant melanoma, motivating the search for additional therapeutic targets and vulnerable pathways. Here we identify a regulator of Wnt/β-catenin signaling, PLEKHA4, as a factor required for melanoma proliferation and survival.

For Wnt Signaling, Fucosylation of LRP6 Is a Bitter Pill.

In this issue of Cell Chemical Biology, Hong et al. (2020) use in situ chemoenzymatic labeling to discover that fucosylation of the Wnt co-receptor LRP6 induces its endocytosis and downregulates Wnt/β-catenin signaling. Their findings reveal a glycosylation-based mechanism for regulating Wnt signaling that could be targeted in cancer.

PLEKHA4/kramer Attenuates Dishevelled Ubiquitination to Modulate Wnt and Planar Cell Polarity Signaling.

Wnt signaling pathways direct key physiological decisions in development. Here, we establish a role for a pleckstrin homology domain-containing protein, PLEKHA4, as a modulator of signaling strength in Wnt-receiving cells. PLEKHA4 oligomerizes into clusters at PI(4,5)P-rich regions of the plasma membrane and recruits the Cullin-3 (CUL3) E3 ubiquitin ligase substrate adaptor Kelch-like protein 12 (KLHL12) to these assemblies.