The CagA oncoprotein disrupts Wnt/PCP signaling and promotes hyperproliferation of pyloric gland base cells.

strains that deliver the oncoprotein CagA into gastric epithelial cells are the major etiologic agents of upper gastric diseases including gastric cancer. CagA promotes gastric carcinogenesis through interactions with multiple host proteins. Here, we show that CagA also disrupts Wnt-dependent planar cell polarity (Wnt/PCP), which orients cells within the plane of an epithelium and coordinates collective cell behaviors such as convergent extension to enable epithelial elongation during development.

Helicobacter pylori CagA elicits BRCAness to induce genome instability that may underlie bacterial gastric carcinogenesis.

Infection with CagA-producing Helicobacter pylori plays a causative role in the development of gastric cancer. Upon delivery into gastric epithelial cells, CagA deregulates prooncogenic phosphatase SHP2 while inhibiting polarity-regulating kinase PAR1b through complex formation. Here, we show that CagA/PAR1b interaction subverts nuclear translocation of BRCA1 by inhibiting PAR1b-mediated BRCA1 phosphorylation.

Protocol for visualizing conditional interaction between transmembrane and cytoplasmic proteins.

This protocol visualizes dynamic interaction between a transmembrane protein and an intracellular protein induced by clusterization/oligomerization of the transmembrane protein. Association-dissociation of the intracellular region of the transmembrane protein with cytoplasmic protein(s) is detected by proximity ligation assay. Since a transmembrane protein often resists extraction, biochemical analysis of its dynamic interaction with cytoplasmic effectors is cumbersome.

Hyaluronan Degradation Promotes Cancer via Hippo-YAP Signaling: An Intervention Point for Cancer Therapy.

High-molecular-weight hyaluronan acts as a ligand of the tumor-suppressive Hippo signal, whereas degradation of hyaluronan from a high-molecular-weight form to a low-molecular-weight forms by hyaluronidase 2 inhibits Hippo signal activation and thereby activates the pro-oncogenic transcriptional coactivator yes-associated protein (YAP), which creates a cancer-predisposing microenvironment and drives neoplastic transformation of cells through both cell-autonomous and non-cell-autonomous mechanisms. In fact, accumulation of low-molecular-weight hyaluronan in tissue stroma is observed in many types of cancers. Since inhibition of YAP activity suppresses tumor growth in vivo, pharmacological intervention of the Hippo-YAP signal is an attractive approach for future drug development.

High-Molecular-Weight Hyaluronan Is a Hippo Pathway Ligand Directing Cell Density-Dependent Growth Inhibition via PAR1b.

High-molecular-weight hyaluronan, a major component of the extracellular matrix, is anti-oncogenic, whereas low-molecular-weight hyaluronan is pro-oncogenic, though the mechanisms underlying the size-dependent opposite bioactivities of hyaluronan remain uncertain. We show here that treatment with high-molecular-weight hyaluronan stimulates tumor-suppressive Hippo signaling in breast epithelial cells. Mechanistically, clustering of the CD44 extracellular domain by high-molecular-weight hyaluronan leads to recruitment of the polarity-regulating kinase PAR1b by the CD44 intracellular domain, which results in disruption of the Hippo signaling-inhibitory PAR1b-MST complex.