Matriptase activation of Gq drives epithelial disruption and inflammation via RSK and DUOX.

Epithelial tissues are primed to respond to insults by activating epithelial cell motility and rapid inflammation. Such responses are also elicited upon overexpression of the membrane-bound protease, Matriptase, or mutation of its inhibitor, Hai1. Unrestricted Matriptase activity also predisposes to carcinoma. How Matriptase leads to these cellular outcomes is unknown. We demonstrate that zebrafish hai1a mutants show increased H2O2, NfκB signalling, and IP3R -mediated calcium flashes, and that these promote inflammation, but do not generate epithelial cell motility. In contrast, inhibition of the Gq subunit in hai1a mutants rescues both the inflammation and epithelial phenotypes, with the latter recapitulated by the DAG analogue, PMA. We demonstrate that hai1a has elevated MAPK pathway activity, inhibition of which rescues the epidermal defects. Finally, we identify RSK kinases as MAPK targets disrupting adherens junctions in hai1a mutants. Our work maps novel signalling cascades mediating the potent effects of Matriptase on epithelia, with implications for tissue damage response and carcinoma progression.

Cancer occurs when normal processes in the cell become corrupted or unregulated. Many proteins can contribute, including one enzyme called Matriptase that cuts other proteins at specific sites. Matriptase activity is tightly controlled by a protein called Hai1. In mice and zebrafish, when Hai1 cannot adequately control Matriptase activity, invasive cancers with severe inflammation develop. However, it is unclear how unregulated Matriptase leads to both inflammation and cancer invasion. One outcome of Matriptase activity is removal of proteins called Cadherins from the cell surface. These proteins have a role in cell adhesion: they act like glue to stick cells together. Without them, cells can dissociate from a tissue and move away, a critical step in cancer cells invading other organs. However, it is unknown exactly how Matriptase triggers the removal of Cadherins from the cell surface to promote invasion. Previous work has shown that Matriptase switches on a receptor called Proteinase-activated receptor 2, or Par2 for short, which is known to activate many enzymes, including one called phospholipase C. When activated, this enzyme releases two signals into the cell: a sugar called inositol triphosphate, IP3; and a lipid or fat called diacylglycerol, DAG. It is possible that these two signals have a role to play in how Matriptase removes Cadherins from the cell surface. To find out, Ma et al. mapped the effects of Matriptase in zebrafish lacking the Hai1 protein. This revealed that Matriptase increases IP3 and DAG levels, which initiate both inflammation and invasion. IP3 promotes inflammation by switching on pro-inflammatory signals inside the cell such as the chemical hydrogen peroxide. At the same time, DAG promotes cell invasion by activating a well-known cancer signalling pathway called MAPK. This pathway activates a protein called RSK. Ma et al. show that this protein is required to remove Cadherins from the surface of cells, thus connecting Matriptase's activation of phospholipase C with its role in disrupting cell adhesion. An increase in the ratio of Matriptase to HAI-1 (the human equivalent of Hai1) is present in many cancers. For this reason, the signal cascades described by Ma et al. may be of interest in developing treatments for these cancers. Understanding how these signals work together could lead to more direct targeted anti-cancer approaches in the future.

Scoping review and international multi-centre cohort study investigating teaching, knowledge and beliefs regarding physical activity as a health intervention among medical students: a comparison between Singapore and the UK.

INTRODUCTION: Physical inactivity is a global challenge and physicians must promote physical activity (PA) among their patients. Nevertheless, PA counselling remains inadequate due to limitations in knowledge, education and information availability. This study evaluates the understanding of PA as a health intervention and knowledge of World Health Organization (WHO) guidelines among Singapore and United Kingdom (UK) medical students, the next generation of physicians. METHODS: Students from Singapore (Yong Loo Lin School of Medicine and Lee Kong Chian School of Medicine) and the UK (Universities of Cardiff, Leicester, Oxford and Birmingham) were invited to complete a 12-item online survey. Questions assessed knowledge of WHO guidelines, understanding of PA in health and illness, personal PA levels and exposure to PA counselling in clinical practice. RESULTS: Among 633 Singapore and UK students who completed the questionnaire, 94.8% believed that PA was important in preventing disease, but only 70.9% recognised its importance in treating disease. The majority (85.3%) indicated participation in PA and exercise. General understanding of WHO guidelines for adults was poor, with less than half (46.8%) correctly answering this section. 3 (0.5%) students identified that PA in adults could be accumulated in multiple ways. Understanding of PA in health and familiarity with guidelines did not differ significantly between Singapore and UK students. CONCLUSION: There is considerable room for improvement in the knowledge of WHO guidelines and the role of PA in health. Education should begin during the undergraduate phase so that future doctors are better equipped to counsel their patients.