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Our results identify TRPM7 kinase as a key modulator of phospholipase C signaling and store-operated Ca entry in platelets. The protection of mice from acute ischemic disease without developing intracranial hemorrhage indicates that TRPM7 kinase might be a promising antithrombotic target.

Invasive lobular carcinoma of the breast (ILC) is strongly estrogen-driven and represents a unique context for estrogen receptor (ER) signaling. In ILC, ER controls the expression of the Wnt ligand WNT4, which is critical for endocrine response and anti-estrogen resistance. However, signaling mediated by WNT4 is cell type- and tissue-specific, and has not been explored in ILC. We utilized reverse phase protein array (RPPA) to characterize ER and WNT4-driven signaling in ILC cells and identified that WNT4 mediates downstream mTOR signaling via phosphorylation of S6 Kinase. Additionally, ER and WNT4 control levels of MCL-1, which is associated with regulation of mitochondrial function. In this context, WNT4 knockdown led to decreased ATP production and increased mitochondrial fragmentation. WNT4 regulation of both mTOR signaling and MCL-1 were also observed in anti-estrogen resistant models of ILC. We identified that high WNT4 expression is associated with similar mTOR pathway activation in ILC and serous ovarian cancer tumors, suggesting that WNT4 signaling is active in multiple tumor types. The identified downstream pathways offer insight into WNT4 signaling and represent potential targets to overcome anti-estrogen resistance for patients with ILC.

BackgroundAlthough cigarette smoking (CS) is by far the most important risk factor of chronic obstructive pulmonary disease (COPD), repeated and sustained infections are clearly linked to disease pathogenesis and are responsible for acute inflammatory flares (i.e. COPD exacerbations). We have previously identified Fatty Acid Binding Protein 5 (FABP5) as an important anti‐inflammatory protein in primary airway epithelial cells. ResultsIn this study we found decreased FABP5 mRNA and protein levels in peripheral blood mononuclear cells (PBMCs) of COPD patients, especially among those who reported episodes of COPD exacerbations. Using wildtype (WT) and FABP5−/− mice, we examined the effects of FABP5 on CS and infection‐induced inflammatory responses. Similarly to what we saw in airway epithelial cells, infection increased FABP5 expression while CS decreased FABP5 expression in mouse lung tissues. CS‐exposed and P. aeruginosa‐infected FABP5−/− mice had significantly increased inflammation as shown by increased lung histopathological score, cell infiltration and inflammatory cytokine levels. Restoration of FABP5 in alveolar macrophages using a lentiviral approach attenuated the CS‐ and bacteria‐induced pulmonary inflammation. And finally, while P. aeruginosa infection increased PPARγ activity, CS or FABP5 knockdown greatly reduced PPARγ activity. ConclusionsThese findings support a model in which CS‐induced FABP5 inhibition contributes to increased inflammation in COPD exacerbations. It is interesting to speculate that the increased inflammation is a result of decreased PPARγ activity.

Background: Wnt protein secretion and paracrine signaling typically require the enzyme PORCN,