Requirement for epithelial p38α in KRAS-driven lung tumor progression.

Malignant transformation entails important changes in the control of cell proliferation through the rewiring of selected signaling pathways. Cancer cells then become very dependent on the proper function of those pathways, and their inhibition offers therapeutic opportunities. Here we identify the stress kinase p38α as a nononcogenic signaling molecule that enables the progression of KrasG12V-driven lung cancer. We demonstrate in vivo that, despite acting as a tumor suppressor in healthy alveolar progenitor cells, p38α contributes to the proliferation and malignization of lung cancer epithelial cells. We show that high expression levels of p38α correlate with poor survival in lung adenocarcinoma patients, and that genetic or chemical inhibition of p38α halts tumor growth in lung cancer mouse models. Moreover, we reveal a lung cancer epithelial cell-autonomous function for p38α promoting the expression of TIMP-1, which in turn stimulates cell proliferation in an autocrine manner. Altogether, our results suggest that epithelial p38α promotes KrasG12V-driven lung cancer progression via maintenance of cellular self-growth stimulatory signals.

A novel role for the non-catalytic intracellular domain of Neprilysins in muscle physiology.

BACKGROUND INFORMATION: Neprilysins (Neps) are membrane-bound M13 endopeptidases responsible for the activation and/or inactivation of peptide signalling events on cell surfaces. By hydrolysing their respective substrates, mammalian Neps are crucial to the metabolism of numerous bioactive peptides, especially in the nervous, immune, cardiovascular and inflammatory systems. On the basis of their involvement in essential physiological processes, proteins of the Nep family constitute putative therapeutic agents as well as targets in different diseases, including Alzheimer's disease. RESULTS: We here demonstrate that overexpression of Neprilysin 4 (Nep4) in Drosophila melanogaster leads to a severe muscle degeneration phenotype. This phenotype is observed for overexpression of full-length Nep4 in somatic muscles and is accompanied by severely impaired movement of larvae and lethality in late larval development. On the contrary, down-regulation of expression caused only the latter two effects. By expressing several mutated and truncated forms of Nep4 in transgenic animals, we show that the intracellular domain is responsible for the observed phenotypes while catalytic activity of the enzyme was apparently dispensable. A yeast two-hybrid screen identified a yet uncharacterised carbohydrate kinase as a first interaction partner of the intracellular domain of Nep4. CONCLUSIONS: These data demonstrate that the physiological significance of Nep4 is not limited to its function as an active peptidase but that the enzyme's intracellular N-terminus is affecting muscle integrity, independent of the protein's enzymatic activity. To our knowledge, this is the first report of an intracellular Nep domain being involved in muscle integrity.

Drosophila neprilysins control insulin signaling and food intake via cleavage of regulatory peptides.

Insulin and IGF signaling are critical to numerous developmental and physiological processes, with perturbations being pathognomonic of various diseases, including diabetes. Although the functional roles of the respective signaling pathways have been extensively studied, the control of insulin production and release is only partially understood. Herein, we show that in Drosophila expression of insulin-like peptides is regulated by neprilysin activity. Concomitant phenotypes of altered neprilysin expression included impaired food intake, reduced body size, and characteristic changes in the metabolite composition. Ectopic expression of a catalytically inactive mutant did not elicit any of the phenotypes, which confirms abnormal peptide hydrolysis as a causative factor. A screen for corresponding substrates of the neprilysin identified distinct peptides that regulate insulin-like peptide expression, feeding behavior, or both. The high functional conservation of neprilysins and their substrates renders the characterized principles applicable to numerous species, including higher eukaryotes and humans.