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. DOI: http://dx.doi.org/10.7554/eLife.19430.00

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

Role of p38α in lung tumor progression

[eng] Tumors evolve by sequentially acquiring genetic abnormalities, like K-Ras activation and Tp53 loss of function, which enable transformed cells to survive, proliferate, invade, and reprogram their microenvironment. Simultaneously, transformed cells need to cope with a stressful scenario, including an accelerated metabolism, genome instability, or immune surveillance. Therefore, cancer cells must rely on some non-oncogenic signaling pathways to tolerate homeostatic control deficiencies, adapt to the new demands, and monitor continuous changes in the microenvironment to respond accordingly. The p38 MAPK signaling pathway is a stress-related pathway that cells use to transduce extracellular cues and orchestrate appropriate responses. p38α, the most widely expressed p38 MAPK family member, has been classically attributed tumor suppressor functions due to its ability to arrest the cell cycle, induce cell differentiation, and trigger apoptosis. Nevertheless, in several human tumor types, p38 MAPK activity levels have been found increased and sometimes correlated to poor survival, suggesting a pro-tumorigenic role. In this study, we observed a negative correlation between p38α mRNA expression levels and the overall survival of lung adenocarcinoma patients. Using a K-RasG12V driven mouse model of lung cancer, we show that indeed p38α signaling plays a dual role during lung tumorigenesis. On one hand, p38α avoids malignant transformation in lung epithelial cells by promoting their differentiation. However, in the transformed lung epithelial cells, p38α enhances proliferation as well as the secretion of inflammatory cytokines to form a favorable niche for cancer progression. p38α also plays a pro-tumorigenic role by promoting tumor vascularization and immunotolerance of tumor-infiltrated myeloid cells. Altogether, our data suggest that targeting this pathway might be therapeutically useful for lung adenocarcinoma.[spa] Los tumores evolucionan al adquirir anormalidades genéticas de manera secuencial, como la activación de K-Ras y la pérdida de funcionalidad de Tp53, que permiten a las células transformadas sobrevivir, proliferar, e invadir, así como acondicionar su microambiente. Simultáneamente, las células transformadas también han de lidiar con situaciones de estrés, incluyendo un metabolismo acelerado, un genoma altamente inestable, o el sistema de vigilancia de las células inmunes. Por lo tanto, las células cancerosas han de apoyarse en vías de señalización no-oncogénicas que les permiten tolerar las deficiencias en los sistemas de control de homeostasis, adaptarse a los nuevos requerimientos funcionales, y monitorizar los cambios en el microambiente para responder de manera apropiada. La vía de las p38 MAPK está íntimamente relacionada con la respuesta al estrés y es utilizada por las células para transducir señales extracelulares y orquestrar las respuestas correspondientes. p38α es el miembro de la familia de p38 MAPK más ampliamente expresado, y se le han atribuido clásicamente funciones supresoras tumorales gracias a su habilidad para detener el ciclo celular, inducir diferenciación, y desencadenar procesos apoptóticos. No obstante, hay evidencia de que el nivel de actividad de p38 MAPK podría estar incrementado en varios tipos de tumor humanos y, en algunos casos, se ha correlacionado con una baja supervivencia, lo que sugiere un papel pro-tumoral. En este estudio, hemos observado una correlación negativa entre los niveles de expresión de p38α y la supervivencia en pacientes de adenocarcinoma pulmonar. Hemos usado un modelo murino de cáncer de pulmón inducido por la expresión del oncogén K-Ras para demostrar que, efectivamente, p38α juega un papel dual durante el desarrollo de la carcinogénesis de pulmón. Por una parte, p38α evita la transformación maligna de las células pulmonares epiteliales sanas mediante la inducción de diferenciación celular. Sin embargo, en las células epiteliales pulmonares transformadas, p38α estimula la proliferación y la secreción de citocinas inflamatorias que preparan un nicho favorable para la progresión tumoral. p38α también juega un rol pro-tumorigénico al promover la vascularización del tumor y la immunotolerancia por parte de las células mieloides infiltradas. En conjunto, nuestros datos sugieren que la inhibición de esta vía de señalización podría ser útil en términos terapéuticos para los casos de adenocarcinoma de pulmón

Gadd45 gamma and Map3k4 Interactions Regulate Mouse Testis Determination via p38 MAPK-Mediated Control of Sry Expression

SummaryLoss of the kinase MAP3K4 causes mouse embryonic gonadal sex reversal due to reduced expression of the testis-determining gene, Sry. However, because of widespread expression of MAP3K4, the cellular basis of this misregulation was unclear. Here, we show that mice lacking Gadd45γ also exhibit XY gonadal sex reversal caused by disruption to Sry expression. Gadd45γ is expressed in a dynamic fashion in somatic cells of the developing gonads from 10.5 days postcoitum (dpc) to 12.5 dpc. Gadd45γ and Map3k4 genetically interact during sex determination, and transgenic overexpression of Map3k4 rescues gonadal defects in Gadd45γ-deficient embryos. Sex reversal in both mutants is associated with reduced phosphorylation of p38 MAPK and GATA4. In addition, embryos lacking both p38α and p38β also exhibit XY gonadal sex reversal. Taken together, our data suggest a requirement for GADD45γ in promoting MAP3K4-mediated activation of p38 MAPK signaling in embryonic gonadal somatic cells for testis determination in the mouse