Regulation of Hippo signaling pathway in cancer: A MicroRNA perspective

Recent studies have suggested that Hippo signaling is not only involved in controlling organ size in Drosophila but can also regulate cell proliferation, tissue homeostasis, differentiation, apoptosis and regeneration. Any dysregulation of Hippo signaling, especially the hyper activation of its downstream effectors YAP/TAZ, can lead to uncontrolled cell proliferation and malignant transformation. In majority of cancers, expression of YAP/TAZ is extremely high and this increased expression of YAP/TAZ has been shown to be an independent predictor of prognosis and indicator of increased cell proliferation, metastasis and poor survival. In this review, we have summarized the most recent findings about the cross talk of Hippo signaling pathway with other signaling pathways and its regulation by different miRNAs in various cancer types. Recent evidence has suggested that Hippo pathway is also involved in mediating the resistance of different cancer cells to chemotherapeutic drugs and in a few cancer types, this is brought about by regulating miRNAs. Therefore, the delineation of the underlying mechanisms regulating the chemotherapeutic resistance might help in developing better treatment options. This review has attempted to provide an overview of different drugs/options which can be utilized to target oncogenic YAP/TAZ proteins for therapeutic interventions.     

Regulation of cross-talk in yeast MAPK signaling pathways

MAP kinase (MAPK) modules are conserved three-kinase cascades that serve central roles in intracellular signal transduction in eukaryotic cells. MAPK pathways of different inputs and outputs use overlapping sets of signaling components. In yeast, for example, three MAPK pathways (pheromone response, filamentous growth response, and osmostress adaptation) all use the same Ste11 MAPK kinase kinase (MAPKKK). How undesirable leakage of signal, or cross-talk, is prevented between these pathways has been a subject of intensive study. This review discusses recent findings from yeast that indicate that there is no single mechanism, but that a combination of four general strategies (docking interactions, scaffold proteins, cross-pathway inhibition, and kinetic insulation) are utilized for the prevention of cross-talk between any two MAPK modules.     

Regulation of Nod1-mediated signaling pathways

Nod1 is a member of the NLR/Nod/CATERPILLER family. It acts as a sensor for intracellular bacteria by recognizing specific glycopeptides derived from peptidoglycan. Nod1 activation mediates distinct cellular responses including activation of MAP kinases, IL-8 release, apoptosis and suppression of several estrogen-dependent responses in MCF-7 cells. Here we have extended these studies by identifying key regulatory steps in Nod1-dependent signaling pathways. We provide multiple lines of data showing that Nod1-dependent apoptosis is a caspase 8-mediated event and that apoptosis requires RIP2. In contrast, several lines of evidence show that Nod1-dependent JNK activation and IL-8 production did not require the presence of caspase 8 but required activation of TAK1 as well as RIP2. Thus, we have identified several key control points that lie downstream of Nod1. This work provides the basis for further studies of the biological significance and regulation of the Nod1 pathway.     

Organ size control by Hippo and TOR pathways

The determination of final organ size is a highly coordinated and complex process that relies on the precise regulation of cell number and/or cell size. Perturbation of organ size control contributes to many human diseases, including hypertrophy, degenerative diseases, and cancer. Hippo and TOR are among the key signaling pathways involved in the regulation of organ size through their respective functions in the regulation of cell number and cell size. Here, we review the general mechanisms that regulate organ growth, describe how Hippo and TOR control key aspects of growth, and discuss recent findings that highlight a possible coordination between Hippo and TOR in organ size regulation.     

Regulation of Hippo pathway components by FSH in testis

The transition of testicular Sertoli cells (Sc) from a proliferative state during infancy to a non proliferative functionally mature state at the onset of puberty is essential for proper spermatogenic progression. The Hippo signaling pathway is a conserved growth control pathway that has been shown to play a crucial role in regulating proliferation and differentiation of different cell types. However, the expression pattern of the pathway components relative to proliferative infant Sc and functionally mature pubertal Sc is not known. In this study, we show that the Hippo pathway components are differentially expressed in infant and pubertal rat Sc. Interestingly, Hippo transducer- YAP was found to be significantly up-regulated in pubertal Sc as compared to infant Sc. Follicle stimulating hormone (FSH) was found to up-regulate Yap expression in pubertal Sc but not in infant Sc. Moreover, FSH induced the phosphorylation of YAP at Ser 127 residue (which is associated with its inactivation) in pubertal Sc. This indicated negative regulation of YAP by FSH mediated signaling in pubertal Sc. Our results demonstrated the differential expression of Hippo pathway genes in infant and pubertal Sc and also established an important role of FSH in regulating YAP expression and phosphorylation in Sc.     

A mathematical model of metabolic insulin signaling pathways

We develop a mathematical model that explicitly represents many of the known signaling components mediating translocation of the insulin-responsive glucose transporter GLUT4 to gain insight into the complexities of metabolic insulin signaling pathways. A novel mechanistic model of postreceptor events including phosphorylation of insulin receptor substrate-1, activation of phosphatidylinositol 3-kinase, and subsequent activation of downstream kinases Akt and protein kinase C-zeta is coupled with previously validated subsystem models of insulin receptor binding, receptor recycling, and GLUT4 translocation. A system of differential equations is defined by the structure of the model. Rate constants and model parameters are constrained by published experimental data. Model simulations of insulin dose-response experiments agree with published experimental data and also generate expected qualitative behaviors such as sequential signal amplification and increased sensitivity of downstream components. We examined the consequences of incorporating feedback pathways as well as representing pathological conditions, such as increased levels of protein tyrosine phosphatases, to illustrate the utility of our model for exploring molecular mechanisms. We conclude that mathematical modeling of signal transduction pathways is a useful approach for gaining insight into the complexities of metabolic insulin signaling.     

Chemical modulation of glycerolipid signaling and metabolic pathways

Thirty years ago, glycerolipids captured the attention of biochemical researchers as novel cellular signaling entities. We now recognize that these biomolecules occupy signaling nodes critical to a number of physiological and pathological processes. Thus, glycerolipid-metabolizing enzymes present attractive targets for new therapies. A number of fields—ranging from neuroscience and cancer to diabetes and obesity—have elucidated the signaling properties of glycerolipids. The biochemical literature teems with newly emerging small molecule inhibitors capable of manipulating glycerolipid metabolism and signaling. This ever-expanding pool of chemical modulators appears daunting to those interested in exploiting glycerolipid-signaling pathways in their model system of choice. This review distills the current body of literature surrounding glycerolipid metabolism into a more approachable format, facilitating the application of small molecule inhibitors to novel systems. This article is part of a Special Issue entitled Tools to study lipid functions.     

Regulation of stress-activated protein kinase signaling pathways by protein phosphatases.

Stress-activated protein kinase (SAPK) signaling plays essential roles in eliciting adequate cellular responses to stresses and proinflammatory cytokines. SAPK pathways are composed of three successive protein kinase reactions. The phosphorylation of SAPK signaling components on Ser/Thr or Thr/Tyr residues suggests the involvement of various protein phosphatases in the negative regulation of these systems. Accumulating evidence indicates that three families of protein phosphatases, namely the Ser/Thr phosphatases, the Tyr phosphatases and the dual specificity Ser/Thr/Tyr phosphatases regulate these pathways, each mediating a distinct function. Differences in substrate specificities and regulatory mechanisms for these phosphatases form the molecular basis for the complex regulation of SAPK signaling. Here we describe the properties of the protein phosphatases responsible for the regulation of SAPK signaling pathways.     

Modulation of inflammatory signaling pathways by phytochemicals in ovarian cancer

Inflammation has been suggested to be involved in cancer development and progression. Many clinical and experimental studies have shown that inflammation could contribute to ovarian carcinogenesis through activation of the NF-κB and AP-1 pathways by chronic inflammatory mediators. Phytochemicals, which are natural compounds derived from fruits and vegetables, have shown anti-inflammatory and anti-cancer effects. Due to their relatively low toxicity and easy accessibility, phytochemicals have been investigated for their chemopreventive potential against various cancers. In this review, we discuss the role of phytochemicals in preventing ovarian cancer through anti-inflammatory mechanisms.