The Hippo pathway is an evolutionarily conserved signalling pathway with key roles in organ development, epithelial homeostasis, tissue regeneration, wound healing and immune modulation. Many of ...these roles are mediated by the transcriptional effectors YAP and TAZ, which direct gene expression via control of the TEAD family of transcription factors. Dysregulated Hippo pathway and YAP/TAZ-TEAD activity is associated with various diseases, most notably cancer, making this pathway an attractive target for therapeutic intervention. This Review highlights the key findings from studies of Hippo pathway signalling across biological processes and diseases, and discusses new strategies and therapeutic implications of targeting this pathway.
The highly conserved protein kinase mechanistic target of rapamycin (mTOR; originally known as mammalian target of rapamycin) is a central cell growth regulator connecting cellular metabolism and ...growth with a wide range of environmental inputs as part of mTOR complex 1 (mTORC1) and mTORC2. In this Review, we introduce the landmark discoveries in the mTOR field, starting from the isolation of rapamycin to the molecular characterizations of key components of the mTORC signalling network with an emphasis on amino acid sensing, and discuss the perspectives of mTORC inhibitors in therapeutic applications.
Autophagy is a cellular degradative pathway that plays diverse roles in maintaining cellular homeostasis. Cellular stress caused by starvation, organelle damage, or proteotoxic aggregates can ...increase autophagy, which uses the degradative capacity of lysosomal enzymes to mitigate intracellular stresses. Early studies have shown a role for autophagy in the suppression of tumorigenesis. However, work in genetically engineered mouse models and in vitro cell studies have now shown that autophagy can be either cancer‐promoting or inhibiting. Here, we summarize the effects of autophagy on cancer initiation, progression, immune infiltration, and metabolism. We also discuss the efforts to pharmacologically target autophagy in the clinic and highlight future areas for exploration.
This review summarizes the diverse contributions of the cellular degradation pathway autophagy to cancer initiation, progression, immune infiltration, and metabolism, and discusses related potential therapeutic intervention points.
The Hippo pathway was initially identified in Drosophila melanogaster screens for tissue growth two decades ago and has been a subject extensively studied in both Drosophila and mammals in the last ...several years. The core of the Hippo pathway consists of a kinase cascade, transcription coactivators, and DNA-binding partners. Recent studies have expanded the Hippo pathway as a complex signaling network with >30 components. This pathway is regulated by intrinsic cell machineries, such as cell-cell contact, cell polarity, and actin cytoskeleton, as well as a wide range of signals, including cellular energy status, mechanical cues, and hormonal signals that act through G-protein-coupled receptors. The major functions of the Hippo pathway have been defined to restrict tissue growth in adults and modulate cell proliferation, differentiation, and migration in developing organs. Furthermore, dysregulation of the Hippo pathway leads to aberrant cell growth and neoplasia. In this review, we focus on recent developments in our understanding of the molecular actions of the core Hippo kinase cascade and discuss key open questions in the regulation and function of the Hippo pathway.
mTOR, a serine/threonine kinase, is a master regulator of cellular metabolism. mTOR regulates cell growth and proliferation in response to a wide range of cues, and its signaling pathway is ...deregulated in many human diseases. mTOR also plays a crucial role in regulating autophagy. This Review provides an overview of the mTOR signaling pathway, the mechanisms of mTOR in autophagy regulation, and the clinical implications of mTOR inhibitors in disease treatment.
Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are two homologous transcriptional coactivators that promote cell proliferation, stem cell maintenance, and ...tissue homeostasis. Under favorable conditions, YAP and TAZ are active to promote cell growth through a transcriptional program mediated by the TEAD family transcription factors. Given the indispensability of cellular energy and metabolites for survival and growth, YAP and TAZ are inhibited when energy level is low. Indeed, glucose, fatty acids, hormones, and other metabolic factors have been recently revealed to regulate YAP and TAZ. Conversely, YAP and TAZ are also involved in metabolism regulation, such as to promote glycolysis, lipogenesis, and glutaminolysis, suggesting YAP and TAZ as emerging nodes in coordinating nutrient availability with cell growth and tissue homeostasis. In this Review, we summarize recent findings and provide a current overview of YAP and TAZ in metabolism by focusing on the role of YAP and TAZ as integrators for metabolic cues and cell growth.
This Review discusses the emerging roles of the Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) in metabolism by focusing on the role of YAP and TAZ as integrators for metabolic cues and cell growth.
The Hippo pathway was initially discovered in
Drosophila melanogaster
as a key regulator of tissue growth. It is an evolutionarily conserved signaling cascade regulating numerous biological ...processes, including cell growth and fate decision, organ size control, and regeneration. The core of the Hippo pathway in mammals consists of a kinase cascade, MST1 2 and LATS1 2, as well as downstream effectors, transcriptional coactivators YAP and TAZ. These core components of the Hippo pathway control transcriptional programs involved in cell proliferation, survival, mobility, stemness, and differentiation. The Hippo pathway is tightly regulated by both intrinsic and extrinsic signals, such as mechanical force, cell-cell contact, polarity, energy status, stress, and many diffusible hormonal factors, the majority of which act through G protein-coupled receptors. Here, we review the current understanding of molecular mechanisms by which signals regulate the Hippo pathway with an emphasis on mechanotransduction and the effects of this pathway on basic biology and human diseases.
Hippo pathway components are structurally and functionally conserved and are notable for their role in controlling organ size. More diverse functions of the Hippo pathway have been recognized, ...including development, tissue homeostasis, wound healing and regeneration, immunity, and tumorigenesis. During embryogenesis, different signaling pathways are repeatedly and cooperatively activated, leading to differential gene expression in specific developmental contexts. In this article, we present an overview on the regulation and function of the Hippo pathway in mammalian early development. We introduce the Hippo pathway components and major upstream signals that act through this pathway to influence embryogenesis. We also discuss the roles of Hippo pathway in tissue specification and organ development during organogenesis.
The evolutionary conserved Hippo pathway functions to limit tissue and organ growth and its deregulation contributes to human cancer.Hippo pathway crosstalks with numerous developmental signaling pathways.Hippo signaling plays critical roles in early embryonic development as low Hippo activity is required for trophoblast differentiation and high Hippo activity permits inner cell mass formation.Hippo pathway positively or negatively regulates development of multiple tissues/organs.
Two decades of studies in multiple model organisms have established the Hippo pathway as a key regulator of organ size and tissue homeostasis. By inhibiting YAP and TAZ transcription co-activators, ...the Hippo pathway regulates cell proliferation, apoptosis, and stemness in response to a wide range of extracellular and intracellular signals, including cell-cell contact, cell polarity, mechanical cues, ligands of G-protein-coupled receptors, and cellular energy status. Dysregulation of the Hippo pathway exerts a significant impact on cancer development. Further investigation of the functions and regulatory mechanisms of this pathway will help uncovering the mystery of organ size control and identify new targets for cancer treatment.
In response to a variety of cellular signals, the Hippo pathway plays key roles in regulating tissue homeostasis, stemness, and cancer development.
Control of cell number is crucial in animal development and tissue homeostasis, and its dysregulation may result in tumor formation or organ degeneration. The Hippo pathway in both Drosophila and ...mammals regulates cell number by modulating cell proliferation, cell death, and cell differentiation. Recently, numerous upstream components involved in the Hippo pathway have been identified, such as cell polarity, mechanotransduction, and G-protein-coupled receptor (GPCR) signaling. Actin cytoskeleton or cellular tension appears to be the master mediator that integrates and transmits upstream signals to the core Hippo signaling cascade. Here, we review regulatory mechanisms of the Hippo pathway and discuss potential implications involved in different physiological and pathological conditions.
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