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The mTOR pathway integrates a diverse set of environmental cues, such as growth factor signals and nutritional status, to direct eukaryotic cell growth. Over the past two and a half decades, mapping of the mTOR signalling landscape has revealed that mTOR controls biomass accumulation and metabolism by modulating key cellular processes, including protein synthesis and autophagy. Given the pathway’s central role in maintaining cellular and physiological homeostasis, dysregulation of mTOR signalling has been implicated in metabolic disorders, neurodegeneration, cancer and ageing. In this Review, we highlight recent advances in our understanding of the complex regulation of the mTOR pathway and discuss its function in the context of physiology, human disease and pharmacological intervention.The mTOR pathway integrates diverse environmental cues to control biomass accumulation and metabolism by modulating key cellular processes, including protein synthesis and autophagy. Dysregulation of mTOR signalling has been implicated in metabolic disorders, neurodegeneration, cancer and ageing, and is thus a promising target for pharmacological intervention.

Exciting new discoveries have transformed the view of the lysosome from a static organelle dedicated to the disposal and recycling of cellular waste to a highly dynamic structure that mediates the adaptation of cell metabolism to environmental cues. Lysosome-mediated signalling pathways and transcription programmes are able to sense the status of cellular metabolism and control the switch between anabolism and catabolism by regulating lysosomal biogenesis and autophagy. The lysosome also extensively communicates with other cellular structures by exchanging content and information and by establishing membrane contact sites. It is now clear that lysosome positioning is a dynamically regulated process and a crucial determinant of lysosomal function. Finally, growing evidence indicates that the role of lysosomal dysfunction in human diseases goes beyond rare inherited diseases, such as lysosomal storage disorders, to include common neurodegenerative and metabolic diseases, as well as cancer. Together, these discoveries highlight the lysosome as a regulatory hub for cellular and organismal homeostasis, and an attractive therapeutic target for a broad variety of disease conditions.Lysosomes are mainly associated with cellular waste disposal. But it has recently been discovered that by integrating various environmental cues, they have a broader role as regulatory hubs for cellular and organismal homeostasis. The modulation of lysosome function could thus be a promising therapeutic strategy for the treatment of cancer as well as metabolic and neurodegenerative disorders.

The Hippo pathway effectors YAP and TAZ regulate normal and tumorigenic organ growth. Recent studies in vitro and in mouse models have shown that these two transcription co-activators can also promote tissue regeneration. This property could be exploited for regenerative medicine, as long as the therapeutic approaches can minimize the potential for cancer development.

Cell behaviour is strongly influenced by physical, mechanical contacts between cells and their extracellular matrix. We review how the transcriptional regulators YAP and TAZ integrate mechanical cues with the response to soluble signals and metabolic pathways to control multiple aspects of cell behaviour, including proliferation, cell plasticity and stemness essential for tissue regeneration. Corruption of cell-environment interplay leads to aberrant YAP and TAZ activation that is instrumental for multiple diseases, including cancer. Stefano Piccolo and co-authors review recent insights into how YAP and TAZ transcription factors respond to the tissue environment, and how they mediate altered cell behaviour. Feedback mechanisms and crosstalk with other pathways are discussed, as are outstanding questions in the field.

Linkages between the outer membrane of Gram-negative bacteria and the peptidoglycan layer are crucial for the maintenance of cellular integrity and enable survival in challenging environments 1 – 5 . The function of the outer membrane is dependent on outer membrane proteins (OMPs), which are inserted into the membrane by the β-barrel assembly machine 6 , 7 (BAM). Growing Escherichia coli cells segregate old OMPs towards the poles by a process known as binary partitioning, the basis of which is unknown 8 . Here we demonstrate that peptidoglycan underpins the spatiotemporal organization of OMPs. Mature, tetrapeptide-rich peptidoglycan binds to BAM components and suppresses OMP foldase activity. Nascent peptidoglycan, which is enriched in pentapeptides and concentrated at septa 9 , associates with BAM poorly and has little effect on its activity, leading to preferential insertion of OMPs at division sites. The synchronization of OMP biogenesis with cell wall growth results in the binary partitioning of OMPs as cells divide. Our study reveals that Gram-negative bacteria coordinate the assembly of two major cell envelope layers by rendering OMP biogenesis responsive to peptidoglycan maturation, a potential vulnerability that could be exploited in future antibiotic design. Peptidoglycan stem peptides in the Gram-negative bacterial cell wall regulate the insertion of essential outer membrane proteins, thus representing a potential target for antibiotic design.

Bone metastases remain a serious health concern because of limited therapeutic options. Here, we report that crosstalk between ROR1–HER3 and the Hippo–YAP pathway promotes breast cancer bone metastasis in a long noncoding RNA-dependent fashion. Mechanistically, the orphan receptor tyrosine kinase ROR1 phosphorylates HER3 at a previously unidentified site Tyr1307, following neuregulin stimulation, independently of other ErbB family members. p-HER3 Tyr1307 recruits the LLGL2– MAYA –NSUN6 RNA–protein complex to methylate Hippo/MST1 at Lys59. This methylation leads to MST1 inactivation and activation of YAP target genes in tumour cells, which elicits osteoclast differentiation and bone metastasis. Furthermore, increased ROR1, p-HER3 Tyr1307 and  MAYA  levels correlate with tumour metastasis and unfavourable outcomes. Our data provide insights into the mechanistic regulation and linkage of the ROR1–HER3 and Hippo–YAP pathway in a cancer-specific context, and also imply valuable therapeutic targets for bone metastasis and possible therapy-resistant tumours. Li  et al.  show that ROR1–HER3 receptor tyrosine kinase signalling in breast cancer cells inhibits the MST1/2 Hippo pathway kinases through a lncRNA termed MAYA . The resulting activation of YAP promotes osteoclast differentiation for bone metastasis.

Key Points Simple models combined with quantitative time-lapse measurements of cell growth and division are an essential first step towards generating and falsifying mechanistic hypotheses for the homeostasis of cell size and the cell cycle. The recently discovered adder paradigm for cell size control, in which cells add a fixed amount of material between consecutive divisions or DNA replication initiations, has been established in several bacterial species and seems to be widespread. However, the vast majority of bacterial phyla have not yet been investigated. Classic and recent data have indicated that average cell size depends on three key variables: the concentration of DNA replication initiation sites, the average time between DNA replication initiation and cell division, and the mass-doubling time. This dependence accounts for the classic Growth Law, which links cell size to the nutrient quality of the medium, and highlights the need for the simultaneous measurement of a range of cell variables to investigate cell size mutants or perturbations. DnaA, MreB and FtsZ are key regulators of DNA replication initiation, cell growth and cell division, respectively, but currently there is no overarching view of how molecular mechanisms coordinate cell cycle events and cell growth to achieve cell size control and robust genome inheritance. It is remarkable how robustly a bacterial species can maintain its preferred size. In this Review, Willis and Huang explore classic and current knowledge of the mechanisms that coordinate bacterial cell size with essential growth and cell cycle processes. It is remarkable how robustly a bacterial species can maintain its preferred size. This capacity is intimately related to control of the cell cycle: cell size and growth rate determine the duration of the cell cycle, which must accommodate the initiation and completion of DNA replication, and the assembly of the division apparatus during steady growth. Although we still lack an integrated view of the interconnections among events in the cell cycle, cell growth and cell size, the development of high-throughput imaging and image-processing protocols has stimulated a renaissance in the field. In this Review, we summarize recent findings, present simple classic models for cell size control, introduce high-throughput data-collection techniques, and explore the mechanisms that coordinate cell size with essential growth and cell cycle processes.

The Hippo–YAP (Yes-associated protein) pathway is an evolutionarily and functionally conserved regulator of organ size and growth with crucial roles in cell proliferation, apoptosis, and differentiation. This pathway has great potential for therapeutic manipulation in different disease states and to promote organ regeneration. In this Review, we summarize findings from the past decade revealing the function and regulation of the Hippo–YAP pathway in cardiac development, growth, homeostasis, disease, and regeneration. In particular, we highlight the roles of the Hippo–YAP pathway in endogenous heart muscle renewal, including the pivotal role of the Hippo–YAP pathway in regulating cardiomyocyte proliferation and differentiation, stress response, and mechanical signalling. The human heart lacks the capacity to self-repair; therefore, the loss of cardiomyocytes after injury such as myocardial infarction can result in heart failure and death. Despite substantial advances in the treatment of heart failure, an enormous unmet clinical need exists for alternative treatment options. Targeting the Hippo–YAP pathway has tremendous potential for developing therapeutic strategies for cardiac repair and regeneration for currently intractable cardiovascular diseases such as heart failure. The lessons learned from cardiac repair and regeneration studies will also bring new insights into the regeneration of other tissues with limited regenerative capacity.

The Hippo pathway was discovered as a conserved tumour suppressor pathway restricting cell proliferation and apoptosis. However, the upstream signals that regulate the Hippo pathway in the context of organ size control and cancer prevention are largely unknown. Here, we report that glucose, the ubiquitous energy source used for ATP generation, regulates the Hippo pathway downstream effector YAP. We show that both the Hippo pathway and AMP-activated protein kinase (AMPK) were activated during glucose starvation, resulting in phosphorylation of YAP and contributing to its inactivation. We also identified glucose-transporter 3 ( GLUT3 ) as a YAP-regulated gene involved in glucose metabolism. Together, these results demonstrate that glucose-mediated energy homeostasis is an upstream event involved in regulation of the Hippo pathway and, potentially, an oncogenic function of YAP in promoting glycolysis, thereby providing an exciting link between glucose metabolism and the Hippo pathway in tissue maintenance and cancer prevention. In two related papers, Chen and colleagues and Guan and colleagues report a crucial role for the AMPK and Hippo pathways in glucose homeostasis. Starvation triggers AMPK-mediated phosphorylation and inactivation of YAP.

YAP (Yes-associated protein) is a transcription co-activator in the Hippo tumour suppressor pathway and controls cell growth, tissue homeostasis and organ size. YAP is inhibited by the kinase Lats, which phosphorylates YAP to induce its cytoplasmic localization and proteasomal degradation. YAP induces gene expression by binding to the TEAD family transcription factors. Dysregulation of the Hippo–YAP pathway is frequently observed in human cancers. Here we show that cellular energy stress induces YAP phosphorylation, in part due to AMPK-dependent Lats activation, thereby inhibiting YAP activity. Moreover, AMPK directly phosphorylates YAP Ser 94, a residue essential for the interaction with TEAD, thus disrupting the YAP–TEAD interaction. AMPK-induced YAP inhibition can suppress oncogenic transformation of Lats-null cells with high YAP activity. Our study establishes a molecular mechanism and functional significance of AMPK in linking cellular energy status to the Hippo–YAP pathway. In two related papers, Chen and colleagues and Guan and colleagues report a crucial role for the AMPK and Hippo pathways in glucose homeostasis. Starvation triggers AMPK-mediated phosphorylation and inactivation of YAP.