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The mechanism of insulin action is a central theme in biology and medicine. In addition to the rather rare condition of insulin deficiency caused by autoimmune destruction of pancreatic β-cells, genetic and acquired abnormalities of insulin action underlie the far more common conditions of type 2 diabetes, obesity and insulin resistance. The latter predisposes to diseases ranging from hypertension to Alzheimer disease and cancer. Hence, understanding the biochemical and cellular properties of insulin receptor signalling is arguably a priority in biomedical research. In the past decade, major progress has led to the delineation of mechanisms of glucose transport, lipid synthesis, storage and mobilization. In addition to direct effects of insulin on signalling kinases and metabolic enzymes, the discovery of mechanisms of insulin-regulated gene transcription has led to a reassessment of the general principles of insulin action. These advances will accelerate the discovery of new treatment modalities for diabetes.

WNT ligands induce Ca 2+ signalling on target cells. PKD1 (polycystin 1) is considered an orphan, atypical G-protein-coupled receptor complexed with TRPP2 (polycystin 2 or PKD2), a Ca 2+ -permeable ion channel. Inactivating mutations in their genes cause autosomal dominant polycystic kidney disease (ADPKD), one of the most common genetic diseases. Here, we show that WNTs bind to the extracellular domain of PKD1 and induce whole-cell currents and Ca 2+ influx dependent on TRPP2. Pathogenic PKD1 or PKD2 mutations that abrogate complex formation, compromise cell surface expression of PKD1, or reduce TRPP2 channel activity suppress activation by WNTs. Pkd2 −/− fibroblasts lack WNT-induced Ca 2+ currents and are unable to polarize during directed cell migration. In Xenopus embryos, pkd1, Dishevelled 2 (dvl2) and wnt9a act within the same pathway to preserve normal tubulogenesis. These data define PKD1 as a WNT (co)receptor and implicate defective WNT/Ca 2+ signalling as one of the causes of ADPKD. Seokho et al. report that Wnt ligands bind the extracellular domain of polycystin 1 (PKD1) and induce Ca 2+ influx through the Ca 2+ -permeable ion channel TRPP2. This activity is abrogated by PKD1 mutations linked to polycystic kidney disease.

Biological information can be shared between cells via extracellular vesicles. However, how cargo carried by extracellular vesicles elicits biological responses remains unresolved. Deciphering the molecular mechanisms that govern packaging and targeted delivery of extracellular vesicle cargo will be required to establish extracellular vesicles as important signalling entities.

The altered metabolic programme of cancer cells facilitates their cell-autonomous proliferation and survival. In normal cells, signal transduction pathways control core cellular functions, including metabolism, to couple the signals from exogenous growth factors, cytokines or hormones to adaptive changes in cell physiology. The ubiquitous, growth factor-regulated phosphoinositide 3-kinase (PI3K)–AKT signalling network has diverse downstream effects on cellular metabolism, through either direct regulation of nutrient transporters and metabolic enzymes or the control of transcription factors that regulate the expression of key components of metabolic pathways. Aberrant activation of this signalling network is one of the most frequent events in human cancer and serves to disconnect the control of cell growth, survival and metabolism from exogenous growth stimuli. Here we discuss our current understanding of the molecular events controlling cellular metabolism downstream of PI3K and AKT and of how these events couple two major hallmarks of cancer: growth factor independence through oncogenic signalling and metabolic reprogramming to support cell survival and proliferation.This Review discusses the PI3K–AKT signalling network and its control of cancer cell metabolism through both direct and indirect regulation of nutrient transport and metabolic enzymes, thereby connecting oncogenic signalling and metabolic reprogramming to support cancer cell survival and proliferation.

Cells constantly adapt their metabolism to meet their energy needs and respond to nutrient availability. Eukaryotes have evolved a very sophisticated system to sense low cellular ATP levels via the serine/threonine kinase AMP-activated protein kinase (AMPK) complex. Under conditions of low energy, AMPK phosphorylates specific enzymes and growth control nodes to increase ATP generation and decrease ATP consumption. In the past decade, the discovery of numerous new AMPK substrates has led to a more complete understanding of the minimal number of steps required to reprogramme cellular metabolism from anabolism to catabolism. This energy switch controls cell growth and several other cellular processes, including lipid and glucose metabolism and autophagy. Recent studies have revealed that one ancestral function of AMPK is to promote mitochondrial health, and multiple newly discovered targets of AMPK are involved in various aspects of mitochondrial homeostasis, including mitophagy. This Review discusses how AMPK functions as a central mediator of the cellular response to energetic stress and mitochondrial insults and coordinates multiple features of autophagy and mitochondrial biology.

Key Points Vascular endothelial growth factor receptor (VEGFR) signalling is tightly regulated at different levels: ligand and receptor expression, the presence of co-receptors and accessory proteins (that is, neuropilins, proteoglycans and integrins, among others) and inactivating tyrosine phosphatases. Together, these control the rate of cellular uptake, degradation and recycling. Canonical versus non-canonical signalling indicates VEGF-dependent versus non-VEGF-dependent activation of VEGFR2. Among the latter are mechanical forces, gremlins, galectins, lactate and low-density lipoprotein (LDL) cholesterol. VEGFR signalling output is regulated by crosstalk with numerous receptor systems, including fibroblast growth factor receptor (FGFR), AXL, Delta–Notch and Hippo pathways. VEGFR2 endocytosis and subsequent cytoplasmic trafficking have a key role in regulation of ERK signalling, which is crucial for numerous VEGF biological activities, including arterial fate determination, proliferation and migration. VEGF-dependent regulation of permeability involves T cell-soecific adapter (TSAd) and junctional SRC activation and crosstalk with AXL-dependent PI3K activation. Protein tyrosine phosphatases have important roles in regulation of specific VEGFR2-activated intracellular signalling events. Vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) are crucial for the formation and remodelling of blood vessels. VEGFR2, which is the main endothelial VEGFR, is regulated by receptor-interacting proteins, endocytosis and trafficking. Recent insights have been gained into these layers of regulation and the crosstalk between VEGFR2 signalling and other endothelial signalling cascades. Vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) are uniquely required to balance the formation of new blood vessels with the maintenance and remodelling of existing ones, during development and in adult tissues. Recent advances have greatly expanded our understanding of the tight and multi-level regulation of VEGFR2 signalling, which is the primary focus of this Review. Important insights have been gained into the regulatory roles of VEGFR-interacting proteins (such as neuropilins, proteoglycans, integrins and protein tyrosine phosphatases); the dynamics of VEGFR2 endocytosis, trafficking and signalling; and the crosstalk between VEGF-induced signalling and other endothelial signalling cascades. A clear understanding of this multifaceted signalling web is key to successful therapeutic suppression or stimulation of vascular growth.

Although organelles compartmentalize eukaryotic cells, they can communicate and integrate their activities by connecting at membrane contact sites (MCSs). The roles of MCSs in biology are becoming increasingly clear, with MCSs now known to function in intracellular signalling, lipid metabolism, membrane dynamics, organelle biogenesis and the cellular stress response.

PI3Ks are a family of lipid kinases that phosphorylate intracellular inositol lipids to regulate signalling and intracellular vesicular traffic. Mammals have eight isoforms of PI3K, divided into three classes. The class I PI3Ks generate 3-phosphoinositide lipids, which directly activate signal transduction pathways. In addition to being frequently genetically activated in cancer, similar mutations in class I PI3Ks have now also been found in a human non-malignant overgrowth syndrome and a primary immune disorder that predisposes to lymphoma. The class II and class III PI3Ks are regulators of membrane traffic along the endocytic route, in endosomal recycling and autophagy, with an often indirect effect on cell signalling. Here, we summarize current knowledge of the different PI3K classes and isoforms, focusing on recently uncovered biological functions and the mechanisms by which these kinases are activated. Deeper insight into the PI3K isoforms will undoubtedly continue to contribute to a better understanding of fundamental cell biological processes and, ultimately, of human disease.Phosphoinositide 3-kinases (PI3Ks) are lipid kinases that generate 3-phosphoinositides, which govern cellular signal transduction and membrane trafficking. The PI3K family comprises three classes of enzymes, which include several isoforms and complexes; the myriad of cellular functions and means of regulation of these enzymes are now coming into focus.

Key Points Rho GTPases regulate a wide range of cellular responses, including changes to the cytoskeleton and cell adhesion. Their activity therefore needs to be precisely controlled to determine which response occurs, depending on the context and stimulus. Most Rho GTPases cycle between an active GTP-bound and an inactive GDP-bound form, a process that is regulated by guanine nucleotide exchange factors (GEFs), GTPase-activating proteins (GAPs) and guanine nucleotide dissociation inhibitors (GDIs). In their GTP-bound form, they interact with a diverse range of different targets to induce cellular responses. In addition to GTP–GDP cycling, Rho GTPases are regulated by a diverse range of post-translational modifications, including phosphorylation, ubiquitylation and sumoylation, which alter their localization, activity and stability. GEFs, GAPs and GDIs are also regulated by post-translational modifications, which in turn affect their activity, stability and ability to form protein complexes. These changes then impinge on where and when Rho GTPases are activated. The spatiotemporal activation of Rho GTPases is coordinated by a complex network of post-translational modifications and protein–protein interactions. This determines which Rho GTPase targets are activated, and hence the cellular outcome. Rho GTPases, which cycle between a GTP-bound active form and a GDP-bound inactive form, regulate cytoskeletal and cell adhesion dynamics and thus are crucial for the coordination of cell migration, cell polarity and cell cycle progression. Rho GTPases and their regulators (GEFs, GAPs and GDIs) are also regulated by post-translational modifications and the formation of regulatory complexes to ensure precise spatiotemporal Rho GTPase activation. Rho GTPases regulate cytoskeletal and cell adhesion dynamics and thereby coordinate a wide range of cellular processes, including cell migration, cell polarity and cell cycle progression. Most Rho GTPases cycle between a GTP-bound active conformation and a GDP-bound inactive conformation to regulate their ability to activate effector proteins and to elicit cellular responses. However, it has become apparent that Rho GTPases are regulated by post-translational modifications and the formation of specific protein complexes, in addition to GTP–GDP cycling. The canonical regulators of Rho GTPases — guanine nucleotide exchange factors, GTPase-activating proteins and guanine nucleotide dissociation inhibitors — are regulated similarly, creating a complex network of interactions to determine the precise spatiotemporal activation of Rho GTPases.

Epithelial tissue integrity is maintained through specialized intercellular junctions known to coordinate homeostatic processes. In this context, outside-in signaling and mechanotransduction through desmosomal cadherins, the building blocks of desmosomes and main stress bearers in epithelial tissue, are only starting to emerge. To better understand the dual function of desmosomal cadherins in structural integrity and cellular signaling, we here performed a systematic, unbiased review on pathogenic signaling effectors identified in models and patients with pemphigus vulgaris (PV). PV is an autoimmune blistering disorder characterized by disruption of desmosomal transadhesion through autoantibodies mainly targeting the desmosomal cadherins desmoglein (Dsg) 3 or Dsg1 and Dsg3. The survey of functionally validated pathogenic pathways published since inception in 1977 up to mid-2024 identifies 128 studies and 128 signaling molecules, highlighting a coherent network of biomechanical, bioelectrical, and biochemical signaling events. This in-depth analysis will stimulate future research as well as development of potential therapeutic applications beyond PV.