Pancreatic β cells are essential for glucose homeostasis through the regulated secretion of insulin in response to rising glucose levels. A critical component of this process is the precise and timely positioning of insulin secretory granules (ISGs) at the secretion sites on the plasma membrane. This positioning is mediated by molecular motors that transport ISGs along cytoskeletal tracks, including microtubules (MTs) and actin filaments. Despite their importance, the roles of molecular motors in insulin-secreting β cells remain incompletely understood. In this review, we summarize current findings on the involvement of molecular motors both in ISG transport, directly regulating granule availability for secretion, and in the organization of other subcellular structures, thereby indirectly influencing secretion. These indirect roles include kinesin-1-mediated microtubule sliding that configures the β cell-specific MT network, the spatial organization of calcium channels, and mitochondrial positioning, among others. We also draw parallels between β cells and neurons, proposing that insights from neuronal motor protein studies can guide future research directions in β cell biology.
The skin is a dynamic, regenerative organ capable of withstanding diverse internal and external stresses, supported by tissue-resident stem cells. A complex signaling network regulates interactions between epidermal stem cells, dermal cells, immune cells, and the extracellular matrix to maintain tissue integrity. Disruptions in these signaling pathways can impair cellular communication, alter stem cell lineage commitment, and compromise epidermal stem cell identity, ultimately resulting in a loss of coordinated tissue function. In this review, we highlight recent insights into three key signaling factors-metabolic, mechanical, and inflammatory cues-that regulate epidermal stem cell behavior during homeostasis, regeneration, and aging. We further discuss how dysregulation of these pathways contributes to pathological skin remodeling and explore emerging intervention strategies targeting signaling molecules to restore epidermal stem cell function and skin health.
Within the family of protein kinases there is a subgroup of 'evolutionarily related members of the total human kinome' that are devoid (or have very limited) enzymatic activity. These proteins, so-called pseudokinases, play important functions thanks to their capacity to establish regulatory protein-protein interactions. Specifically, this opinion article focuses on a group of pseudokinases called Tribbles. Tribbles (Trbl) was originally discovered in Drosophila, followed by the subsequent identification of their orthologs in mammals (TRIB1, TRIB2, TRIB3, and STK40). Work over the last decades has shown how these proteins contribute to fine-tuning key signaling pathways involved in the regulation of proliferation, differentiation, inflammation and adaptation to nutritional changes. Accordingly, dysregulation of Tribbles proteins (TRIBs) contributes to the establishment and progression of insulin resistance, obesity, type II diabetes, atherosclerosis and cancer. Here, we will discuss some of the mechanisms by which Tribbles pseudokinases carry out their functions and the crucial importance of cell context in defining the precise role played by each of the TRIBs, with emphasis on TRIB1 and TRIB3, under different physiopathological situations.
Metastatic colonization is governed by the earliest interactions between disseminated tumor cells (DTCs) and the tissue microenvironment. Extracellular vesicles (EVs) have emerged as critical mediators of this early communication, conditioning distant organs before and after DTC arrival. Despite extensive characterization of cancer EV cargoes and functions, a fundamental question remains unresolved: when, where, and to which cell types cancer EVs are delivered during the initial stages of metastatic colonization. This knowledge gap stems from limitations of conventional in vitro and in vivo assays, which lack physiological architecture or sufficient spatiotemporal resolution. Recent advances in physiological metastatic models, including organotypic ex vivo models, together with innovative EV labeling and tracking technologies, now enable direct visualization of EV transfer within native-like tissue contexts. Here, we propose a conceptual framework in which metastatic colonization is "decoded" as a spatiotemporally orchestrated EV-mediated intercellular signaling, where EV distribution, tropism, and recipient-cell responses collectively define DTC fate. We discuss how integrating these emerging platforms can decode EV-mediated communication during metastatic colonization that leads to therapeutic development.
Isoform generation is a strategy for fine-tuning the activity of essential proteins, particularly during cell differentiation and cancer development. The coding sequence of mRNA is determined by alternative splicing during pre-mRNA processing, allowing the generation of different mRNA variants from a single gene. Alternative splicing is modulated by several pathways, including the selection of transcription initiation and termination sites. The activity of RNA-binding proteins involved in splicing is affected by spatial factors, including RNA folding, separation in local bio-condensates, and the three-dimensional organization of chromatin. The length of untranslated regions and the selection of alternative polyadenylation sites impact mRNA stability and translation accessibility, ultimately controlling the abundance of specific isoforms. This review highlights recent discoveries about the nuclear factors that modify alternative splicing, thereby coordinating the variety of mRNA and protein isoforms with cell state.
Primary cilia are sensory organelles that host various signalling receptors and proteins to coordinate signalling pathways essential for tissue homeostasis. This review explores the molecular mechanisms by which intraflagellar transport (IFT) machinery, the BBSome coat complex, small GTPases, and various secondary messenger signalling molecules cooperate to establish and maintain ciliary composition. We discuss how IFT trains, guided by kinesin-2 and dynein-2 motors, traffic receptors and signalling components into and out of the cilium, and how the lipid composition within the cilium plays a regulatory function. We also described how secondary messengers such as cAMP and Ca2+ coordinate ciliary signalling outputs, including hedgehog and insulin secretion. Finally, we have also discussed how the BBSome selects cargo for export and the role of small GTPases in its trafficking, together ensuring the compositional integrity and signalling fidelity of this organelle. A mechanistic understanding of these integrated trafficking and signalling systems provides a framework for elucidating the pathogenesis of ciliopathies and identifying potential therapeutic targets.
Ras proteins modulate key cellular signalling pathways and drive excessive proliferation when mutated in cancer. However, they also influence actin cytoskeleton organisation. In the model organism Dictyostelium, domains of active Ras pattern the plasma membrane and locally reorganise the actin cortex, driving the formation of actin-based protrusions. Recent work has identified analogous Ras-dependent actin structures in cancer cells, including actin waves, protrusions and membrane blebs, which promote cell survival and motility. In addition, Ras activation induces changes to signalling networks and gene expression that result in cell-wide changes to actin network architecture, cortex mechanics and cell shape. This review examines how the local and global effects of Ras signalling on the actin cytoskeleton are coordinated and how they contribute to cytoskeletal plasticity during cancer progression.
Signal packaging is a fundamental mechanism that enables cells to manufacture, target, stabilize, and amplify chemical cues. By organizing chemokines, lipid mediators, and guidance factors into glycan lattices, lipid-protein carriers, membrane nanodomains, extracellular vesicles, and other structures, cells transform intrinsically labile chemical cues into long-lived, interpretable instructions. Such packaging maintains gradients in crowded tissues and ensures timely delivery to targeted recipients, thus transforming chemical signals into actively orchestrated and effective programs. Failures in this system contribute to metastasis, chronic inflammation, and barrier dysfunction. In this review, we highlight compartmentalized signal packaging as an evolutionary design principle for cellular communication and discuss how recognizing this information layer provides new insights into the control, engineering, and dysregulation of cellular guidance systems.
Serotonin (5-HT), a conserved monoamine derived from tryptophan metabolism, has emerged as a multifaceted regulator in cancer biology. Beyond receptor signaling, serotonylation allows transglutaminase 2 (TGM2) to covalently incorporate serotonin into target proteins, linking intracellular serotonin availability to regulation of tumor metabolism, chromatin state, and immune function. Despite recent progress, the determinants of substrate selection and the physiological scope of serotonylation remain incompletely defined. In this review, we integrate advances in serotonin metabolism and receptor signaling with emerging insights into serotonylation, emphasizing its roles in tumors and the tumor microenvironment, and outline priorities for future investigation.
Deep learning (DL) has revolutionized bioimage analysis, enabling unprecedented insights into cellular dynamics. This review provides an overview of state-of-the-art DL approaches for quantifying cellular dynamics from 2D microscopy images, considering the three fundamental steps in dynamics analysis: identifying objects in space through segmentation, connecting them through time via tracking, and extracting meaningful measurements from their resulting trajectories. We highlight how recent methodological innovations in DL are complementing more classical, long-established algorithms, and discuss emerging trends as well as the importance of ensuring that DL-powered cellular dynamics analysis remains scientifically sound and accessible. By discussing methodological advances and pointing to available practical tools, this review aims to bridge the gap between computational expertise and biological applications, providing guidance to help navigate this rapidly evolving field and identify approaches that are relevant to specific research questions.
Receptor tyrosine kinases and other cell surface receptors are tightly regulated by endocytosis, which controls both the duration and spatial organisation of their downstream signalling. In cancers, altered internalisation and trafficking lead to sustained or misrouted signalling that promotes uncontrolled cell growth and survival. Motor proteins and their cargo adaptors are central to receptor signalling since they determine intracellular endosome positioning, recycling, and degradation. While their roles in intracellular transport have long been studied, the dysfunction of motors and adaptors in the context of aberrant receptor signalling and cancer progression has only recently begun to emerge. In this review, we highlight recent advances in understanding motor and adaptor function in healthy cells, discuss evidence implicating these proteins in oncogenic signalling, and consider how these insights may guide future directions in the field.
The cell cycle is marked by dynamic fluctuations in reactive oxygen species (ROS). While low levels of ROS can stimulate cell proliferation, excessive ROS lead to cell cycle arrest. Notably, cell cycle arrest can further generate more ROS, creating a bidirectional relationship that underscores the necessity for cells to finely tune ROS levels to maintain homeostasis and ensure proper cell cycle progression. Unlike classical cell cycle checkpoint systems, ROS directly oxidise cysteine residues in critical cell cycle regulators, with examples ranging from cyclins and cyclin-dependent kinases to APC/C, CDK inhibitors, and other CDK regulators, altering their functions. This review explores the interplay between ROS and the cell cycle, emphasizing how understanding their relationship could enhance therapeutic outcomes.
p97, also known as valosin-containing protein (VCP), is an evolutionarily conserved ATPase that functions upstream of the two major protein degradation pathways: the ubiquitin-proteasome system (UPS) and autophagy. In this capacity, it plays a central role in maintaining protein homeostasis and genome stability. The roles of the UPS and autophagy in regulating immune responses including within the tumour microenvironment (TME), are well established. However, the contribution of p97 to shaping immune responses in the TME has only recently begun to emerge. Recent findings indicate that p97 not only affects cancer cells directly but also plays a critical role in the heterogeneous TME, acting as a key driver of tumour progression, therapy resistance, and metastatic initiation. In this review, we will discuss the role of the p97 system in tumour immunity. A deeper understanding of how p97 regulates immune responses is essential for advancing cancer biology and oncology.
Signal transduction is a complex system governing cellular behavior across physiological and pathological contexts. Advances in systems biology have positioned cell modeling as a powerful tool for reconstructing the dynamics and trajectories of disease processes. Nevertheless, despite progress in AI-assisted model generation, parameter estimation remains a challenge, especially under data constraints. In contrast, molecular dynamics simulations offer crucial, high-resolution insights by uncovering conformational activation mechanisms and by extracting kinetic parameters; however, they face scalability limitations. This review focuses on modeling of the ErbB signaling system, highlighting recent advances at both the cellular and molecular scales. Emerging trends, such as simulation data reuse, machine learning-guided network inference, and modeling within realistic environmental contexts, are now driving a compelling integration of these molecular and cellular modeling paradigms.
There are many ways for a cell to die, but each cell only dies once, causing an inherent variability that results from common triggers activating interconnected signaling networks that diverge at key decision points during cell death initiation, progression, and execution. Despite the death of each cell being a unique biomolecular event, shared features allow us to categorize the process depending on the pathways activated and their outcomes. Here we outline core concepts about the dynamic interplay between cell death pathways, focusing on apoptosis, necroptosis, pyroptosis, and ferroptosis. We highlight unresolved decision points, including the dynamics of pore formation and the points of no return. We also discuss conceptual commonalities across systems and outline key recent developments that refine our understanding of the dynamic regulation of cell death.
Mechanical forces shape cellular form and function by regulating key cellular processes; however, when dysregulated, they contribute to disease. Excessive forces can be detrimental to cells, damaging cytoskeleton, deforming nuclei, and even rupturing the cell itself. To counteract these effects, cells deploy protective mechanisms that enhance mechanical resilience. Emerging evidence highlights a novel strategy for rapid tension release via force-dependent actin polymerization mediated by formin-family proteins such as Dia1. Acting as a mechanical "safety valve", Dia1 buffers otherwise damaging stress and promotes zyxin-mediated repair, preserving cytoskeletal architecture, safeguarding the nucleus, and maintaining cellular integrity. Loss of Dia1 disrupts signaling cascades that converge on key mechanotransduction processes governing cell fate and disease progression. In this review, we explore recent advances in force-dependent actin polymerization and its role in cytoskeletal protection, nuclear homeostasis, and cellular adaptation to mechanical forces.
The cell plasma membrane of eukaryotic cells is a fantastically complex and important system ensuring the transport of information from the environment towards individual cells and vice versa. It provides a mechanical and chemical delimitation of the cell, enabling cell migration, the formation of tissues, as well as the transport of electrical signals. The watchmaker's approach of understanding this complex system by rebuilding aspects of it in minimal systems using purified and reconstituted proteins has proven to be very powerful and has delivered crucial insights into key mechanisms governing cell membrane activities and organisation. However, recent advances have been limited, and it remains to be seen whether functional mimics of the cell surface can be engineered and what advantage those would deliver compared to more traditional methods of synthetic biology. This piece summarises some of the recent advances and gives a perspective on where the field could go.
Lipids are now recognized as central regulators of cellular signaling, extending well beyond their traditional roles in membrane structure and energy storage. As spatially confined and rapidly inducible messengers, signaling lipids integrate membrane dynamics, metabolism, and signal transduction to control processes like inflammation, immune responses, vesicular trafficking, cytoskeletal organization, and cell fate decisions. This review highlights key mechanistic principles underlying lipid signaling specificity, including localized biosynthesis, enzymatic turnover, and receptor engagement. We trace the evolution of the field from classical eicosanoids and phosphoinositides to sphingolipids, lysophospholipids, and endocannabinoids, and focus on emerging mediators such as fatty acid esters of hydroxy fatty acids, specialized pro-resolving mediators, and lysophosphatidylserines. We conclude by discussing how dysregulated lipid signaling contributes to disease and outline future directions, emphasizing membrane contact sites, signaling crosstalk, and advances in lipidomics and imaging.
Membrane trafficking is an essential aspect of cellular physiology, determining the spatial distribution of macromolecules within a cell in response to conditions such as nutrient availability and cellular stress. Much of this trafficking happens at intracellular membrane delimited vesicles and organelles-here referred to as endomembranes. Actin cytoskeletal dynamics contribute to intracellular force production, including fueling aspects of membrane trafficking on endomembranes. Cellular membrane trafficking and actin dynamics have traditionally been studied as separate specializations. Yet, actin networks interact with membranes and contribute to membrane remodeling, organelle motility, and cargo sorting. Here, we propose a conceptual framework for how actin filament networks participate in endomembrane trafficking and describe examples of each of the putative functions. Furthermore, we describe how aberrant actin-endomembrane interactions contribute to disease states and pose some open questions for the field.
LINE-1 (L1) retrotransposons are increasingly recognized as key players in cancer biology. While traditionally viewed as mutators through their endonuclease (EN) activity, recent findings show that L1 elements can also activate innate immune pathways independently of EN activity, particularly type I interferon signaling via "viral mimicry." These dual functions position L1 at the intersection of genome regulation and innate immune response. From this perspective, this mini-review discusses recent and still debated insights into L1's role in cancer, including non-cell-autonomous effects mediated by extracellular vesicles, its role in promoting cellular plasticity, and therapeutic opportunities through reverse transcriptase inhibition. Together, these findings highlight L1 retrotransposons as drivers of tumor development and potential clinical targets.