The human Hippo pathway restricts tissue growth primarily through mammalian Ste20-like kinase 1/2 (MST1/2) and large tumor suppressor 1/2 (LATS1/2)-mediated regulation of transcriptional activators Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ). When this brake is lifted, nuclear YAP/TAZ cooperate with transcriptional enhanced associate domain transcription factors 1-4 (TEAD1-4) to drive context-specific transcriptional programs that support proliferation, survival, and repair. Therapeutic strategies targeting TEADs using lipid pocket binders, interface 3 (Ω-loop) protein-protein interaction inhibitors, and degraders have opened promising avenues to inhibit this signaling pathway in cancers. Alongside reported clinical antitumor efficacy in mesothelioma and neurofibromatosis type 2 (NF-2)-deficient tumors (see Garralda et al., Ann Oncol 36: S562 [2025]; Yap et al. Nat Med 31: 4281-4290 [2025]; and Yap et al. Cancer Res 83: CT006 [2023]), kidney-related adverse effects have recently emerged, characterized nonclinically or clinically by proteinuria, albuminuria, podocyte injury, and tubular degeneration. Evidence from genetics, organoids, and human-induced pluripotent stem cell (hiPSC) models indicates that YAP/TAZ-TEAD activity is integral to podocyte and tubular homeostasis, providing a mechanistic explanation for the kidney susceptibility. In this review, we summarize nonclinical and early clinical safety observations with pan-TEAD inhibitors, highlight organs most at risk, and discuss approaches that could be taken to optimize the therapeutic index of TEAD inhibitors, like paralog selectivity, adaptive/intermittent dosing, and monitoring of translational biomarkers with pharmacodynamic readouts. Integrating the mechanistic insights and safety lessons learned so far from targeting this pathway could guide safer clinical development of TEAD-directed therapies in the future.
Cells experience and respond to both biochemical and mechanical signals throughout embryonic development and adult homeostasis. Bone and liver represent hard and soft tissues, respectively, and they are critically controlled by their mechanoenvironment. Although the significance of mechanotransduction, the process by which mechanical forces are converted into biological cues, has been acknowledged since the nineteenth century, only recent advances have begun to reveal the molecular underpinnings bridging biophysical stimuli and gene regulation. This review synthesizes the latest insights into mechanotransduction, with a focus on the Hippo/Yes-associated protein (YAP) pathway in development, regeneration, and disorders of the bone and liver, which are differentially controlled by mechanotransduction mediated by YAP/transcriptional coactivator with PDZ-binding motif (TAZ). Studies in bone and liver reveal that cells adapt to their distinct mechanoenvironment by differentially controlling their normal ranges of YAP/TAZ activities, deviation from which causes diseases.
Studies of the Hippo signaling pathway have revealed a highly complex network of interacting regulatory mechanisms that together control pathway output and tissue growth. An overriding theme of this regulation is that it functions to link basic cellular architecture and processes to pathway function, thereby allowing tissue growth to be coordinated with cell shape and tissue morphogenesis. One such mechanism involves the transmembrane protein Crumbs and its partner Expanded, which recruit and activate the core kinases, Tao-1, Hippo, and Warts, to the junctional cortex. In parallel, Kibra and its partner Merlin recruit and activate pathway components at the apicomedial cell cortex. Both mechanisms physically and functionally interact with apical and basolateral polarity components, leading to significant cross talk between these pathways. Importantly, mechanical tension, generated within cells by actomyosin contractile networks and transmitted between cells through intercellular junctions, controls pathway output via multiple mechanisms in distinct cellular domains. In this review, we discuss these regulatory mechanisms, with particular attention to those that function upstream of the core kinases, their organization within epithelial cells, and how this organization allows cells to sense mechanical tension to shape growth in developing tissues.
The universal calcium sensor calmodulin decodes calcium signals by translating calcium ion fluctuations to protein-level responses. Consequently, calmodulin couples calcium signals to a multitude of physiological functions. Calmodulin interacts with an extensive network of proteins, some of which harbor calmodulin as a constitutively bound subunit, whereas others recruit calmodulin in response to a calcium signal. Depending on cellular context, calmodulin can either amplify or dampen calcium signals through positive and negative regulatory mechanisms. This multifaceted nature of calmodulin signaling requires meticulous control, which is conferred by sophisticated genetic and protein-level architecture. The physiological importance of calmodulin is underscored by the discovery of rare and life-threatening pathogenic mutations with a complex phenotypic spectrum.
The Hippo pathway is a central regulator of tissue homeostasis, organ growth, and tumorigenesis. NF2 (Neurofibromin 2, also known as Merlin) functions as a pivotal upstream component that integrates biochemical and mechanical cues to restrain the activity of the transcriptional coactivators Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), thereby limiting cell proliferation. In addition, NF2 regulates members of the Motin family proteins (AMOT, AMOTL1, and AMOTL2) through ubiquitin-mediated turnover to modulate YAP/TAZ signaling output. Moreover, NF2 controls AMOT proteolytic processing to reorganize the actin cytoskeleton, thereby influencing cell motility. Through these mechanisms, NF2 establishes a multilayered regulatory system that coordinates cell proliferation and cell migration. This review summarizes recent advances in how NF2 regulates YAP/TAZ and AMOT functions, focusing on their roles in tumor formation, metastasis, and angiogenesis.
The Hippo signaling pathway and its effectors Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) have emerged as central regulators of respiratory biology, playing essential functions in the development, homeostasis, and regeneration of the lung and trachea. Here, we review the spatiotemporal control of core pathway components in murine and human lungs, highlighting how YAP and TAZ integrate mechanical and molecular cues to govern epithelial patterning, mesenchymal function, vascular integrity, and stem cell behavior. We provide an overview of the mechanisms by which Hippo-YAP/TAZ signaling directs lung injury repair, while also exploring how its dysregulation contributes to fibrosis, vascular remodeling, and lung tumorigenesis. Finally, we discuss the importance of restoring or targeting YAP/TAZ-TEAD activity in the lung and consider the opportunities and challenges associated with pharmacologic inhibition in pulmonary disease.
AMP-activated protein kinase (AMPK)-related kinases, especially NUAK1 and NUAK2, have emerged as crucial modulators of Hippo signaling, linking cellular stress, mechanical tension, and metabolic cues to cell growth and survival. By transmitting these signals to the Hippo cascade, either by directly inhibiting large tumor suppressor 1 and 2 (LATS1/2) or by driving cytoskeletal remodeling, NUAKs effectively keep Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) in an active state. Excessive expression or activity of NUAKs can dysregulate the Hippo pathway to drive disease, promoting oncogenesis, fibrosis, and contributing to other disorders. Thus, NUAK1 and NUAK2 are attractive, druggable therapeutic targets. Accordingly, small-molecule NUAK inhibitors are in development, several of which have been shown to reactivate Hippo signaling, restore YAP/TAZ cytoplasmic retention, and suppress aberrant cancer cell proliferation and fibrosis. Future work aimed at exploring NUAK regulation and function will not only provide new molecular insights in their mode of action but will also help guide the development of inhibitors that can restore Hippo pathway activity in diverse disease contexts.
Phase separation provides cells with a powerful strategy to organize signaling and transcriptional programs through dynamic, membrane-less condensates. The Hippo pathway offers a striking example of this principle. The first evidence came from transcriptional coactivator with PDZ-binding motif (TAZ), which forms nuclear condensates that recruit TEA domain transcription factors (TEADs), transcriptional elongation complexes, and chromatin modifiers to drive efficient and specific gene expression. Subsequent studies have revealed that many upstream Hippo components also undergo phase separation: Polarity proteins and core kinase modules form condensates at the membrane or in the cytoplasm, resulting in either activation or inhibition of the pathway, whereas Yes-associated protein (YAP) undergoes context-dependent phase separation under stress or signaling cues to reshape enhancer topology and modulate transcription. In addition, membrane-associated Merlin (neurofibromin 2 [NF2]) assembles phosphatidylinositol 4-phosphate (PI4P)-dependent solid-like condensates that function as organizing platforms for Hippo activation, as shown in Drosophila, while the core mammalian Ste20-like (MST)/Salvador (SAV)/large tumor suppressor (LATS) kinase module itself forms evolutionarily conserved condensates that enhance signaling efficiency. These findings establish phase separation as a central organizing mechanism in Hippo signaling and suggest a broader paradigm in which condensates provide spatial, temporal, and functional control of diverse signaling pathways.
The Hippo pathway regulates cell proliferation, cell death, and differentiation, and thus plays a key role in organ size control and tissue homeostasis throughout animal development and adult life. Aberrant Hippo signaling is a key driver of human cancer, developmental disorders, other pathological conditions, and aging. Yes-associated protein (YAP) and its paralog, transcriptional coactivator with PDZ-binding motif (TAZ), are two transcriptional coactivators that mediate the major functions of the Hippo pathway by binding to specific transcription factors, such as members of the transcriptional enhanced associate domain (TEAD) family. In this review, we provide an updated overview of this transcriptional module within the Hippo pathway, discuss how it modulates gene transcription to contribute to development and disease, and propose outstanding questions that warrant further investigation in future studies.
Transient receptor potential (TRP) cation channels play diverse roles in cellular Ca2+ signaling. First, as Ca2+-permeable channels that respond to a variety of stimuli, TRP channels can directly initiate cellular Ca2+ signals. Second, as nonselective cation channels, TRP channel activation leads to membrane depolarization, influencing Ca2+ influx via voltage-gated and store-operated Ca2+ channels. Finally, Ca2+ modulates the activity of most TRP channels, allowing them to function as molecular effectors downstream from intracellular Ca2+ signals. The past decade has seen a transformation of the TRP field. Once lacking high-resolution structures, we now have cryogenic electron microscopy (cryo-EM) structures across all seven TRP subfamilies, including multiple ligand-bound, lipid-bound, Ca2+-bound, and disease-mutant states. The rapid expansion of cryo-EM structures across all TRP subfamilies has transformed our understanding of Ca2+ permeation, selectivity, and Ca2+-dependent gating. These structures, together with functional and computational approaches, reveal how TRP channels coordinate Ca2+, how Ca2+ binding modulates pore opening or inactivation, and why some TRPs are highly Ca2+ selective while others are Ca2+ impermeable. This structural framework now underpins efforts to develop targeted therapies for a wide range of TRP-related diseases.
Transcriptional-enhanced associate (TEA)/transcriptional enhanced factor (TEF) domain transcription factors (TEAD1-4) regulate the transcriptional output of Hippo signaling by interacting with the coactivators Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) and play a crucial role in animal development and tumorigenesis. Much of the regulation of the TEAD-YAP/TAZ complex is through the regulation of nuclear translocation and degradation of YAP/TAZ by the upstream Hippo pathway regulators. However, TEADs undergo several posttranslational modifications, which are mostly independent of upstream Hippo pathway components. Alternative splicing of TEAD1 has also been reported to modulate TEAD activities posttranscriptionally. In addition, TEADs can bind to Vestigial-like (VGLL) proteins, which regulate distinct transcription programs that influence tumor growth, immunity, and development. VGLL1-3 may act as transcriptional activators or repressors, while VGLL4 functions primarily as a repressor by competing with YAP/TAZ for TEAD binding. Here, we discuss the Hippo-independent regulations and functions of TEADs, as well as the role of the TEAD-VGLL complex in development and disease, shedding light on therapeutic strategies of targeting the TEAD-VGLL complex.
Mechanical cues regulate Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) not only through upstream Hippo kinases but also by controlling nuclear envelope properties. Forces transmitted from the cytoskeleton to the nucleus through linkers of nucleoskeleton and cytoskeleton (LINC) complexes and the lamina tune nuclear stiffness and deformation thresholds, while nuclear pore complexes act as mechanogated transport channels that can favor YAP nuclear localization under load. In parallel, inner nuclear membrane (INM) proteins and the lamina organize chromatin-lamina contacts that set transcriptional competence once YAP enters the nucleus. Emerging work further implicates additional INM components, including NEMP1 and LEM-domain proteins (e.g., Emerin, LAP2β), in coupling nuclear mechanics, transport, and chromatin organization to YAP output. Together, these modules integrate force transmission, transport, and chromatin organization to determine the magnitude and selectivity of YAP-dependent transcription under mechanical stress.
Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) (YAP/TAZ) are key transcriptional coregulators that govern mammalian cell fate through complex epigenetic mechanisms. As core effectors of the Hippo signaling pathway, they integrate diverse cellular signals-including those mechanical, metabolic, or biochemical in nature-to control lineage specification, organ development, and tissue homeostasis. Although they have been traditionally known for their roles in the control of organ size and tumorigenesis, more recent evidence has revealed their function as important epigenetic modulators that reshape chromatin landscapes to direct cell fate transitions across multiple tissue contexts. Through interactions with chromatin-modifying complexes, the transcriptional machinery, and lineage-specific factors, YAP/TAZ coordinate enhancer activation, superenhancer formation, and chromatin looping to establish transcriptional programs essential for cellular identity. This work reviews the current understanding of YAP/TAZ-mediated epigenetic regulation and examines their tissue-specific roles. We propose a unified mechanistic framework by which the level of YAP/TAZ activity determines enhancer landscapes that favor either differentiated or progenitor-like cellular states, providing a potential basis for applications to regenerative medicine and therapeutic interventions.
In a canonical view of Hippo signaling, the upstream kinases Hippo/MST and Warts (Wts)/large tumor suppressor (LATS) act as an on/off switch that controls phosphorylation and nuclear access of the key pathway effectors, Yorkie (Yki)/Yes-associated protein 1 (YAP1)/transcriptional coactivator with PDZ-binding motif (TAZ). However, studies in flies and mammals have revealed multiple additional regulators that directly associate with Yki/YAP1, often via PPxY motif/WW domain interactions, and fine-tune Hippo pathway activity. In this review, we highlight such "tuners" located at the endosomal membranes, the cell cortex, and in the nucleus, which regulate Yki/YAP1 turnover, nucleocytoplasmic shuttling, and nuclear activity. These factors can set the overall levels of available Yki/YAP1 via sequestration in various subcellular compartments and endosomal/proteasomal degradation. Nuclear "tuners" can direct the Hippo pathway toward specific cellular outcomes, in part through unique transcriptional programs established in concert with Yki/YAP1. Future efforts will be directed at elucidating how the activities of these multiple regulators are coordinated in vivo.
Mitochondria act as dynamic signaling hubs, constantly adapting to tissue-specific metabolic demands to ensure cell homeostasis. Central to this role is their capacity to take up calcium (Ca2+) into the matrix, a process that regulates energy production, cell death pathways, and broader cellular signaling. For decades, mitochondrial Ca2+ (mt-Ca2+) uptake was firmly established at the physiological level, yet the identity of the proteins involved remained elusive. The breakthrough discovery of the mitochondrial calcium uniporter complex (MCUC) has finally enabled genetic dissection of mt-Ca2+ fluxes and revealed its pivotal role in health and disease. Here, we retrace the trajectory of the field from the pioneering observations of the 1960s to the molecular era of the MCUC, emphasizing the latest advances in its regulation, integration into cellular networks, and pharmacological targeting.
Selenocysteine (Sec) incorporation is a uniquely complex and essential form of ribosomal recoding that redefines in-frame UGA codons through an evolutionarily ancient apparatus. Eukaryotic selenoprotein biosynthesis requires a specialized tRNA as well as elongation and selenium-donor factors, and incorporation depends on a 3' untranslated region (UTR) RNA structure, the Sec insertion sequence (SECIS) element. The SECIS is recognized by SECIS-binding protein 2 (SECISBP2/SBP2), resulting in recruitment of the Sec-specific elongation factor eEFSec. Here, we delve into the evolutionary and biochemical basis for Sec incorporation in eukaryotes, summarizing the current understanding of the cis and trans determinants that tune this form of recoding.
The Hippo pathway prevents tissue overgrowth and tumorigenesis in many organs across species. Not surprisingly, this pathway limits the proliferation of progenitor cells in diverse regions of the nervous system, and its dysregulation can lead to neural tumors in humans. However, the functions of the Hippo pathway extend beyond proliferation control. Recent studies have revealed a remarkable functional diversity across neural lineages, encompassing morphogenesis, cell fate, tissue maintenance, and repair. This review synthesizes current evidence on the roles and regulation of the Hippo pathway in neural progenitor cells, glial cells, and neurons, highlighting context-dependent mechanisms and outstanding questions. With the core molecular machinery and many fundamental cellular functions of the Hippo pathway now established, the field is entering a new phase: unraveling the functional significance and regulatory complexity of Hippo signaling in physiologically relevant contexts-both normal and diseased-promises to deepen our mechanistic understanding of neural development and homeostasis, and unlock new strategies for tumor therapy and neural repair.
The Hippo signaling pathway, first identified in Drosophila, is a conserved regulator of organ size and tissue homeostasis that balances proliferation and apoptosis. In mammals, its core kinases mammalian Sterile 20-like kinases 1 and 2 (MST1/2) and large tumor suppressor kinases 1 and 2 (LATS1/2) restrict the transcriptional coactivators Yes-associated protein 1 (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), whose nuclear translocation drives cell proliferation and survival. In the intestine, YAP/TAZ activity is normally repressed to maintain homeostasis, but transient activation following injury promotes regeneration. Injury-induced YAP signaling triggers a regenerative transcriptional program marked by fetal gene re-expression and the emergence of Clusterin (Clu)-positive revival stem cells (revSCs), which restore leucine-rich repeat-containing G-protein-coupled receptor 5-positive (Lgr5+) intestinal stem cells and epithelial integrity. Cross talk between Hippo, Wingless-related integration site (WNT), transforming growth factor β (TGF-β), and p53 signaling orchestrates this dynamic repair process, with precise temporal control of YAP essential for successful regeneration. Dysregulation of these interactions contributes to colorectal cancer tumorigenesis, highlighting the Hippo pathway as a central hub linking intestinal homeostasis, regeneration, and cancer.
