Cold Spring Harbor perspectives in biology最新文献

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.

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.

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.

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.

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.

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.

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.