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.
