Understanding the roles of the Hippo pathway kinases LATS1/2 in the lung epithelium
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Abstract
The lung is a complex organ composed of specialized epithelial cells that coordinate to mediate gas exchange between air and blood and serve as a line of defense against environmental toxins and pathogens. Resident epithelial stem cells in the lung play important roles in mounting effective and efficient responses to these harmful agents, ensuring tissue repair and resilience. The Hippo signaling pathway plays a pivotal role in lung development and regulating epithelial cell behavior. It is critical for translating extracellular signals, such as mechanical cues like tissue stiffness, extracellular matrix tension and cell density, into cellular responses that control growth, differentiation, and tissue architecture. Key effectors of the Hippo pathway signaling include large tumor suppressor 1 (LATS1) and large tumor suppressor 2 (LATS2) kinases, which control the activity of the transcriptional effectors yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ). Low LATS1/2 kinase activity results in nuclear accumulation of YAP/TAZ, promoting YAP/TAZ interactions with transcription factors that together promote the expression of genes related to stem cell renewal, cell proliferation and cell survival. In the work presented here, the consequences of YAP/TAZ hyperactivation, through LATS1 and LATS2 deletion, were assessed in different populations of lung epithelial cells in adult mouse lungs. These populations included Keratin 5 (KRT5) positive basal cells (BCs), Secretoglobin family 1A member 1 (SCGB1A1) positive secretory cells (SCs) and surfactant protein C (SFTPC) positive alveolar type 2 (AT2) cells. The loss of LATS1/2 signaling in basal cells led to marked proliferation characterized by specific expression patterns of the basal stem cell marker, tumor protein 63 (P63), and the proliferation marker, Kiel 67 (Ki67), suggesting that basement membrane-derived cues may help maintain basal stem cell identity and support cell expansion. In AT2 cells, loss of LATS1/2 signaling appeared to cause septal thickening, implying that unchecked YAP/TAZ activation in AT2 cells, even in the absence of injury, may contribute to lung disease or potentially facilitate lung cancer development. In contrast to these models, where increased epithelial proliferation indicated a role for YAP/TAZ in basal and AT2 cells in driving tumor formation, the loss of LATS1/2 in SCs uncovered an unexpected and unique function for YAP/TAZ. Prolonged YAP/TAZ activation in SCs led to the emergence of abnormal alveolar type 1 (AT1)-like cells in the airways, characterized by markers typical of immature or pathological AT1 states. This aberrant differentiation was accompanied by heightened inflammation and an increase in AT2 cell populations that expressed markers linked to an inflammatory phenotype. These altered AT2 cells also lacked nuclear YAP/TAZ and the capacity to differentiate into mature AT1 cells, indicating a potential blockage in normal alveolar regeneration. The loss of LATS1/2 in SCs therefore uncovered a novel, non-tumorigenic role for YAP/TAZ activity in SCs. Collectively, these models emphasize the importance of understanding Hippo signaling dynamics within specific lung epithelial cell types. This nuanced knowledge could enable a more strategic approach to targeting Hippo pathway components in lung disease and cancer, allowing for interventions that are finely tuned to each cell type's role in disease progression.
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2025