Claudin-18: unexpected regulator of lung alveolar epithelial cell proliferation
Darrell N. Kotton
Darrell N. Kotton
Published February 5, 2018
Citation Information: J Clin Invest. 2018;128(3):903-905. https://doi.org/10.1172/JCI99799.
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Commentary

Claudin-18: unexpected regulator of lung alveolar epithelial cell proliferation

Abstract

Claudin 18 (CLDN18) is a tight junction protein that is highly expressed in the lung. While mice lacking CLDN18 exhibit the expected loss of epithelial integrity in the lung, these animals also have unexpectedly large lungs. In this issue of the JCI, Zhou, Flodby, and colleagues reveal that the increased lung size of Cldn18–/– mice is the result of increased type 2 alveolar epithelial (AT2) cell proliferation. This increase in proliferation was shown to be driven by translocation of the transcriptional regulator Yes-associated protein (YAP) to the nucleus and subsequent induction of proliferative pathways. CLDN18-deficent mice also had increased frequency of lung adenocarcinomas. Together, the results of this study advance our understanding of the mechanisms that likely regulate homeostasis of the normal lung as well as promote the proliferative state of malignant cells found in lung adenocarcinomas thought to originate from AT2 cells.

Authors

Darrell N. Kotton

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Figure 1

Schematic summarizing the effects of CLDN18 deficiency in type 2 alveolar epithelial (AT2) cells.

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Schematic summarizing the effects of CLDN18 deficiency in type 2 alveola...
(A) Normally CLDN18 in AT2 cells is found as part of a membrane complex in epithelial apical tight junctions, bound to the tight junction (TJ) protein ZO-1, as well bound to Hippo kinases (p-LATS), and phosphorylated YAP (p-YAP). The phosphorylation of YAP by p-LATS sequesters p-YAP protein in the cytoplasm bound to CLDN18 in the apical junction protein complex. (B) In contrast, loss of CLDN18 in AT2 cells results in loss of tight junction epithelial barrier function as well as loss of p-LATS activity, allowing dephosphorylated YAP to translocate to the nucleus where it promotes proliferation.