LMTK2 switches on canonical TGF-ß1 signaling in human bronchial epithelia.

ABSTRACT

Transforming Growth Factor (TGF-ß1) is a critical pro-fibrotic mediator in chronic lung disease, and there are no specific strategies to mitigate its adverse effects. Activation of TGF-ß1 signaling is a multipart process involving ligands, transmembrane receptors, and transcription factors. In addition, an intricate network of adaptor proteins fine-tunes the signaling strength, duration, and activity. Namely, Smad7 recruits growth arrest and DNA damage (GADD34) protein that then interacts with the catalytic subunit of phosphoprotein phosphatase 1 (PP1c) to inactivate TGF-ß Receptor (TßR)-I and downregulate TGF-ß1 signaling. Little is known about how TGF-ß1 releases TßR-I from the GADD34-PP1c inhibition to activate its signaling. Transmembrane Lemur Tyrosine Kinase 2 (LMTK2) is a PP1c inhibitor, and our published data showed that TGF-ß1 recruits LMTK2 to the cell surface. Here, we tested the hypothesis that TGF-ß1 recruits LMTK2 to inhibit PP1c, allowing activation of TßR-I. First, LMTK2 interacted with the TGF-ß1 pathway in the human bronchial epithelium at multiple checkpoints. Second, TGF-ß1 inhibited PP1c by an LMTK2-dependent mechanism. Third, TGF-ß1 utilized LMTK2 to activate canonical Smad3-mediated signaling. We propose a model whereby the LMTK2-PP1c and Smad7-GADD34-PP1c complexes serve as on-and-off switches in the TGF-ß1 signaling in human bronchial epithelium.