LMTK2 switches on canonical TGF-β1 signaling in human bronchial epithelial cells

Transforming growth factor (TGF-beta 1) is a critical profibrotic mediator in chronic lung disease, and there are no specific strategies to mitigate its adverse effects. Activation of TGF-beta 1 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-beta receptor (T beta R)-I and downregulate TGF-beta 1 signaling. Little is known about how TGF-beta 1 releases T beta R-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-beta 1 recruits LMTK2 to the cell surface. Here, we tested the hypothesis that TGF-beta 1 recruits LMTK2 to inhibit PP1c, allowing activation of T beta R-I. First, LMTK2 interacted with the TGF-beta 1 pathway in the human bronchial epithelium at multiple checkpoints. Second, TGF-beta 1 inhibited PP1c by an LMTK2-dependent mechanism. Third, TGF-beta 1 used 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-beta 1 signaling in human bronchial epithelium.