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

Transforming growth factor (TGF-β1) is a critical profibrotic mediator in chronic lung disease, and there are no specific strategies to mitigate its adverse effects. Activation of TGF-β1 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-β receptor (TβR)-I and downregulate TGF-β1 signaling. Little is known about how TGF-β1 releases TβR-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-β1 recruits LMTK2 to the cell surface. Here, we tested the hypothesis that TGF-β1 recruits LMTK2 to inhibit PP1c, allowing activation of TβR-I. First, LMTK2 interacted with the TGF-β1 pathway in the human bronchial epithelium at multiple checkpoints. Second, TGF-β1 inhibited PP1c by an LMTK2-dependent mechanism. Third, TGF-β1 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-β1 signaling in human bronchial epithelium.NEW & NOTEWORTHY Activation of the transforming growth factor (TGF)-β1 signaling pathway is complex, involving many ligands, transmembrane receptors, transcription factors, and modulating proteins. The mechanisms of TGF-β1 signaling activation/inactivation are not fully understood. We propose for the first time a model by which transmembrane lemur tyrosine kinase 2 (LMTK2) forms a complex with phosphoprotein phosphatase 1 (PP1c) to activate TGF-β1 signaling and Smad7, growth arrest and DNA damage (GADD34), and PP1C form a complex to inactivate TGF-β1 signaling in human bronchial epithelium.