Translocation of TRPV4-PI3K γ complexes to the plasma membrane drives myofibroblast transdifferentiation.

Translocation of TRPV4-PI3Kγ complexes to the plasma membrane drives myofibroblast transdifferentiation. Sci Signal. 2019 Nov 12;12(607): Authors: Grove LM, Mohan ML, Abraham S, Scheraga RG, Southern BD, Crish JF, Naga Prasad SV, Olman MA Abstract Myofibroblasts are key contributors to pathological fibrotic conditions of several major organs. The transdifferentiation of fibroblasts into myofibroblasts requires both a mechanical signal and transforming growth factor-β (TGF-β) signaling. The cation channel transient receptor potential vanilloid 4 (TRPV4) is a critical mediator of myofibroblast transdifferentiation and in vivo fibrosis through its mechanosensitivity to extracellular matrix stiffness. Here, we showed that TRPV4 promoted the transdifferentiation of human and mouse lung fibroblasts through its interaction with phosphoinositide 3-kinase γ (PI3Kγ), forming nanomolar-affinity, intracellular TRPV4-PI3Kγ complexes. TGF-β induced the recruitment of TRPV4-PI3Kγ complexes to the plasma membrane and increased the activities of both TRPV4 and PI3Kγ. Using gain- and loss-of-function approaches, we showed that both TRPV4 and PI3Kγ were required for myofibroblast transdifferentiation as assessed by the increased production of α-smooth muscle actin and its incorporation into stress fibers, cytoskeletal changes, collagen-1 production, and contractile force. Expression of various mutant forms of the PI3Kγ catalytic subunit (p1...
Source: Science Signaling - Category: Biomedical Science Authors: Tags: Sci Signal Source Type: research