Translocation of TRPV4-PI3Kgamma complexes to the plasma membrane drives myofibroblast transdifferentiation #MMPMID31719171
Grove LM; Mohan ML; Abraham S; Scheraga RG; Southern BD; Crish JF; Naga Prasad SV; Olman MA
Sci Signal 2019[Nov]; 12 (607): ? PMID31719171show ga
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-beta (TGF-beta) 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 gamma (PI3Kgamma), forming nanomolar-affinity, intracellular TRPV4-PI3Kgamma complexes. TGF-beta induced the recruitment of TRPV4-PI3Kgamma complexes to the plasma membrane and increased the activities of both TRPV4 and PI3Kgamma. Using gain- and loss-of-function approaches, we showed that both TRPV4 and PI3Kgamma were required for myofibroblast transdifferentiation as assessed by the increased production of alpha-smooth muscle actin and its incorporation into stress fibers, cytoskeletal changes, collagen-1 production, and contractile force. Expression of various mutant forms of the PI3Kgamma catalytic subunit (p110gamma) in cells lacking PI3Kgamma revealed that only the noncatalytic, amino-terminal domain of p110gamma was necessary and sufficient for TGF-beta-induced TRPV4 plasma membrane recruitment and myofibroblast transdifferentiation. These data suggest that TGF-beta stimulates a noncanonical scaffolding action of PI3Kgamma, which recruits TRPV4-PI3Kgamma complexes to the plasma membrane, thereby increasing myofibroblast transdifferentiation. Given that both TRPV4 and PI3Kgamma have pleiotropic actions, targeting the interaction between them could provide a specific therapeutic approach for inhibiting myofibroblast transdifferentiation.
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Sci+Signal 2019 ; 12 (607): ?
