TGFB1 (TGF-β1)
TGFB1 (transforming growth factor beta 1) is a secreted signal that arrests epithelial proliferation in healthy tissue and, once a tumor has lost the ability to respond, drives invasion and immune suppression instead.
Function
TGF-β1 is secreted as an inactive complex bound to its processing peptide (LAP) and to latent TGF-β-binding proteins in the extracellular matrix; mechanical force, proteases, or integrins release the active factor. It signals through a receptor complex that phosphorylates SMAD2/3, which with SMAD4 enters the nucleus and regulates transcription. In epithelial cells the output is cytostatic: SMAD complexes induce p15 and p21, repress MYC, and hold the cell in G1. The same signal promotes fibroblast proliferation and matrix production, and TGF-β1 drives fibrosis.
In cancer
Early tumors respond to the cytostatic signal; late tumors lose SMAD4 or the pathway’s growth-arrest arm and then respond to TGF-β1’s other outputs - epithelial-mesenchymal transition, matrix remodeling, angiogenesis, and immunosuppression. The cytokine is thus a tumor suppressor early and a tumor promoter late, a switch determined by the tumor’s own mutations. TGF-β1 is also a component of the senescence-associated secretory phenotype and of the immunosuppressive microenvironment that checkpoint inhibitors struggle to penetrate.
Notes
- Human gene symbol: TGFB1; UniProt P01137; 390 amino acids (precursor); TGF-β family.