Transforming growth factor-β (TGF-β)-induced up-regulation of TGF-β receptors at the cell surface amplifies the TGF-β response.

ABSTRACT: Functional activation of the transforming growth factor-β (TGF-β) receptors (TGFBRs) is carefully regulated through integration of post-translational modifications, spatial regulation at the cellular level, and TGFBR availability at the cell surface. Although the bulk of TGFBRs resides inside the cells, AKT Ser/Thr kinase (AKT) activation in response to insulin or other growth factors rapidly induces transport of TGFBRs to the cell surface, thereby increasing the cell's responsiveness to TGF-β. We now demonstrate that TGF-β itself induces a rapid translocation of its own receptors to the cell surface and thus amplifies its own response. This mechanism of response amplification, which hitherto has not been reported for other cell-surface receptors, depended on AKT activation and TGF-β type I receptor kinase. In addition to an increase in cell-surface TGFBR levels, TGF-β treatment promoted TGFBR internalization, suggesting an overall amplification of TGFBR cycling. The TGF-β-induced increase in receptor presentation at the cell surface amplified TGF-β-induced SMAD family member (SMAD) activation and gene expression. Furthermore, bone morphogenetic protein 4 (BMP-4), which also induces AKT activation, increased TGFBR levels at the cell surface, leading to enhanced autocrine activation of TGF-β-responsive SMADs and gene expression, providing context for the activation of TGF-β signaling in response to BMP during development. In summary, our results indicate that TGF-β- and BMP-induced activation of low levels of cell surface-associated TGFBRs rapidly mobilizes additional TGFBRs from intracellular stores to the cell surface, increasing the abundance of cell-surface TGFBRs and cells' responsiveness to TGF-β signaling.

SUBMITTER: Duan D 

PROVIDER: S-EPMC6544840 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature