Transforming growth factor-{beta} (TGF-{beta})-induced up-regulation of TGF-{beta} receptors at the cell surface amplifies the TGF-{beta} response [Cell Biology] (Journal of Biological Chemistry)

Functional activation of the transforming growth factor-? (TGF-?) 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-?. We now demonstrate that TGF-? 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-? type I receptor kinase. In addition to an increase in cell-surface TGFBR levels, TGF-? treatment promoted TGFBR internalization, suggesting an overall amplification of TGFBR cycling. The TGF-?-induced increase in receptor presentation at the cell surface amplified TGF-?-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-?-responsive SMADs and gene expression, providing context for the activation of TGF-? signaling in response to BMP during development. In description, our results indicate that TGF-?- 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-? signaling.