Upstream and downstream (transduction)

A plethora of different factors affect which ligands bind to which receptors and the downstream cellular response that they initiate.

Transforming growth factor-β (TGF-β) is a superfamily of cytokines that play a significant upstream role in regulating of morphogenesis, homeostasis, cell proliferation, and differentiation.

[3][4] TGF-β is pleiotropic and multifunctional, meaning they are able to act on a wide variety of cell types.

There are three kinds of contextual factors that determine the shape the TGF-β response: the signal transduction components, the transcriptional cofactors and the epigenetic state of the cell.

[7] The type I receptors can be divided into two groups, which depends on the cytoplasmic R-Smads that they bind and phosphorylate.

The extracellular type II and type I kinase receptors binding to the TGF-β ligands.
The type II receptors phosphorylate the type I receptors; the type I receptors are then enabled to phosphorylate cytoplasmic R-Smads, which then act as transcriptional regulators.