upstream and downstream (transduction) upstream and downstream (transduction) the upstream signaling pathway is triggered by the binding of a signaling molecule, a ligand, to a receiving molecule, a receptor. receptors and ligands exist in many different forms, and only recognize/bond to particular molecules. upstream extracellular signaling transduce a variety of intracellular cascades. 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. receptors and ligands are common upstream signaling molecules that dictate the downstream elements of the signal pathway. a plethora of different factors affect which ligands bind to which receptors and the downstream cellular response that they initiate. tgf-β the extracellular type ii and type i kinase receptors binding to the tgf-β ligands. 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. the significance of tgf-β is apparent with the human diseases that occur when tgf-β processes are disrupted, such as cancer, and skeletal, intestinal and cardiovascular diseases. tgf-β is pleiotropic and multifunctional, meaning they are able to act on a wide variety of cell types. mechanism the effects of transforming growth factor-β (tgf-β) are determined by cellular context. 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. the different ligands and receptors of tgf-β are significant as well in the composition signal transduction pathway. the signal transduction components: ligand isoforms, ligand traps, co-receptors, receptor sub-types, inhibitory smad proteins, crosstalk inputs the transcriptional cofactors of smad proteins: pluripotency factors, lineage regulators, dna-binding cofactors, hats and hdacs, snf, chromatin readers the epigenetic factors: heterochromatin, pluripotency marks, lineage marks, emt marks, ips cell marks, oncogenic marks. upstream pathway 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. signaling is initiated by the binding of tgf-β to its serine/threonine receptors. the serene/threonine receptors are the type ii and type i receptors on the cell membrane. binding of a tgf-β members induces assembly of a heterotetrameric complex of two type i and two type ii receptors at the plasma membrane. individual members of the tgf-β family bind to a certain set of characteristic combination of these type i and type ii receptors. the type i receptors can be divided into two groups, which depends on the cytoplasmic r-smads that they bind and phosphorylate. the first group of type i receptors (alk1/2/3/6) bind and activate the r-smads, smad1/5/8. the second group of type i reactors (alk4/5/7) act on the r-smads, smad2/3. the phosphorylated r-smads then form complexes and the signals are funneled through two regulatory smad (r-smad) channels (smad1/5/8 or smad2/3). after the ligand-receptor complexes phosphorylate the cytoplasmic r-smads, the signal is then sent through smad 1/5/8 or smad 2/3. this leads to the downstream signal cascade and cellular gene targeting. downstream pathway tgf-β regulates multiple downstream processes and cellular functions. the pathway is highly variable based on cellular context. tgf-β downstream signaling cascade includes regulation of cell growth, cell proliferation, cell differentiation, and apoptosis.