TGF-β signaling as a demonstration of upstream signaling Information

The upstream signaling pathway is triggered by the binding of a signaling molecule, a Ligand, to a receiving molecule, Receptor (biochemistry).  Receptors and ligands exist in many different forms, and they will only recognize/bond particular molecules. Upstream extracellular signaling transduce an endless variety of intracellular cascades. ^[1] 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 it initiates.

TGF-β

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. ^[2] 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. ^{[3] [4]} TGF-β is pleiotropic and multifunctional, meaning they are able to act on a wide variety of cell types. ^[5]

Determinants of TGF-β action

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. ^{[6] [2]}

Contextual Factors that determines TGF-β response

• 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 TGF-β Signaling Pathway

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. ^{[7] [2]} 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. ^[8] Individual members of the TGF-β family bind to a certain set of characteristic combination of these type I and type II receptors. ^[9] 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). ^{[8] [2]} 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. ^{[5] [7]}

Downstream TGF-β Signaling 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. ^[10]

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