Paring the very certain in vivo functions of the various TGF ligands as identified from such a easy activation mechanism deduced from in vitro experiments or BI-0115 Inhibitor structure studies evidently animal studies with such a uncomplicated activation mechanism deduced from in vitro experiments or raises the challenge: How can this array ofissue: Howbe derived from a receptor be derivedmechanism that functions can this array of functions assembly from a receptor structure studies evidently raises the results in subsequent activation ofto subsequent activation of seemingly only pathways, i.e., either the seemingly only two distinctive (canonical) two distinctive (canonical) assembly mechanism that leads SMAD1/5/8- or the SMAD2/3 signalingor the SMAD2/3 signaling cascade (See also Figure 1). pathways, i.e., either the SMAD1/5/8- cascade (See also Figure 1).Figure 1. Usual depiction from the canonical TGF signaling pathways. This sketch neglects the presence Figure 1. Usual depiction from the canonical TGF signaling pathways. This sketch neglects the presence of distinct receptors of either subtype as well as that of heteromeric ligands. Assuming that within this of distinctive receptors of either subtype at the same time as that of heteromeric ligands. Assuming that within this scenario the individual SMAD proteins of each branches, SMAD 1/5/8 or SMAD 2/3, are activated scenario the individual SMAD proteins of each branches, SMAD 1/5/8 or SMAD 2/3, are activated similarly, a a consequence a powerful signaling convergence be postulated. This results inside a restricted similarly, asas consequence a sturdy signaling convergence need to has to be postulated. This benefits in a restricted signal specification the central question how these how these development factors can then act as signal specification top toleading to the central question growth variables can then act as morphogens morphogens with functions. with extremely distincthighly distinct functions.It appears illogical that on the a single hand Nature has diversified development variables of this household to much more than 30 recognized members, but in the very same time restricted the signaling outcome of all ligands toCells 2019, eight,3 ofIt seems illogical that around the one particular hand Nature has diversified growth variables of this household to more than 30 identified members, but at the exact same time restricted the signaling outcome of all ligands to initiate intracellular signaling pathways in just two distinct “flavors”. How Nature handles this apparent discrepancy and may well produce ligand-specific signaling outcomes under these circumstances, continues to be a focus of numerous analysis labs worldwide. 1 achievable way out from this dilemma would be that what exactly is slovenly described as SMAD1/5/8 (or SMAD2/3) signaling, does not constitute a single cascade in which all 3 (or the two) R-SMADs, i.e., SMAD1, SMAD5, and SMAD8, qualitatively and quantitatively provide an identical signal, which would then invariably result in identical gene transcription events for the three (or the two, respectively) SMAD variables. Initial