Paring the hugely particular in vivo functions with the diverse TGF ligands as identified from such a basic activation mechanism deduced from in vitro experiments or structure research evidently animal studies with such a straightforward 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 research evidently raises the results in subsequent activation ofto subsequent activation of seemingly only pathways, i.e., either the seemingly only two Angiopoietin-like protein 6 Proteins Storage & Stability various (canonical) two different (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 with the canonical TGF signaling pathways. This sketch neglects the presence Figure 1. Usual depiction with the canonical TGF signaling pathways. This sketch neglects the presence of distinct receptors of either subtype too 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 in this situation the person SMAD proteins of each branches, SMAD 1/5/8 or SMAD 2/3, are activated situation the individual SMAD proteins of both branches, SMAD 1/5/8 or SMAD 2/3, are activated similarly, a a consequence a powerful signaling convergence be postulated. This benefits in a limited similarly, asas consequence a powerful signaling convergence have to has to be postulated. This outcomes within a limited signal specification the central question how these how these development aspects can then act as signal specification top toleading for the central question development components can then act as morphogens morphogens with functions. with very distincthighly distinct functions.It seems illogical that around the one hand Nature has diversified growth variables of this household to more than 30 recognized members, but in the identical time restricted the signaling PHA-543613 Protocol outcome of all ligands toCells 2019, 8,3 ofIt appears illogical that on the a single hand Nature has diversified growth things of this loved ones to extra than 30 recognized members, but in the similar time restricted the signaling outcome of all ligands to initiate intracellular signaling pathways in just two distinctive “flavors”. How Nature handles this obvious discrepancy and may well generate ligand-specific signaling outcomes beneath these situations, is still a concentrate of several research labs worldwide. One attainable way out from this dilemma will be that what is slovenly described as SMAD1/5/8 (or SMAD2/3) signaling, does not constitute a single cascade in which all three (or the two) R-SMADs, i.e., SMAD1, SMAD5, and SMAD8, qualitatively and quantitatively provide an identical signal, which would then invariably bring about identical gene transcription events for the 3 (or the two, respectively) SMAD variables. Initial characterization with the TGF/BMP pathway employed classical in vitro tools to detect SMAD activation, i.e., antibodies detecting phosphorylation of conserved serine residues within the C-terminus [7,8] or reporter-gene assays working with a minimal promoter element (e.g., BRE-luc [9] or CAGA-luc [10]). They are even so incapable to discriminate among SMAD1, five, and eight (or amongst SMAD2 and three) activation and may only specify the certain SMAD branch. SMAD proteins resemble classical transcription factors that co.