G to these distinctive HSP40 custom synthesis splice types couldn’t be observed, on the other hand it have to be noted that the overall binding of radioactively labeled BMP4 to ActRIIB was rather low). This indicates that a removal of a short segment inside the extracellular aspect close to the transmembrane segment significantly impairs activin ligand binding [88]. Even though the presence or absence of the intracellular splice segment did not have an effect on activin A binding nothing at all is identified with regards to whether each splice types differ in activin A-mediated receptor activation or downstream SMAD signaling. On the other hand, information from an animal model recommend that the ActRIIB B4 splice type, which lacks each splice insertions, can compensate for the other three splice variants and therefore all 4 types possibly present functional sort II receptors [115]. In another study Liu et al. could show that in the osteoblast precursor cell line 2T3 BMP2 can induce SMAD signaling also as expression of alkaline phosphatase via ActRIIB [116]. Although the splice form of the ActRIIB receptor addressed within this study is not recognized, this observation could possibly also point towards cell-type dependent functionality of ActRIIB. While it’s unclear from these limited data which role the variety II receptor ActRIIB requires up inside the signaling of distinct TGF members and by which mechanism these different effects are mediated, these examples break the simplification of all ligand-interacting type II receptor exerting the identical function and which is frequently referred to within the following quote: “BMPs signal by means of two different kinds of serine/threonine kinase receptors. Three distinct form II receptors [BMP receptor II (BMPRII), activin receptor II (ActRII), and ActRIIB] and three variety I receptors [BMPRIA, BMPRI1B, and activin receptor-like kinase two (ALK2)] have been identified. The mechanism of receptor activation includes BMP-induced phosphorylation of two sequentially acting kinases, using the type I receptor actingCells 2019, 8,14 ofas a substrate for the sort II receptor kinase. Activated BMP type I receptors relay the signal to the cytoplasm by phosphorylating their immediate downstream targets, SMAD1, SMAD5, and SMAD8 proteins.” [117]. In addition to the fact that the potentially distinctive functionality of ActRII and ActRIIB can possibly diversify the signaling outcome to get a subset of BMP ligands, utilization with the activin variety II receptors can add additional complexity if unique TGF/BMP CDK1 site ligands are present at the identical time. Activin A and various SMAD2/3-activating GDFs, e.g., GDF1, GDF3, GDF8, GDF10, GDF11, also employ ActRII and ActRIIB to initiate downstream signaling. Even so, in contrast to most SMAD1/5/8-activating BMPs, for instance BMP2, BMP4, BMP7, GDF5, etc., the SMAD2/3-activating activins and GDFs bind (in vitro) both activin variety II receptors with significantly greater affinities (see e.g.,: [52,118,119]). Hence, the activin form II receptors can exert a dual signaling activity in a complicated setting in which activin A and BMP2 (or even a equivalent pair of SMAD2/3- and SMAD1/5/8-activating TGF ligands) are simultaneously present with each other with either activin sort II- and their respective variety I receptor. In the absence of BMPRII, activin A and BMP2 will directly compete for binding towards the (shared) activin form II receptor. Because activin A binds ActRII with a lot greater affinity in comparison with BMP2, it is going to competitively impede the recruitment of activin sort II receptors by BMP2. As a consequence, activin A will act as a competitive antagonist of B.