Fect of ActRIIB on TGF ligand signaling could be regarded as SMAD-branch dependent at first sight. Having said that, Perron and Dodd cIAP-1 Molecular Weight showed that BMP7-evoked chemotaxis of monocytic cells is because of a ErbB2/HER2 Gene ID non-canonical, SMAD-independent signaling and hence the unique involvement of ActRIIB in TGF signaling follows a much more complex mechanism [110]. A similar albeit indirect obtaining was also produced by New and coworkers in a studyCells 2019, 8,13 ofinvestigating the unique biological function of the activin kind II receptors ActRII and ActRIIB [113]. Introducing mRNAs encoding for truncated ActRII or ActRIIB receptors (using the kinase domain deleted and thus acting dominant adverse) into Xenopus embryos revealed that the truncated ActRIIB receptor triggered axial defects. In contrast, the truncated ActRII receptors caused the formation of a secondary axes related to the phenotype made by inhibition of BMP4 signaling. Considering that this phenotype couldn’t be established by the truncated ActRIIB receptor it indicates, that BMP4 doesn’t transduce signals through this receptor. Our personal experiments investigating form II receptor usage showed that also BMP2 didn’t activate SMAD1/5/8 signaling, if ActRIIB was co-transfected with ALK3 in COS cells, while ActRII and BMPRII in mixture with ALK3 had been capable to accomplish so (unpublished information, Weber, D.; Sebald, W. and Nickel J.). This comes as a surprise as in vitro interaction analyses utilizing surface plasmon resonance (SPR) showed that the extracellular domain of ActRIIB bound BMP2 (as well as GDF5) together with the highest apparent binding affinity in comparison to the other form II receptors while the differences between the 3 type II receptors had been rather modest (about 6-fold) [52]. But, what explanation can be provided that a ligand-receptor assembly consisting of BMP2, ALK3, and ActRIIB doesn’t form an active signaling complex, though a complex in which ActRIIB is replaced by either BMPRII or ActRII, each of which share greater than 65 amino acid identity with ActRIIB, do so Crystal structure analyses of two ternary complexes of BMP2 bound to ALK3 and ActRIIB (PDB entries 2H62 and 2H64, [46]) and to ALK3 and ActRII (PDB entry 2GOO, [114]) didn’t reveal any structural differences inside the complex architectures that could clarify distinct receptor activation. It should be noted that four alternative splice forms (termed B1 to B4) exist for the sort II receptor ActRIIB [88]. These splice types differ by inclusion of a short peptide segment (8 mer) in the extracellular domain just ahead in the transmembrane helix and/or a further peptide insertion (24 mer) inside the intracellular domain also situated in close proximity towards the transmembrane segment. Splice forms B1 and B2 both harbor the brief segment inside the extracellular domain, but differ within the presence or absence of the intracellular, juxtamembrane segment (B1 contains both insertions, while splice form B2 harbors only the extracellular insertion and as a result closely resembles the form II receptor ActRII). The splice forms B3 and B4 both lack the insertion inside the extracellular domain and similarly differ inside the presence or absence from the intracellular splice segment. Radioligand binding of activin A to the four distinctive ActRIIB splice forms revealed that splice types B3 and B4 exhibited decreased ligand binding, even though splice forms B1 and B2 that each contain the extracellular insertion segment did not show any distinction in activin A binding compared to ActRII (for BMP4 differential bindin.