Mechanisms of BMP–Receptor Interaction and Activation

Thomas D. Mueller1    Department Plant Physiology and Biophysics, Julius-von-Sachs Institute of the University Wuerzburg, Wuerzburg, Germany
1 Corresponding author: email address: mueller@biozentrum.uni-wuerzburg.de

1 Evolutionary Expansion and Diversification of the Transforming Growth Factor β Superfamily

Multicellular organisms require continuous intercellular communication not only during their development but also for homeostasis and survival. Processes such as cell differentiation, proliferation, migration or apoptosis depend on endocrine, paracrine or possibly autocrine stimuli, which at their heart are often, but not exclusively exerted by protein–protein interactions at the cell surface involving a secreted (sometimes also membrane-associated) growth factor, and a transmembrane receptor. During evolution, nature has “recycled” successful examples of above combinations thereby forming larger protein families, in which further homologous growth factors plus their respective receptors were formed possibly by gene duplication and acquired additional functionalities necessary to cope with the increasing complexity of the evolving organisms. The transforming growth factor β (TGFβ) superfamily comprising TGFβs, Activins, and bone morphogenetic proteins (BMPs) as well as growth and differentiation factors (GDFs) presents a prime example of such a protein family with a few growth factors in simple organisms like worms (five TGFβ ligands, for review: Savage-Dunn, 2005) and a large number of ligands in mammals (> 30 TGFβ factors in human, for review: Feng & Derynck, 2005; Hinck, 2012; Mueller & Nickel, 2012; Fig. 1A). An evolutionary expansion in the TGFβ superfamily can be also noted from the observation that homologs of BMPs—in contrast to senso strictu TGFβs and Activins—are already found in worms, whereas homologs of Activins appear for the first time in flies and senso strictu TGFβs emerge in fish and amphibian (Newfeld, Wisotzkey, & Kumar, 1999). This suggests that BMPs are likely the founding members of this growth factor family, which then diverged into Activins and TGFβ. Thus, TGFβs seem to be the evolutionary youngest members despite serving as eponym of the whole superfamily. The later emergence of Activins and TGFβs is also consistent with their encoded functionalities. Activins modulate the reproductive axis (Bilezikjian, Blount, Donaldson, & Vale, 2006) and exert regulatory roles in inflammation and immunity (for reviews: Aleman-Muench & Soldevila, 2012; Hedger, Winnall, Phillips, & de Kretser, 2011), and TGFβs being implicated in the control of immunity (for review: Yoshimura & Muto, 2011) and wound healing (for review: Leask & Abraham, 2004), functions that are not or differently implemented in simpler organisms such as worms or insects. But not only TGFβs and Activin additionally appeared later in evolution, but also the number of BMP homologs expanded dramatically.

In Caenorhabditis elegans, four of the five TGFβ members, dbl1, daf7, tig2, and tig3, could be mapped to the mammalian BMP orthologs, BMP5, GDF8/11, BMP8, and BMP2 (for review: Gumienny & Savage-Dunn, 2013); however, the functional similarities seem limited. For instance, dbl1 and daf7, which are involved in the regulation of body size in the so-called Dauer larval development pathway, possibly exert a similar growth-limiting function as found for GDF8/11 in vertebrates. Despite their limited homology with BMP8 and BMP2, no functions have yet been described for the C. elegans orthologs tig-2 and tig-3, but both members might be involved in patterning. Unc129, whose mature region exhibits limited sequence homology to mammalian BMP8 and GDF6, seems to be involved in axon guidance and signals via a non-TGFβ related noncanonical signaling pathway (Gumienny & Savage-Dunn, 2013). In flies, seven TGFβ members have been identified of which the ligands dpp, gbb, and screw can be mapped to the mammalian BMP2/4 and BMP5/6/7 (Newfeld et al., 1999), myoglianin likely presents an ortholog of GDF8/11 (Lo & Frasch, 1999), and dActivinβ, Dawdle and Maverick are fly Activin-like ligands (Kutty et al., 1998; Nguyen, Parker, & Arora, 2000; Parker, Ellis, Nguyen, & Arora, 2006; Serpe & O'Connor, 2006). Possibly due to the evolutionary smaller distance, the fly BMP orthologs dpp, gbb, and screw exert in vivo function more closely related to their vertebrate/mammalian counterparts. Dpp, the fly ortholog of BMP2 and BMP4, is essential for correct dorsoventral patterning in fly (Irish & Gelbart, 1987), a function it shares with BMP2/swirl in fish (Kishimoto, Lee, Zon, Hammerschmidt, & Schulte-Merker, 1997) and BMP4 in mouse (Winnier, Blessing, Labosky, & Hogan, 1995). Drosophila gbb is involved in the development of the fly's intestinal tract or the eyes similarly as found for BMP6/7 in vertebrates (Helder et al., 1995; Luo et al., 1995; Perr, Ye, & Gitelman, 1999; Wharton et al., 1999). On the contrary, the functions encoded by dActivinβ and the further distant Activin-like members Dawdle and Maverick seem to be more limited to neuronal morphogenesis compared to their vertebrate homologs (Kutty et al., 1998; Nguyen et al., 2000; Ting et al., 2007; Zhu et al., 2008).

With the emergence of vertebrates, the number of TGFβ members not only doubled as evident from the 14 and 19 TGFβ ligands in fish (two Activin orthologs; Thisse, Wright, & Thisse, 2000) of Danio rerio are not listed in Massague (2000) and amphibian (Xenopus laevis), but their encoded functions are now more closely resembling those from mammalian orthologs. For instance, BMP4 exerts a mesoderm-inducing activity in early gastrulation in fish and amphibian identical with its patterning function in mammals (Fainsod, Steinbeisser, & De Robertis, 1994; Koster et al., 1991; Neave, Holder, & Patient, 1997; Nikaido, Tada, Saji, & Ueno, 1997; Schmidt, Suzuki, Ueno, & Kimelman, 1995; Winnier et al.,...