Litwack Bone Morphogenic Protein

1. Auflage 2015
ISBN: 978-0-12-802592-5
Verlag: Elsevier Science & Techn.
Format: EPUB
Kopierschutz: 6 - ePub Watermark

E-Book, Englisch, Band Volume 99, 346 Seiten

Reihe: Vitamins and Hormones

First published in 1943, Vitamins and Hormones is the longest-running serial published by Academic Press. The Series provides up-to-date information on vitamin and hormone research spanning data from molecular biology to the clinic. A volume can focus on a single molecule or on a disease that is related to vitamins or hormones. A hormone is interpreted broadly so that related substances, such as transmitters, cytokines, growth factors and others can be reviewed. This volume focuses on Bone Morphogenic Protein. - Expertise of the contributors - Coverage of a vast array of subjects - In depth current information at the molecular to the clinical levels

Autoren/Hrsg.

Litwack, Gerald

Leseproben

Chapter One 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: [e-mail] Abstract
Bone morphogenetic proteins (BMPs), together with the eponymous transforming growth factor (TGF) ß and the Activins form the TGFß superfamily of ligands. This protein family comprises more than 30 structurally highly related proteins, which determine formation, maintenance, and regeneration of tissues and organs. Their importance for the development of multicellular organisms is evident from their existence in all vertebrates as well as nonvertebrate animals. From their highly specific functions in vivo either a strict relation between a particular ligand and its cognate cellular receptor and/or a stringent regulation to define a distinct temperospatial expression pattern for the various ligands and receptor is expected. However, only a limited number of receptors are found to serve a large number of ligands thus implicating highly promiscuous ligand–receptor interactions instead. Since in tissues a multitude of ligands are often found, which signal via a highly overlapping set of receptors, this raises the question how such promiscuous interactions between different ligands and their receptors can generate concerted and highly specific cellular signals required during embryonic development and tissue homeostasis. Keywords Bone morphogenetic proteins Ligand–receptor interactions Protein–protein recognition BMP receptor activation mechanisms 1 Evolutionary Expansion and Diversification of the Transforming Growth Factor ß 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 ß (TGFß) superfamily comprising TGFßs, 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 TGFß ligands, for review: Savage-Dunn, 2005) and a large number of ligands in mammals (> 30 TGFß factors in human, for review: Feng & Derynck, 2005; Hinck, 2012; Mueller & Nickel, 2012; Fig. 1A). An evolutionary expansion in the TGFß superfamily can be also noted from the observation that homologs of BMPs—in contrast to senso strictu TGFßs and Activins—are already found in worms, whereas homologs of Activins appear for the first time in flies and senso strictu TGFßs 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 TGFß. Thus, TGFßs seem to be the evolutionary youngest members despite serving as eponym of the whole superfamily. The later emergence of Activins and TGFßs 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 TGFßs 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 TGFßs and Activin additionally appeared later in evolution, but also the number of BMP homologs expanded dramatically. Figure 1 (A) Phylogenetic analysis of the TGFß ligand superfamily. The TGFßs can be classified into four subgroups indicated on the left: (I) sensu stricto TGFßs, (II) Activin/Inhibins, (III) BMPs/GDFs, and (IV) others. Type I and type II receptor recruitment is indicated, the activation of either the SMAD1/5/8 or SMAD2/3 pathway is marked by light or dark gray-shaded boxes, respectively. (B) Phylogenetic analysis of the TGFß receptors showing the classification into type I and type II receptors. Light and dark gray boxes indicate the activation of either SMAD1/5/8 or SMAD2/3. (C) TGFß proteins are expressed as pre-proproteins containing a signal peptide (SP), a prodomain, which in TGFßs is covalently dimerized by disulfide bonds (marked by asterisks), a proteolytic processing site (RXXR) and a mature region containing the characteristic cystine-knot motif comprising six conserved cysteine residues (marked by bars). Some TGFßs lack a seventh cysteine residue (marked by two asterisks) involved in covalent dimer formation. (D) Architecture of the TGFß receptors comprising a signal peptide (SP), an extracellular ligand-binding domain (ECD), a single-span transmembrane element, and an intracellular kinase domain. Type I receptors differ by an additional membrane-proximal glycine/serine-rich motif (GS-box). Furthermore, BMPRII has a unique C-terminal domain (marked by an asterisks), which recruits additional signaling proteins. In Caenorhabditis elegans, four of the five TGFß 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-TGFß related noncanonical signaling pathway (Gumienny & Savage-Dunn, 2013). In flies, seven TGFß 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 dActivinß, 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 dActivinß 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 TGFß members not only doubled as evident from the 14 and 19 TGFß 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.,...