SurveyRecent advances in BMP receptor signaling
Introduction
Bone Morphogenetic Proteins (BMPs) were originally described to act as bone growth factors. The BMP family of cytokines comprises over 20 different ligands that belong to the Transforming Growth Factor β (TGFβ) superfamily. After secretion and cleavage from the propeptide, BMPs either bind to the extracellular matrix, soluble antagonists, co-receptors or to transmembrane serine/threonine kinase receptors. Latter induces signal transduction, which can result in transcriptional responses (e.g. Smad signaling) or non-transcriptional responses (e.g. cytoskeletal rearrangements).
It is the concert of extracellular modulators, transmembrane receptors, co-receptors, and cytosolic receptor-associated proteins, which determines signaling specificity. These important players in BMP signaling are described in this review, referring to early developmental processes as well as to diseases caused by alterations in the BMP pathway.
Section snippets
Role of BMPs during early vertebrate development
The establishment of the dorsal–ventral (DV) axis is one of the first key events during early development. Spemann and Mangold could show that secreted ligands from the dorsal blastopore lip (Spemann organizer) are essential for proper embryonic patterning [1]. Further genetic studies in Xenopus, Drosophila and Zebrafish suggested that gradients of BMPs drive differentiation of ectodermal cells into central nervous system, neural crest, and epidermis [2], [3], [4].
In Xenopus, BMPs were shown to
Ligands
BMPs are expressed as large precursor proteins. The raw molecule carries an N-terminal signal peptide, which directs the protein to the secretory pathway, a prodomain that ensures proper folding, and the C-terminal mature peptide. Each monomer is stabilized by three intramolecular disulfide bonds, formed between six highly conserved cysteines, a structure known as cystine knot motif. The active signaling molecule is typically formed through homodimerization. Dimers are covalently linked via a
Regulation and finetuning of BMP signaling
The initial steps of signal transduction, i.e. binding of the ligand to distinct receptors, subsequent internalization of the ligand–receptor complex, and initiation of signaling pathways, are tightly controlled. Each BMP signaling molecule is subject to interaction with an extensive range of proteins. Antagonists bind and inactivate the ligands, decoy-receptors sequester ligands at the cell surface, co-receptors and intracellular proteins interact with the receptors to regulate downstream
Downstream signaling
Binding of BMPs to their receptor complexes may trigger Smad as well as non-Smad signaling cascades (Fig. 2). As mentioned previously, the selected signaling route depends on many factors. In the following paragraphs we highlight recent findings in Smad and non-Smad pathways as well as in non-transcriptional responses that are triggered by BMPs.
BMPs in cell polarity and migration
Polarization is characterized by spatiotemporal distribution of proteins, giving cells an overall direction and it is necessary to trigger migration. Extensions at the leading front of a polarized cell are termed protrusions. They occur as broad lamellipodia or spike-like filopdia, usually formed by Actin polymerization. Protrusions function as matrix-associated traction sites that pull the cell forward [110]. Migration is mediated by chemotactic cytokines and/or interaction of the cell with
Mutations in BMP receptors cause vascular and skeletal diseases
In this paragraph we give two examples of how alterations of BMP signaling cause severe human disorders. Familial and idiopathic pulmonary arterial hypertension (PAH) is caused by over 40 unique heterozygous germline loss of function mutations in BRII [143], [144]. In addition, mutations in the Alk1 gene have been reported to cause PAH [145]. Pathophysiological consequences appear to mainly rely on smooth muscle cells for which BMP acts as a negative growth regulator. PAH is characterized by
Conclusion
From the data described in our review it becomes most evident, that in order to manipulate the pleiotropic effects of BMPs, for example by small molecule inhibitors, antagonists or super-agonists, it is of special importance to understand the molecular mechanism and the contributing signaling molecules in detail, to exclude unwanted side effects of novel therapeutic targets. This, however, is the current challenge of successfully developing new regenerative therapies.
Acknowledgements
We thank Raghu Bhushan for suggestions regarding the manuscript and the entire Knaus group for providing feedback on the figures.
Christina Sieber (middle) holds a Diploma in biology from the Julius-Maximilians-Universität Würzburg (2004) and a PhD in biochemistry from the Freie Universität Berlin (2009). Tina joined the group of Petra Knaus during her undergraduate studies in 2002. Her thesis was mainly concerned with GDF5 signaling and the role of the BMP co-receptor Ror2 in BMP signaling. At present, Tina works as a scientific writer and is funded by the Innovationsfonds, which was established in the course of the
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Christina Sieber (middle) holds a Diploma in biology from the Julius-Maximilians-Universität Würzburg (2004) and a PhD in biochemistry from the Freie Universität Berlin (2009). Tina joined the group of Petra Knaus during her undergraduate studies in 2002. Her thesis was mainly concerned with GDF5 signaling and the role of the BMP co-receptor Ror2 in BMP signaling. At present, Tina works as a scientific writer and is funded by the Innovationsfonds, which was established in the course of the excellence initiative of the Freie Universität Berlin.
Jessica Kopf (left) obtained her Dipl.-Ing. in medical biotechnology at the Technische Universität Berlin in 2008. She is now a PhD student at the Berlin-Brandenburg School for Regenerative Therapies (BSRT) and works on an interdisciplinary project under the supervision of Petra Knaus (Freie Universität Berlin) and Georg Duda (Charité Universitätsmedizin Berlin, Julius Wolff Institut). Her current research investigates the influences of biological and mechanical factors on stem cell behavior during the process of bone healing/regeneration. She is especially interested in the question how mechanical strain affects BMP signaling cascades.
Christian Hiepen (right) started as a technician before he obtained his MSc degree in molecular biology at the University of Applied Science Gelsenkirchen (2008). During his studies he gained research experience in industry by generating knockout mice and establishing RNAi based targeting techniques at Taconic-Artemis (Cologne). In 2007, Chris performed his master thesis at Bart Vanhaesebroeck's Center for Cell Signalling (Queen Mary University London), investigating the role of distinct PI3K isoforms in endothelial cells. He joined Petra Knaus's lab in October 2008 as a member of the DFG funded Berlin Brandenburg School for Regenerative Therapies (BSRT). In his PhD thesis Chris focuses on non-Smad pathways and the role of co-receptors in BMP signal transduction.
Petra Knaus is a biochemist and cell biologist with a PhD in molecular neurobiology. She has started her research on TGFβ signal transduction as a Postdoctoral Fellow in Harvey Lodish's lab at the Whitehead Institute for Biomedical Research (Cambridge, MA, USA). As an independent group leader in the Department of Walter Sebald at the Biocenter (Würzburg, Germany) Petra started her research on BMP receptor signaling. Since 2004 she has been full professor at the Department of Chemistry and Biochemistry at the Freie Universität Berlin, Germany. With her research team she is studying the molecular mechanism of BMP and TGFβ signal transduction. Finetuning and dynamic signaling events under physiological and pathophysiological conditions are in the focus of these studies. Photo taken by Stephen Mueller.