Elsevier

Cytokine & Growth Factor Reviews

Volume 20, Issues 5–6, October–December 2009, Pages 343-355
Cytokine & Growth Factor Reviews

Survey
Recent advances in BMP receptor signaling

https://doi.org/10.1016/j.cytogfr.2009.10.007Get rights and content

Abstract

Bone Morphogenetic Proteins (BMPs) play an important role during organ development and during regeneration after tissue damage. BMPs signal via transmembrane serine/threonine kinase receptors. From our current understanding heteromeric complexes of type I and type II receptors are required for signal propagation. Presently, three type I and three type II receptors are known to bind BMPs with different affinities. Ligands and receptors eventually oligomerize via defined modes into signaling complexes. Co-receptors recruit into these complexes to either inhibit or to promote signaling. The Smad pathway, initiated by phosphorylation through the activated type I receptors, results in transcriptional regulation of early target genes. However, on its way to the nucleus, Smads represent signaling platforms for other pathways, which eventually finetune BMP signal transduction. We also describe BMP-induced signaling cascades leading to cytoskeletal rearrangements, non-transcriptional and non-Smad pathways. BMPs induce a plethora of different cellular effects ranging from stem cell maintenance, migration, differentiation, proliferation to apoptosis. The molecular mechanism, by which the same ligand induces these manifold effects, depends on the cellular context. Here we try to give a current picture of the most important players in regulating and directing BMP signaling towards the desired cellular outcome. Examples of BMP action during development, but also physiological and pathophysiological conditions in the adult organism are presented.

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

References (149)

  • J. Greenwald et al.

    The BMP7/ActRII extracellular domain complex provides new insights into the cooperative nature of receptor assembly

    Mol Cell

    (2003)
  • A. Nohe et al.

    The mode of bone morphogenetic protein (BMP) receptor oligomerization determines different BMP-2 signaling pathways

    J Biol Chem

    (2002)
  • K. Lehmann et al.

    A New Subtype of Brachydactyly Type B Caused by Point Mutations in the Bone Morphogenetic Protein Antagonist NOGGIN

    Am J Hum Genet

    (2007)
  • N.P. Barbara et al.

    Endoglin is an accessory protein that interacts with the signaling receptor complex of multiple members of the transforming growth factor-beta superfamily

    J Biol Chem

    (1999)
  • K.C. Kirkbride et al.

    Bone morphogenetic proteins signal through the transforming growth factor-beta type III receptor

    J Biol Chem

    (2008)
  • J.W. Wertz et al.

    Caveolin-1 regulates BMPRII localization and signaling in vascular smooth muscle cells

    Biochem Biophys Res Commun

    (2008)
  • R. Satow et al.

    Dullard promotes degradation and dephosphorylation of BMP receptors and is required for neural induction

    Dev Cell

    (2006)
  • J. Liliental et al.

    Rack1, a receptor for activated protein kinase C, interacts with integrin beta subunit

    J Biol Chem

    (1998)
  • Q. Meng et al.

    Identification of Tctex2beta, a novel dynein light chain family member that interacts with different transforming growth factor-beta receptors

    J Biol Chem

    (2006)
  • J.L. Wrana

    Regulation of Smad activity

    Cell

    (2000)
  • Y. Shi et al.

    Mechanisms of TGF-beta signaling from cell membrane to the nucleus

    Cell

    (2003)
  • S. Itoh et al.

    Negative regulation of TGF-beta receptor/Smad signal transduction

    Curr Opin Cell Biol

    (2007)
  • M.J. Goumans et al.

    Activin receptor-like kinase (ALK)1 is an antagonistic mediator of lateral TGFbeta/ALK5 signaling

    Mol Cell

    (2003)
  • K.H. Wrighton et al.

    Transforming Growth Factor {beta} Can Stimulate Smad1 Phosphorylation Independently of Bone Morphogenic Protein Receptors

    J Biol Chem

    (2009)
  • L.C. Fuentealba et al.

    Integrating patterning signals: Wnt/GSK3 regulates the duration of the BMP/Smad1 signal

    Cell

    (2007)
  • G. Sapkota et al.

    Balancing BMP signaling through integrated inputs into the Smad1 linker

    Mol Cell

    (2007)
  • L.F. Seet et al.

    Endofin, an endosomal FYVE domain protein

    J Biol Chem

    (2001)
  • K.H. Lau et al.

    Up-regulation of the Wnt, estrogen receptor, insulin-like growth factor-I, and bone morphogenetic protein pathways in C57BL/6J osteoblasts as opposed to C3H/HeJ osteoblasts in part contributes to the differential anabolic response to fluid shear

    J Biol Chem

    (2006)
  • B. Rath et al.

    Compressive forces induce osteogenic gene expression in calvarial osteoblasts

    J Biomech

    (2008)
  • A. Liedert et al.

    Signal transduction pathways involved in mechanotransduction in bone cells

    Biochem Biophys Res Commun

    (2006)
  • A.G. Robling et al.

    Mechanical stimulation of bone in vivo reduces osteocyte expression of Sost/sclerostin

    J Biol Chem

    (2008)
  • C.L. Lin et al.

    Epigallocatechin gallate (EGCG) suppresses beta-amyloid-induced neurotoxicity through inhibiting c-Abl/FE65 nuclear translocation and GSK3 beta activation

    Neurobiol Aging

    (2009)
  • H. Rangaswami et al.

    Type II cGMP-dependent protein kinase mediates osteoblast mechanotransduction

    J Biol Chem

    (2009)
  • J.A. Jadlowiec et al.

    Extracellular matrix-mediated signaling by dentin phosphophoryn involves activation of the Smad pathway independent of bone morphogenetic protein

    J Biol Chem

    (2006)
  • C.F. Lai et al.

    Signal transductions induced by bone morphogenetic protein-2 and transforming growth factor-beta in normal human osteoblastic cells

    J Biol Chem

    (2002)
  • H. Spemann et al.

    Induction of embryonic primordia by implantation of organizers from a different species. 1923

    Int J Dev Biol

    (2001)
  • Y. Sasai et al.

    Endoderm induction by the organizer-secreted factors chordin and noggin in Xenopus animal caps

    Embo J

    (1996)
  • L. Dale et al.

    BMP signalling in early Xenopus development

    Bioessays

    (1999)
  • E.M. De Robertis et al.

    Dorsal-ventral patterning and neural induction in Xenopus embryos

    Annu Rev Cell Dev Biol

    (2004)
  • C. Mieko Mizutani et al.

    EvoD/Vo: the origins of BMP signalling in the neuroectoderm

    Nat Rev Genet

    (2008)
  • H. Kuroda et al.

    Neural induction in Xenopus: requirement for ectodermal and endomesodermal signals via Chordin, Noggin, beta-Catenin, and Cerberus

    PLoS Biol

    (2004)
  • S. Schulte-Merker et al.

    The zebrafish organizer requires chordino

    Nature

    (1997)
  • D. Bachiller et al.

    The organizer factors Chordin and Noggin are required for mouse forebrain development

    Nature

    (2000)
  • L. Collavin et al.

    The secreted Frizzled-related protein Sizzled functions as a negative feedback regulator of extreme ventral mesoderm

    Development

    (2003)
  • Sieber C, Schwaerzer GK, Knaus P. Bone Morphogenetic Proteins: From Local to Systemic Therapeutics; article: BMP...
  • S.C. Little et al.

    Bone morphogenetic protein heterodimers assemble heteromeric type I receptor complexes to pattern the dorsoventral axis

    Nat Cell Biol

    (2009)
  • E. Canalis et al.

    Bone morphogenetic proteins, their antagonists, and the skeleton

    Endocr Rev

    (2003)
  • J.J. Hill et al.

    Regulation of myostatin in vivo by growth and differentiation factor-associated serum protein-1: a novel protein with protease inhibitor and follistatin domains

    Mol Endocrinol

    (2003)
  • H. Zhang et al.

    Mice deficient for BMP2 are nonviable and have defects in amnion/chorion and cardiac development

    Development

    (1996)
  • G. Winnier et al.

    Bone morphogenetic protein-4 is required for mesoderm formation and patterning in the mouse

    Genes Dev

    (1995)
  • Cited by (388)

    View all citing articles on Scopus

    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.

    View full text