Bone Morphogenetic Proteins and Their Receptors

Abstract

Bone morphogenetic proteins (BMPs) are important signalling molecules that were first identified by their ability to induce bone and cartilage, and subsequently were shown to be pleiotropic cytokines controlling a wide variety of biological responses during early development, skeletogenesis and homoeostasis of several tissues. In agreement with their crucial role in many biological processes, mutations in components of the BMP signalling pathway underlie several pathologies. BMPs transmit their signals from membrane to nucleus through distinct combinations of types I and II serine/threonine kinase receptors and their intracellular effectors the Smad proteins. Smad‐mediated transcription of target genes is regulated in a complex manner in which interactions with other transcription factors and signalling pathways define the final response.

Key Concepts

  • Bone morphogenetic proteins (BMPs) are important pleiotropic cytokines controlling a wide variety of biological responses ranging from early development, skeletogenesis and homeostasis of several tissues to suppression of tumorigenesis.

  • In agreement with their crucial role in many biological processes, mutations in components of the BMP signalling pathway underlie several pathologies, including primary pulmonary hypertension and fibrodysplasia ossificans progressiva.

  • BMPs transmit their signals from membrane to nucleus through distinct combinations of types I and II serine/threonine kinase receptors and their intracellular Smad effector proteins.

  • An essential step in most BMP receptor‐controlled responses is the phosphorylation of the receptor‐regulated Smads, Smad1, Smad5 and Smad8, which then associate with the co‐Smad, Smad4, and translocate to the nucleus where they control transcription of BMP target genes.

  • Besides the well‐established BMP/Smad pathway, BMPs can also activate alternative signalling routes, so‐called non‐Smad pathways, which in concert with the Smad pathway determine the BMP‐induced effects.

  • The pleiotropic characteristics of BMPs clearly implicate the need for a tight control of their activities, which is achieved via secreted antagonists which directly bind BMPs and prevent them from binding to their receptors, negative feedback loops mediated by the inhibitory Smads, Smad6 and Smad7, and crosstalk with many different signalling pathways.

  • Differential binding of BMP family members to receptors and extracellular antagonists, their ability to activate certain Smad‐independent signalling pathways, differences in signalling amplitude and duration of both Smad‐dependent and Smad‐independent pathways, and how these interact, define the final outcome of BMP‐induced cellular responses.

Keywords: bone morphogenetic protein; serine/threonine kinase receptor; signal transduction; Smad; transforming growth factor‐β

Figure 1.

Members of the BMP family. A phylogenetic analysis of BMP family members that is based on the amino acid sequence similarities of the mature regions of BMPs. Subfamilies are boxed. All listed family members are mammalian, except Drosophila Dpp, 60A and Screw, Xenopus Vg‐1, chicken dorsalin and sea urchin univin. GDF, growth and differentiation factor; CDMP, cartilage‐derived morphogenetic protein.

Figure 2.

The serine/threonine kinase receptor family. A phylogenetic analysis of mammalian type I and type II receptors that is based on the amino acid sequence similarities between the kinase domains. The ligands binding to each receptor are indicated. Receptors that can bind BMP are indicated in bold.

Figure 3.

Model for activation of BMP receptors: (a) BMP‐mediated heteromeric complex formation of BMPR‐I and BMPR‐II. (b) Activation of the BMPR‐I by the BMPR‐II kinase. BMP induces a heteromeric complex of two type I and two type II receptors. On activation of BMPR‐I the signal is propagated downstream, indicated by an arrow.

Figure 4.

The mammalian Smad family. A phylogenetic analysis of mammalian Smad proteins. The Smads implicated in BMP signalling are indicated in bold.

Figure 5.

BMP intracellular signalling through Smad proteins. Following activation of BMPR‐I, Smad1, Smad5 or Smad8 are phosphorylated and form homomeric complexes as well as heteromeric complexes with Smad4. Trimers appear to be formed; however, the possibility that the complexes consist of hexamers or other compositions has not been excluded. The heteromeric complexes translocate to the nucleus, where they bind directly or in complex with other transcription factors to promoter elements of target genes to regulate transcription. The mechanism by which I‐Smads inhibit BMP signalling is regulated at several levels and involves multiple protein interactions (see text).

Figure 6.

(a) Structure of R‐Smad. (b) Schematic representation of the effect of type I receptor‐mediated phosphorylation of R‐Smad. MH, Mad homology.

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de Gorter, David Jan Jozef, van Bezooijen, Rutger Leo, and ten Dijke, Peter(Sep 2009) Bone Morphogenetic Proteins and Their Receptors. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0002330.pub3]