BMP Signaling

Introduction to BMP signaling

Overview of Bone Morphogenetic Proteins (BMPs)

Bone morphogenic protein (BMP) is a member of the Transforming Growth Factor-β (TGF-β) protein family. TGF-β refers to a group of cytokines, defined as small proteins that trigger signal transduction pathways.¹,² Like many other proteins in this category, BMP has multifaceted roles in cell fate decisions, development, differentiation and tissue homeostasis.

BMP was discovered in the 1960s by M. R. Urist, who demonstrated the role of the protein in ectopic bone formation.¹ Following further characterization and cloning, it was revealed that the role of BMP transcended bone formation.² Extensive research indicates that it plays a role in various cell types, promoting embryonic morphogenesis, adult tissue homeostasis and disease.

Components of the BMP signaling pathway

BMP Ligands and Structure

BMP ligands are synthesized in a precursor form comprising an N-terminal signal peptide, a C-terminal mature peptide and a domain responsible for folding. They are initially found as dimers in the cytoplasm and activated by the proteolytic cleavage, upon which the C-terminal mature ligand can bind receptors on the cell surface.²

BMPs show specificity towards different receptors depending on their classification. The binding partners of BMP belong to the groups of type I and type II serine/threonine kinase receptors known to engage the TGF-β family. The receptor-ligand complexes of BMP largely determine the role of BMP signaling pathways in different tissues and developmental stages.²

BMP Receptors

Three of the seven type I receptors for the TGF-β family bind BMPs. These are type IA activin receptor (ALK2), type IA BMP receptor (ALK3) and type IB BMP receptor (ALK6).²,³

Similarly, three of the four type II receptors in the TGF-β family bind BMPs: type II BMP receptor (BMPR-2), type II activin receptor (ActR-2A) and type IIB activin receptor (ActR-2B).²,³

While the BMP receptors in both classes specifically bind BMPs, the activin receptors can also bind another TGF-β ligand called activin.²

Type I and type II receptors mainly differ in their activity and roles in signaling. Type II receptors are inherently active and able to bind their ligands, which leads to the recruitment of type I receptors. In contrast, type I receptors are only activated upon recruitment and phosphorylation by type II receptors, but are the key mediators of intercellular signaling.³

Intracellular Signaling Mediators

A signal generated by the BMP ligand-receptor engagement is transmitted intercellularly through a group of mediators to initiate a canonical or a non-canonical pathway.

The first group of mediators is SMAD proteins, responsible for transducing TGF-β-derived signals to the nucleus to regulate cell development and differentiation. The SMAD complex consists of a receptor-regulated SMAD (R-SMAD), which the BMP receptors phosphorylate and a co-SMAD, which binds and translocates R-SMAD to the nucleus to act as a transcription factor for gene expression. Inhibitory SMADs (I-SMADs) negatively regulate SMAD activity by blocking receptor interactions with R-SMADs.⁴

Research suggests that BMP ligands and their receptors can activate non-SMAD components, such as the mitogen-activated protein kinase (MAPK) pathway, the phosphoinositide 3-kinase (PI3K/Akt), protein kinase 3 (PKC) and Rho-GTPases, which are integral to cell survival, migration and metabolism.⁵

BMP Antagonists and Inhibitors

A set of extracellular antagonists and intracellular inhibitors tightly regulates BMP signaling.

Extracellular antagonists bind BMP ligands in the extracellular space to sequester them from BMP receptors. Examples include noggin, chordin, gremlin and follistatin.⁶ Intracellular inhibitors like SMAD6 and SMAD7 inhibit the signal transduction pathways triggered by BMP-receptor interactions.⁷

Mechanisms of BMP Signal Transduction

Canonical SMAD-dependent Pathway

The canonical BMP signaling depends on SMAD proteins for signal transduction. This pathway is initiated by BMP ligands binding type I and type II serine/threonine kinase receptors on the cell surface. The constitutively active type II receptor phosphorylates the type I receptor upon BMP binding, activating it in the process.³ The active type I receptor recruits and phosphorylates R-SMADs (SMAD1/5/8), which form complexes with the co-SMAD (SMAD4). This complex can translocate to the nucleus to interact with DNA-binding transcription factors to promote gene expression necessary to develop craniofacial structures, limbs and the skeleton.⁴

Non-canonical (SMAD-independent) Pathways

Besides SMAD, BMP receptors can activate non-canonical pathways by interacting with several proteins, mainly kinases. Below are some examples:

1. BMP, type I and type II receptors interact with TGF-β-activated kinase 1 (TAK1) to facilitate MAPK signaling.⁴
2. The receptor complex can initiate Akt signaling by binding PI3K. This pathway propagates signals to the mammalian target of rapamycin (mTOR) for cell growth and metabolic regulation.⁸
3. BMP receptors can promote cytoskeletal remodeling by interacting with the transforming protein RhoA and the cell division control protein 42 homolog (cdc42).⁴

Regulation and Modulation of BMP signaling

Besides the antagonists and inhibitors, BMP signaling is influenced by several other factors.

Post-translational modifications play a crucial role in SMAD-dependent BMP signaling. Type I receptors phosphorylate SMAD proteins.⁹ In addition, SMAD activity and stability are tightly controlled by ubiquitination and palmitoylation of SMAD.¹⁰,¹¹

BMP receptors undergo endocytosis and intracellular trafficking upon ligand binding to recruit downstream proteins, which can be mediated by clathrin or caveolin.¹²,¹³ Endocytosis and trafficking affect the signal intensity and duration by determining the rate of receptor recycling and degradation.¹⁴

BMP signaling exhibits intricate crosstalks with other signaling pathways involving proteins from the TGF-β family, including Wnt and Notch.⁵,¹⁵ Collectively, these pathways establish regulatory loops that fine-tune BMP-mediated gene expression.

BMP signaling in Development and Tissue Homeostasis

BMP signaling is a coachman that orchestrates several developmental and tissue homeostasis processes.

Early Development and Tissue Maintenance

In early development, BMP signaling is essential for developing the ectoderm and mesoderm layers during gastrulation.16 It plays a central role in anterior-posterior and dorsal-ventral axis patterning to ensure body morphogenesis.¹⁷

Organogenesis

BMP signaling pathways partake in limb patterning and skeletal morphogenesis by regulating the spatial evolution of cell populations. It is also strongly associated with differentiation in neural and cardiovascular development and vessel formation.⁵,¹⁸

Skeletal and Cartilage Development

The SMAD-dependent BMP pathway activates transcription factors, such as Runt-related transcription factor 2 (Runx2) and Distal-less homeobox genes (Dlx), to drive osteoblast differentiation and bone formation.¹⁹,²⁰ It is critical in the development of fetal bone tissue from cartilage models during endochondral ossification.²¹ This pathway activates genes involved in the differentiation and proliferation of osteoblasts and chondrocytes.²¹

Bone Homeostasis

During adult life, BMPs maintain bone remodeling by fine-tuning the activities of osteoblasts and osteoclasts, which ensures a balance between bone formation and resorption.⁴

Vascular Function

BMP ligands are associated with endothelial cell function and integrity, influencing angiogenesis and smooth muscle cell differentiation to regulate circulation.²²

Stem Cell Regulation

BMP signaling pathways are critical to the stem cellniche of bone and cartilage. They control the mesenchymal transition of osteogenic and chondrogenic stem cells while maintaining progenitor proliferation during tissue repair and regeneration.²³

Dysregulation of BMP signaling in disease

Given the broad influence of bone morphogenetic proteins in development and homeostasis, it is no surprise that aberrant BMP signaling is correlated with debilitating diseases.

Skeletal Disorders

Several skeletal pathologies can be attributed to BMP signaling imbalance. A case in point is Fibrodysplasia Ossificans Progressiva (FOP), caused by mutations to the ALK2 receptor that lead to inappropriate bone formation in muscles and soft tissues.²⁴ Impaired BMP signaling was also correlated with impaired bone formation and maintenance in osteoporosis.²⁵ Constitutive activation of BMP signaling, especially BMP2, was observed in ectopic bone formation upon trauma and injury.²⁶

Cardiovascular Diseases

Altered levels of BMP ligands and their receptors have severe implications for cardiovascular diseases. For example, loss-of-function mutations in the BMPR2 receptor can impair vascular remodeling, eventually enhancing pulmonary artery pressure.²⁷ Conversely, overexpression of BMP2 and BMP4 can result in calcification and plaque formation in blood vessels.²⁸

Cancer

The role of BMP in cancer is complicated, as it can act as either a tumor suppressor or promoter.²⁹ BMPs are negative regulators of oncogenes in colon and gastric cancers.³⁰,³¹ As such, mutations in SMAD4 are associated with uncontrolled cell growth and metastasis in colorectal cancer, due to the failure of the SMAD complex to reach the nucleus to promote cell cycle arrest and apoptosis.³² Conversely, BMP ligands BMP2 and BMP7 activate oncogenic pathways leading to invasion and metastasis.³³

Several therapeutic strategies have been developed to target the key components of the BMP signaling pathway. ALK2 stands out as a promising therapeutic target, and several compounds, like LDN-193189 or dorsomorphin analogs, are under investigation for their inhibitory effects.³⁴,³⁵ Additionally, small molecules called macrocyclics are targeted at BMP type I and type II receptors, demonstrating effectiveness in reducing angiogenesis.³⁶

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References

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