Bone morphogenetic protein receptors and signal transduction
TL;DR: The recent development of BMP receptor inhibitors may also prove useful for some clinical diseases induced by hyperactivation of the BMP signalling pathways.
Abstract: Bone morphogenetic proteins (BMPs) exhibit broad spectra of biological activities in various tissues, including bone, cartilage, blood vessels, heart, kidney, neurons, liver and lung. BMPs are members of the transforming growth factor-beta (TGF-beta) family that bind to type II and type I serine-threonine kinase receptors, and transduce signals through Smad and non-Smad signalling pathways. Recent findings have revealed that BMP signalling is finely tuned by various mechanisms in both positive and negative fashions. Perturbations of BMP signalling pathways are linked to a wide variety of clinical disorders, including vascular diseases, skeletal diseases and cancer. Administration of recombinant BMP ligands and increasing endogenous expression of BMPs provide therapeutic effects on some diseases. The recent development of BMP receptor inhibitors may also prove useful for some clinical diseases induced by hyperactivation of the BMP signalling pathways.
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TL;DR: Transforming growth factor β (TGF-β) family members signal via heterotetrameric complexes of type I and type II dual specificity kinase receptors that are controlled by posttranslational modifications, such as phosphorylation, ubiquitylation, sumoylation, and neddylation.
Abstract: Transforming growth factor beta (TGF-beta) family members signal via heterotetrameric complexes of type I and type II dual specificity kinase receptors. The activation and stability of the receptor ...
432 citations
Cites background from "Bone morphogenetic protein receptor..."
...It is likely that conserved serine residues in the juxtamembrane GS domain of BMP type I receptors are the acceptors for phosphorylation by the paired BMP type II receptor in the heterotetrameric receptor complexes, leading to activation of the type I receptor kinase (Miyazono et al. 2010)....
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TL;DR: Accumulating evidence indicates that Runx2 is the key integrator, whereas Hh is a possible modulator, miRNAs are regulators, and β-catenin is a mediator/regulator within the extensive intracellular network.
Abstract: Transforming growth factor-beta (TGF-β)/bone morphogenetic protein (BMP) plays a fundamental role in the regulation of bone organogenesis through the activation of receptor serine/threonine kinases. Perturbations of TGF-β/BMP activity are almost invariably linked to a wide variety of clinical outcomes, i.e., skeletal, extra skeletal anomalies, autoimmune, cancer, and cardiovascular diseases. Phosphorylation of TGF-β (I/II) or BMP receptors activates intracellular downstream Smads, the transducer of TGF-β/BMP signals. This signaling is modulated by various factors and pathways, including transcription factor Runx2. The signaling network in skeletal development and bone formation is overwhelmingly complex and highly time and space specific. Additive, positive, negative, or synergistic effects are observed when TGF-β/BMP interacts with the pathways of MAPK, Wnt, Hedgehog (Hh), Notch, Akt/mTOR, and miRNA to regulate the effects of BMP-induced signaling in bone dynamics. Accumulating evidence indicates that Runx2 is the key integrator, whereas Hh is a possible modulator, miRNAs are regulators, and β-catenin is a mediator/regulator within the extensive intracellular network. This review focuses on the activation of BMP signaling and interaction with other regulatory components and pathways highlighting the molecular mechanisms regarding TGF-β/BMP function and regulation that could allow understanding the complexity of bone tissue dynamics.
430 citations
TL;DR: The TGF-β signalling pathway, its involvement in cancer and current therapeutic approaches, and several molecular targets with great potential in therapeutic interventions have been identified are discussed.
Abstract: The transforming growth factor-β (TGF-β) system signals via protein kinase receptors and SMAD mediators to regulate a large number of biological processes. Alterations of the TGF-β signalling pathway are implicated in human cancer. Prior to tumour initiation and early during progression, TGF-β acts as a tumour suppressor; however, at later stages, it is often a tumour promoter. Knowledge about the mechanisms involved in TGF-β signal transduction has allowed a better understanding of cancer progression, invasion, metastasis and epithelial-to-mesenchymal transition. Furthermore, several molecular targets with great potential in therapeutic interventions have been identified. This review discusses the TGF-β signalling pathway, its involvement in cancer and current therapeutic approaches.
353 citations
Cites background from "Bone morphogenetic protein receptor..."
...BMPs regulate the transcription of several genes involved in osteogenesis, neurogenesis and ventral mesoderm specification (reviewed in [6, 7])....
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...activation) [26], endofin [7] or ERBIN (Erbb2-interacting protein) [27]....
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TL;DR: The knowledge about the mechanisms involved in TGF-β signal transduction has allowed a better understanding of the disease pathogenicity as well as the identification of several molecular targets with great potential in therapeutic interventions.
Abstract: The TGF-β (transforming growth factor-β) system signals via protein kinase receptors and Smad mediators to regulate a plethora of biological processes, including morphogenesis, embryonic development, adult stem cell differentiation, immune regulation, wound healing and inflammation. In addition, alterations of specific components of the TGF-β signalling pathway may contribute to a broad range of pathologies such as cancer, cardiovascular pathology, fibrosis and congenital diseases. The knowledge about the mechanisms involved in TGF-β signal transduction has allowed a better understanding of the disease pathogenicity as well as the identification of several molecular targets with great potential in therapeutic interventions.
345 citations
TL;DR: In this paper, a review of the current knowledge of the molecular basis of differentiation of cultured mesenchymal stromal/stem cells, with a particular focus on chondrogenesis and osteogenesis, is presented.
Abstract: Mesenchymal stromal/stem cells (MSCs) are a population of stromal cells present in the bone marrow and most connective tissues, capable of differentiation into mesenchymal tissues such as bone and cartilage. MSCs are attractive candidates for biological cell-based tissue repair approaches because of their extensive proliferative ability in culture while retaining their mesenchymal multilineage differentiation potential. In addition to its undoubted scientific interest, the prospect of monitoring and controlling MSC differentiation is a crucial regulatory and clinical requirement. Hence, the molecular regulation of MSC differentiation has been extensively studied. Most of the studies are in vitro, because the identity of MSCs in their tissues of origin in vivo remains undefined. This review addresses the current knowledge of the molecular basis of differentiation of cultured MSCs, with a particular focus on chondrogenesis and osteogenesis. Building on the information coming from developmental biology studies of embryonic skeletogenesis, several signaling pathways and transcription factors have been investigated and shown to play critical roles in MSC differentiation. In particular, the Wnt and transforming growth factor-β/bone morphogenetic protein signaling pathways are well known to modulate in MSCs the molecular differentiation into cartilage and bone. Relevant to the emerging concept of stem cell niches is the demonstration that physical factors can also participate in the regulation of MSC differentiation. Knowledge of the regulation of MSC differentiation will be critical in the design of three-dimensional culture systems and bioreactors for automated bioprocessing through mathematical models applied to systems biology and network science.
334 citations
References
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TL;DR: Transforming growth factor-β (TGF-β) proteins regulate cell function, and have key roles in development and carcinogenesis, and combinatorial interactions in the heteromeric receptor and Smad complexes, receptor-interacting and Smadracing proteins, and cooperation with sequence-specific transcription factors allow substantial versatility and diversification of TGF- β family responses.
Abstract: Transforming growth factor-beta (TGF-beta) proteins regulate cell function, and have key roles in development and carcinogenesis The intracellular effectors of TGF-beta signalling, the Smad proteins, are activated by receptors and translocate into the nucleus, where they regulate transcription Although this pathway is inherently simple, combinatorial interactions in the heteromeric receptor and Smad complexes, receptor-interacting and Smad-interacting proteins, and cooperation with sequence-specific transcription factors allow substantial versatility and diversification of TGF-beta family responses Other signalling pathways further regulate Smad activation and function In addition, TGF-beta receptors activate Smad-independent pathways that not only regulate Smad signalling, but also allow Smad-independent TGF-beta responses
4,690 citations
TL;DR: Inhibitory SMADs have been identified that block the activation of these pathway-restricted SMADS that direct transcription to effect the cell's response to TGF-β.
Abstract: The recent identification of the SMAD family of signal transducer proteins has unravelled the mechanisms by which transforming growth factor-beta (TGF-beta) signals from the cell membrane to the nucleus. Pathway-restricted SMADs are phosphorylated by specific cell-surface receptors that have serine/threonine kinase activity, then they oligomerize with the common mediator Smad4 and translocate to the nucleus where they direct transcription to effect the cell's response to TGF-beta. Inhibitory SMADs have been identified that block the activation of these pathway-restricted SMADs.
3,590 citations
"Bone morphogenetic protein receptor..." refers background in this paper
...Signalling receptors for BMPs were identified by 1995, and Smad signalling pathways, including the three classes of Smads, were discovered by 1997 (9)....
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TL;DR: DPC4 is identified as a candidate tumor suppressor gene whose inactivation may play a role in pancreatic and possibly other human cancers.
Abstract: About 90 percent of human pancreatic carcinomas show allelic loss at chromosome 18q. To identify candidate tumor suppressor genes on 18q, a panel of pancreatic carcinomas were analyzed for convergent sites of homozygous deletion. Twenty-five of 84 tumors had homozygous deletions at 18q21.1, a site that excludes DCC (a candidate suppressor gene for colorectal cancer) and includes DPC4, a gene similar in sequence to a Drosophila melanogaster gene (Mad) implicated in a transforming growth factor-β (TGF-β)-like signaling pathway. Potentially inactivating mutations in DPC4 were identified in six of 27 pancreatic carcinomas that did not have homozygous deletions at 18q21.1. These results identify DPC4 as a candidate tumor suppressor gene whose inactivation may play a role in pancreatic and possibly other human cancers.
2,348 citations
"Bone morphogenetic protein receptor..." refers background in this paper
...Mutations of the human SMAD4/DPC4 gene are frequently found in pancreatic cancer, metastatic colon cancer and juvenile polyposis (123, 124)....
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TL;DR: Endoglin is identified as the HHT gene mapping to 9q3 and HHT is established as the first human disease defined by a mutation in a member of the TGF-β receptor complex.
Abstract: Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterized by multisystemic vascular dysplasia and recurrent haemorrhage. Linkage for some families has been established to chromosome 9q33−q34. In the present study, endoglin, a transforming growth factor beta (TGF-beta) binding protein, was analysed as a candidate gene for the disorder based on chromosomal location, expression pattern and function. We have identified mutations in three affected individuals: a C to G substitution converting a tyrosine to a termination codon, a 39 base pair deletion and a 2 base pair deletion which creates a premature termination codon. We have identified endoglin as the HHT gene mapping to 9q3 and have established HHT as the first human disease defined by a mutation in a member of the TGF-beta receptor complex.
1,400 citations
TL;DR: It is shown that FPPH is caused by mutations in BMPR2, encoding a TGF-β type II receptor (BMPR-II), which transduce signals by binding to heteromeric complexes of type I and II receptors, which activates serine/threonine kinases, leading to transcriptional regulation by phosphorylated Smads.
Abstract: Primary pulmonary hypertension (PPH), characterized by obstruction of pre-capillary pulmonary arteries, leads to sustained elevation of pulmonary arterial pressure (mean >25 mm Hg at rest or >30 mm Hg during exercise). The aetiology is unknown, but the histological features reveal proliferation of endothelial and smooth muscle cells with vascular remodelling (Fig. 1). More than one affected relative has been identified in at least 6% of cases (familial PPH, MIM 178600). Familial PPH (FPPH) segregates as an autosomal dominant disorder with reduced penetrance and has been mapped to a locus designated PPH1 on 2q33, with no evidence of heterogeneity. We now show that FPPH is caused by mutations in BMPR2, encoding a TGF-beta type II receptor (BMPR-II). Members of the TGF-beta superfamily transduce signals by binding to heteromeric complexes of type I and II receptors, which activates serine/threonine kinases, leading to transcriptional regulation by phosphorylated Smads. By comparison with in vitro studies, identified defects of BMPR-II in FPPH are predicted to disrupt ligand binding, kinase activity and heteromeric dimer formation. Our data demonstrate the molecular basis of FPPH and underscore the importance in vivo of the TGF-beta signalling pathway in the maintenance of blood vessel integrity.
1,394 citations
"Bone morphogenetic protein receptor..." refers background in this paper
...Endothelial injury and enhanced inflammatory response may act in concert with Bmpr2 heterozygosity to accelerate the development of PAH (51)....
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...Conditional heterozygous and homozygous Bmpr2 deletion in pulmonary endothelium in mice resulted in predisposition to PAH....
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...In agreement with this finding, a nonsense mutation of SMAD8 has been reported in a patient with idiopathic PAH (122)....
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...Familial PAH occurs as an autosomal dominant disorder with reduced penetrance....
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...Nonsense mutations in the C-terminal tail have been found in some patients with familial PAH, indicating that this region plays an important role in signalling activity (46, 47)....
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