BMP signalling: agony and antagony in the family

Brazil, Derek P.; Church, Rachel H.; Surae, Satnam; Godson, Catherine; Martin, Finian

doi:10.1016/j.tcb.2014.12.004

Cited by 273 publications

(228 citation statements)

References 189 publications

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“…Many members of this family, including TGFb itself (Lyon et al, 1997), bind heparin. Together they form complex systems involved in developmental morphogenesis that is not by any means restricted to bone generation (Rider and Mulloy, 2010;Brazil et al, 2015). HS is critical for the functionality of some, but not all, of these morphogenetic systems, and manipulation of their heparin binding properties can be used in drug design and in controlled-release systems for therapeutic proteins (Reguera-Nuñez et al, 2014;Lee et al, 2015).…”

Section: Heparin and Cytokines Growth Factors Selectins And Promentioning

confidence: 99%

Pharmacology of Heparin and Related Drugs

et al. 2015

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Section: Heparin and Cytokines Growth Factors Selectins And Promentioning

confidence: 99%

Pharmacology of Heparin and Related Drugs

et al. 2015

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“…In this study, the authors also noted that they didn't observe a convincing decrease in AGM hematopoiesis when Noggin was used instead of Gremlin1. Gremlin1 was later shown to be an agonist for VEGFA signaling in addition to its many other roles in other signaling pathways (53,54). Furthermore, when the requirement for BMP signaling in ESC cultures was probed by using soluble BMP receptors, which block signaling by competing for the ligands, BMP signaling was indeed shown to be dispensable in ESC cultures once flk1/kdr + hemangioblasts have been formed (21) as in Xenopus embryos.…”

Section: Discussionmentioning

confidence: 99%

Dissecting BMP signaling input into the gene regulatory networks driving specification of the blood stem cell lineage

Kirmizitas

Meiklejohn

Ciau-Uitz

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Hematopoietic stem cells (HSCs) that sustain lifelong blood production are created during embryogenesis. They emerge from a specialized endothelial population, termed hemogenic endothelium (HE), located in the ventral wall of the dorsal aorta (DA). In Xenopus, we have been studying the gene regulatory networks (GRNs) required for the formation of HSCs, and critically found that the hemogenic potential is defined at an earlier time point when precursors to the DA express hematopoietic as well as endothelial genes, in the definitive hemangioblasts (DHs). The GRN for DH programming has been constructed and, here, we show that bone morphogenetic protein (BMP) signaling is essential for the initiation of this GRN. BMP2, -4, and -7 are the principal ligands expressed in the lineage forming the HE. To investigate the requirement and timing of all BMP signaling in HSC ontogeny, we have used a transgenic line, which inducibly expresses an inhibitor of BMP signaling, Noggin, as well as a chemical inhibitor of BMP receptors, DMH1, and described the inputs from BMP signaling into the DH GRN and the HE, as well as into primitive hematopoiesis. BMP signaling is required in at least three points in DH programming: first to initiate the DH GRN through gata2 expression, then for kdr expression to enable the DH to respond to vascular endothelial growth factor A (VEGFA) ligand from the somites, and finally for gata2 expression in the DA, but is dispensable for HE specification after hemangioblasts have been formed.

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“…The BMP pathway can be negatively regulated by BMP antagonists, which are secreted proteins that bind BMP ligands and block their interactions with cognate cell surface receptors (19). A tight balance between BMP and BMP antagonist activity is required during development and normal tissue homeostasis in the adult.…”

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confidence: 99%

Chordin-Like 1 Suppresses Bone Morphogenetic Protein 4-Induced Breast Cancer Cell Migration and Invasion

Cyr-Depauw

Northey

Tabariès

et al. 2016

Molecular and Cellular Biology

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ShcA is an important mediator of ErbB2-and transforming growth factor ␤ (TGF-␤)-induced breast cancer cell migration, invasion, and metastasis. We show that in the context of reduced ShcA levels, the bone morphogenetic protein (BMP) antagonist chordin-like 1 (Chrdl1) is upregulated in numerous breast cancer cells following TGF-␤ stimulation. BMPs have emerged as important modulators of breast cancer aggressiveness, and we have investigated the ability of Chrdl1 to block BMP-induced increases in breast cancer cell migration and invasion. Breast cancer-derived conditioned medium containing elevated concentrations of endogenous Chrdl1, as well as medium containing recombinant Chrdl1, suppresses BMP4-induced signaling in multiple breast cancer cell lines. Live-cell migration assays reveal that BMP4 induces breast cancer migration, which is effectively blocked by Chrdl1. We demonstrate that BMP4 also stimulated breast cancer cell invasion and matrix degradation, in part, through enhanced metalloproteinase 2 (MMP2) and MMP9 activity that is antagonized by Chrdl1. Finally, high Chrdl1 expression was associated with better clinical outcomes in patients with breast cancer. Together, our data reveal that Chrdl1 acts as a negative regulator of malignant breast cancer phenotypes through inhibition of BMP signaling. Breast cancer is a heterogeneous disease that can be subdivided into distinct molecular subtypes through the integration of gene expression and genomics data (1, 2). While ErbB2 ϩ breast cancers are considered a poor-prognosis subtype (3), other signaling pathways can further modulate their malignant phenotypes. The transforming growth factor ␤ (TGF-␤) family is a prominent example that has been shown to enhance the migratory, invasive, and metastatic abilities of ErbB2 ϩ breast cancer cells (4-7). We have previously demonstrated that the ShcA adaptor protein plays an important role, downstream of TGF-␤ and ErbB2 signaling pathways, in mediating these cellular responses (8, 9). Loss of ShcA expression in ErbB2-expressing cells significantly reduced tumor growth, which was the result of reduced proliferation, diminished endothelial cell recruitment, and elevated apoptosis (9). In the present study, through the use of microarray based transcriptional profiling, we identified elevated levels of chordin-like 1 (Chrdl1) in ErbB2 ϩ breast cancer cells following TGF-␤ stimulation; however, this upregulation of Chrdl1 occurs only in the context of diminished ShcA levels.Bone morphogenetic proteins (BMPs) are secreted cytokines that belong to the TGF-␤ family of proteins, and their aberrant expression is observed in numerous cancers, including breast cancer (10). However, much like the TGF-␤ isoforms, there are conflicting reports on whether BMPs exert pro-or antitumorigenic effects on cancer cells (11,12). In breast cancer, BMP4 has been shown to promote cancer cell migration and invasion (13-16). Similarly, BMP7 induces breast cancer cell proliferation, migration/invasion, and metastasis (17, 18). Interestingly, BMP4 an...

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BMP signalling: agony and antagony in the family

Cited by 273 publications

References 189 publications

Pharmacology of Heparin and Related Drugs

Pharmacology of Heparin and Related Drugs

Dissecting BMP signaling input into the gene regulatory networks driving specification of the blood stem cell lineage

Chordin-Like 1 Suppresses Bone Morphogenetic Protein 4-Induced Breast Cancer Cell Migration and Invasion

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