The role of bone morphogenetic proteins in myeloma cell survival

Holien, Toril; Sundan, Anders

doi:10.1016/j.cytogfr.2014.04.009

Cited by 21 publications

(15 citation statements)

References 101 publications

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“…We hypothesized that the antagonizing effect of activin A on BMP-6 and BMP-9 could be caused by competition for receptors that are shared by activin A and BMP-6 or BMP-9. BMP-6 and BMP-9 signals through the type 1 receptor ALK2 in myeloma cells, whereas BMP-2 and BMP-4 do not signal in cells that express ALK2, but lack ALK3 and ALK6, as is the case for the INA-6 myeloma cell line [12,13,15,16]. …”

Section: Resultsmentioning

confidence: 99%

Activin A inhibits BMP-signaling by binding ACVR2A and ACVR2B

et al. 2015

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BackgroundActivins are members of the TGF-β family of ligands that have multiple biological functions in embryonic stem cells as well as in differentiated tissue. Serum levels of activin A were found to be elevated in pathological conditions such as cachexia, osteoporosis and cancer. Signaling by activin A through canonical ALK4-ACVR2 receptor complexes activates the transcription factors SMAD2 and SMAD3. Activin A has a strong affinity to type 2 receptors, a feature that they share with some of the bone morphogenetic proteins (BMPs). Activin A is also elevated in myeloma patients with advanced disease and is involved in myeloma bone disease.ResultsIn this study we investigated effects of activin A binding to receptors that are shared with BMPs using myeloma cell lines with well-characterized BMP-receptor expression and responses. Activin A antagonized BMP-6 and BMP-9, but not BMP-2 and BMP-4. Activin A was able to counteract BMPs that signal through the type 2 receptors ACVR2A and ACVR2B in combination with ALK2, but not BMPs that signal through BMPR2 in combination with ALK3 and ALK6.ConclusionsWe propose that one important way that activin A regulates cell behavior is by antagonizing BMP-ACVR2A/ACVR2B/ALK2 signaling.Electronic supplementary materialThe online version of this article (doi:10.1186/s12964-015-0104-z) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Activin A inhibits BMP-signaling by binding ACVR2A and ACVR2B

et al. 2015

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“…Multiple myeloma cells express high levels of TGF-β mRNA and protein [18]. To exclude the possibility that the SMAD activation following activin treatment was not caused by changes in autocrine TGF-β activity, we first measured TGFB1 mRNA in IH-1 and INA-6 cells treated with activin A and activin B for 4 h (Supplementary Figure S3a,b).…”

Section: Alk2 Knockdown Blunted Activin-induced Smad1/5 Activitymentioning

confidence: 99%

Activins as Dual Specificity TGF-β Family Molecules: SMAD-Activation via Activin- and BMP-Type 1 Receptors

et al. 2020

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Activins belong to the transforming growth factor (TGF)-β family of multifunctional cytokines and signal via the activin receptors ALK4 or ALK7 to activate the SMAD2/3 pathway. In some cases, activins also signal via the bone morphogenetic protein (BMP) receptor ALK2, causing activation of the SMAD1/5/8 pathway. In this study, we aimed to dissect how activin A and activin B homodimers, and activin AB and AC heterodimers activate the two main SMAD branches. We compared the activin-induced signaling dynamics of ALK4/7-SMAD2/3 and ALK2-SMAD1/5 in a multiple myeloma cell line. Signaling via the ALK2-SMAD1/5 pathway exhibited greater differences between ligands than signaling via ALK4/ALK7-SMAD2/3. Interestingly, activin B and activin AB very potently activated SMAD1/5, resembling the activation commonly seen with BMPs. As SMAD1/5 was also activated by activins in other cell types, we propose that dual specificity is a general mechanism for activin ligands. In addition, we found that the antagonist follistatin inhibited signaling by all the tested activins, whereas the antagonist cerberus specifically inhibited activin B. Taken together, we propose that activins may be considered dual specificity TGF-β family members, critically affecting how activins may be considered and targeted clinically.

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“…Most intriguing is the role of BMP4, which presents opposing roles depending on the neoplasm (7,9). In certain malignancies, such as glioblastoma (10) and myeloma (11), high levels of BMP4 are associated with less malignant features while in breast (12), ovarian (13), lung (14), and prostate (15), BMP4 is involved in epithelial-mesenchymal transition (EMT) and metastatic behavior. In gastrointestinal cancers such as pancreas (16), colon (17), and gastric cancer (18), BMP4 has been associated with tumor progression and chemotherapy resistance.…”

Section: Introductionmentioning

confidence: 99%

Effective Inhibition of Bone Morphogenetic Protein Function by Highly Specific Llama-Derived Antibodies

Calpe

Wagner

Khattabi³

et al. 2015

Molecular Cancer Therapeutics

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Bone morphogenetic proteins (BMP) have important but distinct roles in tissue homeostasis and disease, including carcinogenesis and tumor progression. A large number of BMP inhibitors are available to study BMP function; however, as most of these antagonists are promiscuous, evaluating specific effects of individual BMPs is not feasible. Because the oncogenic role of the different BMPs varies for each neoplasm, highly selective BMP inhibitors are required. Here, we describe the generation of three types of llama-derived heavy chain variable domains (VHH) that selectively bind to either BMP4, to BMP2 and 4, or to BMP2, 4, 5, and 6. These generated VHHs have high affinity to their targets and are able to inhibit BMP signaling. Epitope binning and docking modeling have shed light into the basis for their BMP specificity. As opposed to the wide structural reach of natural inhibitors, these small molecules target the grooves and pockets of BMPs involved in receptor binding. In organoid experiments, specific inhibition of BMP4 does not affect the activation of normal stem cells. Furthermore, in vitro inhibition of cancer-derived BMP4 noncanonical signals results in an increase of chemosensitivity in a colorectal cancer cell line. Therefore, because of their high specificity and low off-target effects, these VHHs could represent a therapeutic alternative for BMP4 þ malignancies.

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The role of bone morphogenetic proteins in myeloma cell survival

Cited by 21 publications

References 101 publications

Activin A inhibits BMP-signaling by binding ACVR2A and ACVR2B

Activin A inhibits BMP-signaling by binding ACVR2A and ACVR2B

Activins as Dual Specificity TGF-β Family Molecules: SMAD-Activation via Activin- and BMP-Type 1 Receptors

Effective Inhibition of Bone Morphogenetic Protein Function by Highly Specific Llama-Derived Antibodies

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