Differential regulation of translation and endocytosis of alternatively spliced forms of the type II bone morphogenetic protein (BMP) receptor

Amsalem, Ayelet R.; Marom, Barak; Shapira, Keren E.; Hirschhorn, Tal; Preisler, Livia; Paarmann, Pia; Knaus, Petra; Henis, Yoav I.; Ehrlich, Marcelo

doi:10.1091/mbc.e15-08-0547

Cited by 16 publications

(17 citation statements)

References 71 publications

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“…The plasmids used encoded BMPR2 variants with N-terminal MYC tags between the signal peptide (SP) and the extracellular domain (ECD), and have been described earlier (Fig. 6A) (Amsalem et al, 2016). The levels of BMPR2-LF and BMPR2-SF were highly increased compared with levels in control cells (Fig.…”

Section: Effect Of Bmpr2 Knockdown In Hepg2 Liver Carcinoma Cellsmentioning

confidence: 93%

“…INA-6 shBMPR2 cells were transfected using the Nucleofector device (Amaxa Biosystems, Cologne, Germany) and Amaxa Cell Line Nucleofector Kit R (Lonza, Basel, Switzerland), as previously described (Fagerli et al, 2008). The plasmids encoding the long and short isoforms of BMPR2, BMPR2-LF and BMPR2-SF, were generated earlier as described (Amsalem et al, 2016). A plasmid encoding CD4Δ was used as a negative control (kind gift from Dr Martin Janz, Charité-University Medicine Berlin, Germany).…”

Section: Nanostring Gene Expression Analysismentioning

confidence: 99%

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BMPR2 inhibits activin and BMP signaling via wild-type ALK2

Olsen

Sankar

Elsaadi

et al. 2018

Journal of Cell Science

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TGF-β/BMP superfamily ligands require heteromeric complexes of type 1 and 2 receptors for ligand-dependent downstream signaling. Activin A, a TGF-β superfamily member, inhibits growth of multiple myeloma cells, but the mechanism for this is unknown. We therefore aimed to clarify how activins affect myeloma cell survival. Activin A activates the transcription factors SMAD2/3 through the ALK4 type 1 receptor, but may also activate SMAD1/5/8 through mutated variants of the type 1 receptor ALK2 (also known as ACVR1). We demonstrate that activin A and B activate SMAD1/5/8 in myeloma cells through endogenous wild-type ALK2. Knockdown of the type 2 receptor BMPR2 strongly potentiated activin A- and activin B-induced activation of SMAD1/5/8 and subsequent cell death. Furthermore, activity of BMP6, BMP7 or BMP9, which may also signal via ALK2, was potentiated by knockdown of BMPR2. Similar results were seen in HepG2 liver carcinoma cells. We propose that BMPR2 inhibits ALK2-mediated signaling by preventing ALK2 from oligomerizing with the type 2 receptors ACVR2A and ACVR2B, which are necessary for activation of ALK2 by activins and several BMPs. In conclusion, BMPR2 could be explored as a possible target for therapy in patients with multiple myeloma.This article has an associated First Person interview with the first author of the paper.

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Section: Effect Of Bmpr2 Knockdown In Hepg2 Liver Carcinoma Cellsmentioning

confidence: 93%

Section: Nanostring Gene Expression Analysismentioning

confidence: 99%

BMPR2 inhibits activin and BMP signaling via wild-type ALK2

Olsen

Sankar

Elsaadi

et al. 2018

Journal of Cell Science

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“…Although previous studies have indicated that clathrin/dynamin-dependent endocytosis of BMP type I receptors is conserved in various models, including C. elegans , Drosophila , mouse, and human fibroblasts, the role of endocytosis in BMP signal transduction remains inconclusive, and may depend on the specific endocytic trafficking routes of the receptors in each context 25–27,48,49,55,56 . Our data suggest that the stabilization of Tkv, and its accumulation on the plasma membrane is not sufficient to activate MAD signaling in ISCs, but that AWD-facilitated internalization into Rab5+ endosomes is required.…”

Section: Discussionmentioning

confidence: 99%

AWD regulates timed activation of BMP signaling in intestinal stem cells to maintain tissue homeostasis

Cai

Safyan

et al. 2019

Nat Commun

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Precise control of stem cell (SC) proliferation ensures tissue homeostasis. In the Drosophila intestine, injury-induced regeneration involves initial activation of intestinal SC (ISC) proliferation and subsequent return to quiescence. These two phases of the regenerative response are controlled by differential availability of the BMP type I receptor Thickveins (Tkv), yet how its expression is dynamically regulated remains unclear. Here we show that during homeostasis, the E3 ubiquitin ligase Highwire and the ubiquitin-proteasome system maintain low Tkv protein expression. After ISC activation, Tkv is stabilized by proteasome inhibition and undergoes endocytosis due to the induction of the nucleoside diphosphate kinase Abnormal Wing Disc (AWD). Tkv internalization is required for the activation of the Smad protein Mad, and for the return to quiescence after a regenerative episode. Our data provide insight into the mechanisms ensuring tissue homeostasis by dynamic control of somatic stem cell activity.

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“…Plasmids encoding human HA-BMPRII-LF and human Smad1 subcloned into pEYFP-C1 were described previously 74 – 76 . Human FLAG-tagged Smad1 and murine FLAG-tagged Smad5 were kindly provided by Peter ten Dijke, Leiden, Netherlands.…”

Section: Methodsmentioning

confidence: 99%

IRS4, a novel modulator of BMP/Smad and Akt signalling during early muscle differentiation

Dörpholz

Murgai

Jatzlau

et al. 2017

Sci Rep

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Elaborate regulatory networks of the Bone Morphogenetic Protein (BMP) pathways ensure precise signalling outcome during cell differentiation and tissue homeostasis. Here, we identified IRS4 as a novel regulator of BMP signal transduction and provide molecular insights how it integrates into the signalling pathway. We found that IRS4 interacts with the BMP receptor BMPRII and specifically targets Smad1 for proteasomal degradation consequently leading to repressed BMP/Smad signalling in C2C12 myoblasts while concomitantly activating the PI3K/Akt axis. IRS4 is present in human and primary mouse myoblasts, the expression increases during myogenic differentiation but is downregulated upon final commitment coinciding with Myogenin expression. Functionally, IRS4 promotes myogenesis in C2C12 cells, while IRS4 knockdown inhibits differentiation of myoblasts. We propose that IRS4 is particularly critical in the myoblast stage to serve as a molecular switch between BMP/Smad and Akt signalling and to thereby control cell commitment. These findings provide profound understanding of the role of BMP signalling in early myogenic differentiation and open new ways for targeting the BMP pathway in muscle regeneration.

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Differential regulation of translation and endocytosis of alternatively spliced forms of the type II bone morphogenetic protein (BMP) receptor

Cited by 16 publications

References 71 publications

BMPR2 inhibits activin and BMP signaling via wild-type ALK2

BMPR2 inhibits activin and BMP signaling via wild-type ALK2

AWD regulates timed activation of BMP signaling in intestinal stem cells to maintain tissue homeostasis

IRS4, a novel modulator of BMP/Smad and Akt signalling during early muscle differentiation

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