Homomeric and heteromeric complexes among TGF-β and BMP receptors and their roles in signaling

Ehrlich, Marcelo; Horbelt, Daniel; Marom, Barak; Knaus, Petra; Henis, Yoav I.

doi:10.1016/j.cellsig.2011.04.004

Cited by 75 publications

(81 citation statements)

References 118 publications

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“…Notably, for bone morphogenic protein receptors, differential signaling responses (Nohe et al, 2002) and endocytic routes (Hartung et al, 2006) for preformed and ligand-induced receptor complexes were observed. This led to the hypothesis that low ligand concentrations predominantly activate signaling from preassembled receptor complexes, while increased ligand availability shifts the equilibrium toward signaling from complexes induced by ligand-dependent recruitment (Ehrlich et al, 2011). This hypothesis is intriguing with respect to our time-course measurements.…”

Section: Discussionmentioning

confidence: 89%

“…Preformation of receptor oligomers has also been reported for several families of animal receptors (Springael et al, 2005;Van Craenenbroeck, 2012). Some suggested functional consequences of constitutive receptor complexes are increased avidity for ligands (Ehrlich et al, 2012), enhanced signaling efficiency (Hsieh et al, 2010), and differential signaling specificity (Ehrlich et al, 2011).…”

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confidence: 89%

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Visualization of BRI1 and BAK1(SERK3) Membrane Receptor Heterooligomers during Brassinosteroid Signaling

Bücherl¹,

Esse²,

Kruis³

et al. 2013

Plant Physiology

110

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The leucine-rich repeat receptor-like kinase BRASSINOSTEROID-INSENSITIVE1 (BRI1) is the main ligand-perceiving receptor for brassinosteroids (BRs) in Arabidopsis (Arabidopsis thaliana). Binding of BRs to the ectodomain of plasma membrane (PM)-located BRI1 receptors initiates an intracellular signal transduction cascade that influences various aspects of plant growth and development. Even though the major components of BR signaling have been revealed and the PM was identified as the main site of BRI1 signaling activity, the very first steps of signal transmission are still elusive. Recently, it was shown that the initiation of BR signal transduction requires the interaction of BRI1 with its SOMATIC EMBRYOGENESIS RECEPTOR-LIKE KINASE (SERK) coreceptors. In addition, the resolved structure of the BRI1 ectodomain suggested that BRI1-ASSOCIATED KINASE1 [BAK1](SERK3) may constitute a component of the ligand-perceiving receptor complex. Therefore, we investigated the spatial correlation between BRI1 and BAK1(SERK3) in the natural habitat of both leucine-rich repeat receptor-like kinases using comparative colocalization analysis and fluorescence lifetime imaging microscopy. We show that activation of BR signaling by exogenous ligand application resulted in both elevated colocalization between BRI1 and BAK1(SERK3) and an about 50% increase of receptor heterooligomerization in the PM of live Arabidopsis root epidermal cells. However, large populations of BRI1 and BAK1(SERK3) colocalized independently of BRs. Moreover, we could visualize that approximately 7% of the BRI1 PM pool constitutively heterooligomerizes with BAK1(SERK3) in live root cells. We propose that only small populations of PMlocated BRI1 and BAK1(SERK3) receptors participate in active BR signaling and that the initiation of downstream signal transduction involves preassembled BRI1-BAK1(SERK3) heterooligomers.

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Section: Discussionmentioning

confidence: 89%

mentioning

confidence: 89%

Visualization of BRI1 and BAK1(SERK3) Membrane Receptor Heterooligomers during Brassinosteroid Signaling

Bücherl¹,

Esse²,

Kruis³

et al. 2013

Plant Physiology

110

View full text Add to dashboard Cite

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“…In the present study, we describe the characterization of five anti-BMP4 llama-derived VHHs. Specificity to different BMPs allowed their classification into 3 groups: VHHs specific for BMP4; BMP2, 4; and BMP2, 4,5,6. We demonstrate that their binding affinities are greater than those published for Noggin, a natural BMP antagonist, and for conventional anti-BMP4 antibodies.…”

Section: Introductionmentioning

confidence: 83%

“…They mediate their function by binding to two molecules of type 1 (BMPR1 a , BMPR1 b , or ACVR1) and two molecules of type 2 (BMPR2, ACVRL1, ActRII, or ActRII B ) serine/threonine kinase receptors (2). Depending on the presence or absence of preformed BMPR complexes, the signaling is mediated via the SMAD family of transcription factors following a defined canonical pathway or by less defined noncanonical intracellular effectors (3,4). Translocation to the nucleus of these transcription factors initiates transcription of BMP target genes (5,6).…”

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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“…Transforming growth factor ␤ (TGF-␤) 2 is a multifunctional cytokine that exerts a wide range of biological and cellular effects (1)(2)(3)(4)(5)(6)(7). In the vascular system, TGF-␤ has dichotomous roles in endothelial functions such as proliferation and migration during angiogenesis (8).…”

Section: Yiymentioning

confidence: 99%

Src-mediated Post-translational Regulation of Endoglin Stability and Function Is Critical for Angiogenesis

Pan¹,

Kumar²,

Shah³

et al. 2014

Journal of Biological Chemistry

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Background: Endoglin overexpression promotes angiogenesis but the mechanism of endoglin down-regulation is largely unknown. Results: Endoglin YIY motif is phosphorylated by Src and induces receptor down-regulation. Conclusion: The YIY motif is an endocytic signal for endoglin turnover. Significance: Given that endoglin is a vascular target, defining how endoglin expression is post-translationally regulated is crucial for anti-angiogenic therapies.

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Homomeric and heteromeric complexes among TGF-β and BMP receptors and their roles in signaling

Cited by 75 publications

References 118 publications

Visualization of BRI1 and BAK1(SERK3) Membrane Receptor Heterooligomers during Brassinosteroid Signaling

Visualization of BRI1 and BAK1(SERK3) Membrane Receptor Heterooligomers during Brassinosteroid Signaling

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

Src-mediated Post-translational Regulation of Endoglin Stability and Function Is Critical for Angiogenesis

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