Dynamics and interaction of caveolin-1 isoforms with BMP-receptors

Nohe, Anja; Keating, Eleonora; Underhill, T. Michael; Knaus, Petra; Petersen, Nils O.

doi:10.1242/jcs.01402

Cited by 91 publications

(113 citation statements)

References 40 publications

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“…BMPR-I and BMPR-II are continuously internalized mainly via the clathrin-mediated pathway mainly, while BMPR-II is also additionally endocytosed via lipid rafts (32, 64 -65). Ligand activation to preformed receptor complexes (PFCs) can induce Smad phosphorylation at the plasma membrane even before clathrin-coated pit (CCP) formation or internalization, while receptor endocytosis is required for the continuation of signal transduction and target gene expression (32,64). Internalized cell surface receptors are either recycled to the plasma membrane or transported to lysosomes for degradation (66).…”

Section: Discussionmentioning

confidence: 99%

Molecular Consequences of the ACVR1R206H Mutation of Fibrodysplasia Ossificans Progressiva

Song

Kim²,

Woo

et al. 2010

Journal of Biological Chemistry

103

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Fibrodysplasia ossificans progressiva (FOP), a rare genetic and catastrophic disorder characterized by progressive heterotopic ossification, is caused by a point mutation, c.617G>A; p.R206H, in the activin A receptor type 1 (ACVR1) gene, one of the bone morphogenetic protein type I receptors (BMPR-Is). Although altered BMP signaling has been suggested to explain the pathogenesis, the molecular consequences of this mutation are still elusive. Here we studied the impact of ACVR1 R206H mutation on BMP signaling and its downstream signaling cascades in murine myogenic C2C12 cells and HEK 293 cells. We found that ACVR1 was the most abundant of the BMPR-Is expressed in mesenchymal cells but its contribution to osteogenic BMP signal transduction was minor. The R206H mutant caused weak activation of the BMP signaling pathway, unlike the Q207D mutant, a strong and constitutively active form. The R206H mutant showed a decreased binding affinity for FKBP1A/FKBP12, a known safeguard molecule against the leakage of transforming growth factor (TGF)-␤ or BMP signaling. The decreased binding affinity of FKBP1A to the mutant R206H ACVR1 resulted in leaky activation of the BMP signal, and moreover, it decreased steady-state R206H ACVR1 protein levels. Interestingly, while WT ACVR1 and FKBP1A were broadly distributed in plasma membrane and cytoplasm without BMP-2 stimulation and then localized in plasma membrane on BMP-2 stimulation, R206H ACVR1 and FKBP1A were mainly distributed in plasma membrane regardless of BMP-2 stimulation. The impaired binding to FKBP1A and an altered subcellular distribution by R206H ACVR1 mutation may result in mild activation of osteogenic BMP-signaling in extraskeletal sites such as muscle, which eventually lead to delayed and progressive ectopic bone formation in FOP patients.

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Section: Discussionmentioning

confidence: 99%

Molecular Consequences of the ACVR1R206H Mutation of Fibrodysplasia Ossificans Progressiva

Song

Kim²,

Woo

et al. 2010

Journal of Biological Chemistry

103

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“…Several studies suggest that several signaling cascades, including TGF-b, BMP, Wnt, and MAPK, internalize via the caveolin endocytosis to produce different outputs from those via the clathrin-dependent pathway (Di Guglielmo et al, 2003;Nohe et al, 2005;Hartung et al, 2006;Sprenger et al, 2006). Cell surface receptors, such as epidermal growth factor receptor (EGFR), is also shown to be associated with the plasma membrane microdomain, where their tyrosine kinases become inactivated (Couet et al, 1997;Waugh et al, 1999;Lajoie et al, 2007).…”

Section: Two Pathways From the Plasma Membrane To The Endosomesmentioning

confidence: 99%

Membrane dynamics in mammalian embryogenesis: Implication in signal regulation

Wada

Sun‐Wada

Kawamura

et al. 2016

Birth Defects Research Pt C

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Eukaryotes have evolved an array of membrane compartments constituting secretory and endocytic pathways that allow the flow of materials. Both pathways perform important regulatory roles. The secretory pathway is essential for the production of extracellular, secreted signal molecules, but its function is not restricted to a mere route connecting intra-and extracellular compartments. Post-translational modifications also play an integral function in the secretory pathway and are implicated in developmental regulation. The endocytic pathway serves as a platform for relaying signals from the extracellular stimuli to intracellular mediators, and then ultimately inducing signal termination. Here, we discuss recent studies showing that dysfunction in membrane dynamics causes patterning defects in embryogenesis and tissue morphogenesis in mammals.Birth Defects Research (Part C) 108:33-44, 2016.V C 2016 Wiley Periodicals, Inc.

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“…BMP receptors are present on the cell surface in hetero-oligomeric complexes. Although there are some data indicating that BMPRI and BMPRII are segregated and localized both in clathrin coated vesicles and caveolae [30,31] recent atomic force and combined confocal microscopic results showed, that BMP2 binds with high affinity to BMP receptors localized in caveolae, and the BMPRI receptor is phosphorylated in caveolae [32]. It is known that most of the signalling molecules (receptors, tyrosine kinases etc) are inhibited when bound to caveolin-1, stimulation with specific ligands releases caveolin-1 and the signalling is initiated [33].…”

mentioning

confidence: 99%

“…It is known that most of the signalling molecules (receptors, tyrosine kinases etc) are inhibited when bound to caveolin-1, stimulation with specific ligands releases caveolin-1 and the signalling is initiated [33]. In case of BMP signalling the binding of BMPRII to caveolin-1 inhibits the phosphorylation and the activation of BMPRI in the absence of the ligand [31]. Binding of BMP-2 to its receptors, releases caveolin-1 resulting in proceeding activation of Smad signalling pathway [31].…”

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confidence: 99%

Caveolin-1/Caveolae are in Focus of Regulating EMT and MET

Kiss¹

2017

Histol Cytol Embryol

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During epithelial-mesenchymal transition (EMT) polarized epithelial cells undergo a complex proteomic remodelling, several biochemical and morphological changes converting them into mesenchymal-like cells. [1]. Besides of expressing mesenchymal markers (N-cadherin, vimentin, α-smooth muscle actin etc) they acquire the ability to produce extracellular matrix components, as well as metalloproteinases, inflammatorycytokines, fibrogenic and angiogenic factors [2]. Three types of EMTs have been distinguished so far: epithelial-mesenchymal transition during embryogenesis (type I), EMT associated with inflammation, wound healing, tissue regeneration and organ fibrosis (type II) and tumorigenesis (type III) [3]. EMT is triggered by extracellular signals including various cytokines, growth factors, extracellular matrix components. Transforming growth factorβ (TGFβ) family members are the most important regulators in this process. The TGFβ signalling pathways are generally divided into Smad-dependent and Smad-independent processes. When TGFβ binds to its primary serine/threonine kinase receptor (type II) it induces the formation of a heteroterameric receptor complex. Type II receptor thentrans phosphorylates (activates) the signalling receptor (type I) that can initiate Smad2/3 signalling pathway. The receptor internalization is required for the initiation of downstream signalling [4]. In addition to promoting the signalling process by transporting these molecules to the signalling organelles, the receptor-ligand internalization can control the number of receptors present on the cell surface. Thus, receptor internalization regulates the signalling, receptor turnover, the magnitude and duration of the events. In EMT clathrinmediated as well as caveolar endocytosis (internalization via caveolae) play an important role [5]. Caveolae are small omega-or flask-shaped plasma membrane invaginations, highly hydrophobic membrane domains (lipid rafts) containing a special protein, caveolin-1 [6,7]. It is generally accepted that endocytosis via caveolae directs the receptorligand complex to lysosomal and/or proteasomal degradation [8,9] which downregulates the receptors on the cell surface. Caveolin-1 downregulation together with caveolar internalization of TGFβ receptorsturns off the TGFβ signalling pathway,thereby blocking EMT.TGFβ can induce and/or promote EMT through a Smadindependent pathway as well. In response to TGFβ the type II TGFβ receptor can autophosphorylate tyrosine amino acids (Tyr259, 336 and 424) [10], and can undergo Src-mediated tyrosine phosphorylation as well [11,12]. Thetyrosine phosphorylated TGFβ receptor can activate MAP kinase (MEK) and ERK1/2. Members of the Ras/Raf/MEK/ ERK kinase cascades are present in caveolae and caveolin-1 promotes ERK activation. Kinase suppressor of Ras1 (KSR1) is a caveolin-1 interacting protein, and the KSR1-caveolin-1 interaction is required for the redistribution of MEK/ERK in caveolin-rich fractions, actually caveolin-1 facilitates the formation of KSR1/MEK/ERK complex.KSR1-...

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Dynamics and interaction of caveolin-1 isoforms with BMP-receptors

Cited by 91 publications

References 40 publications

Molecular Consequences of the ACVR1R206H Mutation of Fibrodysplasia Ossificans Progressiva

Molecular Consequences of the ACVR1R206H Mutation of Fibrodysplasia Ossificans Progressiva

Membrane dynamics in mammalian embryogenesis: Implication in signal regulation

Caveolin-1/Caveolae are in Focus of Regulating EMT and MET

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