title: Effect of the distribution and clustering of the type I A BMP receptor (ALK3) with the type II BMP receptor on the activation of signalling pathways.
abstract: Bone morphogenetic proteins (BMPs) play an important role during embryonic development, especially in chondrogenesis, osteogenesis, neurogenesis and hematopoiesis. There are over 19 BMPs known in mammalians, but only three BMP-type-I receptors and three BMP-type-II receptors are known so far to mediate these responses. Previous reports provide evidence to support that oligomerisation of BMP receptors influences the activation of the downstream BMP signalling pathways, the Smad or the p38 MAPK pathway. To further explore the importance of BMP receptor clustering in signalling, image correlation spectroscopy has been used to investigate the clustering and distribution of BMP receptors at the surface of the cell membrane. Here we demonstrate that the co-expression of the BMP-type-II receptor (BRII) influences the aggregation and the distribution of the BMP-type-Ia receptor (BRIa) in COS7 cells and in A431 cells. We also demonstrate that BMP-2 stimulation of the cells leads to a rearrangement of receptor complexes at the cell surface. Using A431 cells and limb bud-derived mesenchymal cells, we show that co-expression of the BRII and a constitutive active BRIa-ca is necessary for the activation of the Smad pathway. Importantly using a kinase-inactive BRII the rearrangement of BRIa is blocked. Together, these findings suggest that rearrangement of the receptors at the cell surface prior to forming preformed ligand independent complexes plays a critical role in activation of the Smad pathway. It also suggests further that the kinase activity of BRII is needed for signalling beyond the activation of BRIa at the GS domain.
authors.affiliation: Department of Chemistry, University of Western Ontario, London, N6A1B7, Canada.
authors.forename: Anja
authors.initials: A
authors.lastname: Nohe
authors.forename: Eleonora
authors.initials: E
authors.lastname: Keating
authors.forename: T Michael
authors.initials: TM
authors.lastname: Underhill
authors.forename: Petra
authors.initials: P
authors.lastname: Knaus
authors.forename: Nils O
authors.initials: NO
authors.lastname: Petersen
mesh_terms: D000818:Animals; D052005:Bone Morphogenetic Protein Receptors, Type I; D052006:Bone Morphogenetic Protein Receptors, Type II; D019556:COS Cells; D002462:Cell Membrane / Q000378:metabolism*; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D003001:Cloning, Molecular; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D017978:Receptors, Growth Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D051785:Smad Proteins; D013057:Spectrum Analysis; D015534:Trans-Activators / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D017978:Receptors, Growth Factor; D051785:Smad Proteins; D015534:Trans-Activators; D017346:Protein Serine-Threonine Kinases; C498218:BMPR2 protein, human; C498212:Bmpr1a protein, mouse; C498219:Bmpr2 protein, mouse; D052005:Bone Morphogenetic Protein Receptors, Type I; D052006:Bone Morphogenetic Protein Receptors, Type II