scholarly journals Protein associated with SMAD1 (PAWS1/FAM83G) is a substrate for type I bone morphogenetic protein receptors and modulates bone morphogenetic protein signalling

Open Biology ◽  
2014 ◽  
Vol 4 (2) ◽  
pp. 130210 ◽  
Author(s):  
Janis Vogt ◽  
Kevin S. Dingwell ◽  
Lina Herhaus ◽  
Robert Gourlay ◽  
Thomas Macartney ◽  
...  
Keyword(s):  
Bone Morphogenetic Protein ◽  
Bone Morphogenetic Proteins ◽  
Target Genes ◽  
Type I ◽  
Independent Manner ◽  
Bmp Receptor ◽  
Morphogenetic Protein ◽  
Receptor Kinases ◽  
Protein Receptors ◽  
Bmp Pathway

Bone morphogenetic proteins (BMPs) control multiple cellular processes in embryos and adult tissues. BMPs signal through the activation of type I BMP receptor kinases, which then phosphorylate SMADs 1/5/8. In the canonical pathway, this triggers the association of these SMADs with SMAD4 and their translocation to the nucleus, where they regulate gene expression. BMPs can also signal independently of SMAD4, but this pathway is poorly understood. Here, we report the discovery and characterization of PAWS1/FAM83G as a novel SMAD1 interactor. PAWS1 forms a complex with SMAD1 in a SMAD4-independent manner, and BMP signalling induces the phosphorylation of PAWS1 through BMPR1A. The phosphorylation of PAWS1 in response to BMP is essential for activation of the SMAD4-independent BMP target genes NEDD9 and ASNS . Our findings identify PAWS1 as the first non-SMAD substrate for type I BMP receptor kinases and as a novel player in the BMP pathway. We also demonstrate that PAWS1 regulates the expression of several non-BMP target genes, suggesting roles for PAWS1 beyond the BMP pathway.

scholarly journals Formation of Stable Homomeric and Transient Heteromeric Bone Morphogenetic Protein (BMP) Receptor Complexes Regulates Smad Protein Signaling

2011 ◽  
Vol 286 (22) ◽  
pp. 19287-19296 ◽  
Author(s):  
Barak Marom ◽  
Eva Heining ◽  
Petra Knaus ◽  
Yoav I. Henis
Keyword(s):  
Bone Morphogenetic Protein ◽  
Lateral Diffusion ◽  
State Level ◽  
Type I ◽  
Receptor Complexes ◽  
Bmp Receptor ◽  
Transient Nature ◽  
Morphogenetic Protein ◽  
Smad Protein ◽  
Protein Receptors

The type I and type II bone morphogenetic protein receptors (BMPRI and BMPRII) are present at the plasma membrane as monomers and homomeric and heteromeric complexes, which are modulated by ligand binding. The complexes of their extracellular domains with ligand were shown to form heterotetramers. However, the dynamics of the oligomeric interactions among the full-length receptors in live cell membranes were not explored, and the roles of BMP receptor homodimerization were unknown. Here, we investigated these issues by combining patching/immobilization of an epitope-tagged BMP receptor at the cell surface with measurements of the lateral diffusion of a co-expressed, differently tagged BMP receptor by fluorescence recovery after photobleaching (FRAP). These studies led to several novel conclusions. (a) All homomeric complexes (without or with BMP-2) were stable on the patch/FRAP time scale (minutes), whereas the heterocomplexes were transient, a difference that may affect signaling. (b) Patch/FRAP between HA- and myc-tagged BMPRII combined with competition by untagged BMPRIb showed that the heterocomplexes form at the expense of homodimers. (c) Stabilization of BMPRII·BMPRIb heterocomplexes (but not homomeric complexes) by IgG binding to same-tag receptors elevated phospho-Smad formation both without and with BMP-2. These findings suggest two mechanisms that may suppress the tendency of preformed BMP receptor hetero-oligomers to signal without ligand: (a) competition between homo- and heterocomplex formation, which reduces the steady-state level of the latter, and (b) the transient nature of the heterocomplexes, which limits the time during which BMPRI can be phosphorylated by BMPRII in the heterocomplex.

Abstract 382: The Bone Morphogenetic Protein Pathway Mediates the Effects of H11 Kinase/Hsp22 on Cardiac Cell Growth and Survival

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Xiangzhen Sui ◽  
Dan Li ◽  
Nadia Hedhli ◽  
Hongyu Qiu ◽  
Vinciane Gaussin ◽  
...  
Keyword(s):  
Cell Growth ◽  
Bone Morphogenetic Protein ◽  
Bmp Signaling ◽  
Cardiac Cell ◽  
Growth And Survival ◽  
Over Expression ◽  
Bmp Receptor ◽  
Morphogenetic Protein ◽  
Bmp Pathway ◽  
Cell Growth And Survival

The bone morphogenetic protein (BMP) pathway is a major signaling mechanism during cardiac development but it has no clear function in the post-natal heart. Here, we tested the hypothesis that BMP mediates the physiological effect of the cardiac chaperone H11Kinase/Hsp22 (H11K). Expression of H11K increases during both cardiac ischemia and overload, and its cardiac-specific over-expression in a transgenic (TG) mouse is sufficient to provide major protection against ischemia and to promote cardiac cell growth, which involves the activation of phosphatidylinositol-3-kinase (PI3K) and of its effector Akt. We tested whether H11K-induced activation of PI3K is mediated by BMP. Microarray comparison between hearts from TG and wild type (WT) mice showed an up-regulation of the BMP receptor subunits Alk3 and BMPR-II, as well as of the BMP receptor ligand BMP4, which was confirmed at the protein level (P<0.01 vs WT). Activation of the BMP pathway in TG mice was confirmed by increased phosphorylation of the canonical BMP effectors Smad 1/5/8 (P<0.01 vs WT). The mechanism was further studied in isolated cardiac myocytes. Adeno-mediated over-expression of H11K was accompanied by significant 2–3-fold increase in PI3K activity, phospho-Akt, Smad 1/5/8 phosphorylation and cell growth as measured by [3H]phenylalanine incorporation, and by a 70% reduction in H2O2-mediated apoptosis (all values, P<0.01 vs control). All these changes mediated by H11K in myocytes were abolished upon addition of the BMP antagonist noggin. In pull-down experiments, H11K co-precipitated with both Alk3 and BMPR-II, and increased the association of these two subunits into a functional receptor. Accordingly, Smad 1/5/8 phosphorylation in presence of BMP4 was enhanced by 5-fold upon H11K over-expression, whereas it was decreased by 3-fold upon H11K knockdown (both, P<0.01 vs control), which shows that H11K potentiates the BMP receptor signaling pathway. Therefore, potentiation of the BMP receptor pathway by H11K promotes the activation of the PI3K/Akt pathway and dictates the physiological effects of H11K on cardiac cell growth and survival, which shows a novel role for BMP signaling in post-natal heart. This research has received full or partial funding support from the American Heart Association, AHA National Center.

scholarly journals Structure of bone morphogenetic protein 9 procomplex

2015 ◽  
Vol 112 (12) ◽  
pp. 3710-3715 ◽  
Author(s):  
Li-Zhi Mi ◽  
Christopher T. Brown ◽  
Yijie Gao ◽  
Yuan Tian ◽  
Viet Q. Le ◽  
...  
Keyword(s):  
Growth Factor ◽  
Bone Morphogenetic Protein ◽  
Bone Morphogenetic Proteins ◽  
Sequence Conservation ◽  
Type I ◽  
Morphogenetic Protein ◽  
The Matrix ◽  
Bone Morphogenetic Protein 9 ◽  
Small Growth ◽  
Tgf Β1

Bone morphogenetic proteins (BMPs) belong to the TGF-β family, whose 33 members regulate multiple aspects of morphogenesis. TGF-β family members are secreted as procomplexes containing a small growth factor dimer associated with two larger prodomains. As isolated procomplexes, some members are latent, whereas most are active; what determines these differences is unknown. Here, studies on pro-BMP structures and binding to receptors lead to insights into mechanisms that regulate latency in the TGF-β family and into the functions of their highly divergent prodomains. The observed open-armed, nonlatent conformation of pro-BMP9 and pro-BMP7 contrasts with the cross-armed, latent conformation of pro-TGF-β1. Despite markedly different arm orientations in pro-BMP and pro-TGF-β, the arm domain of the prodomain can similarly associate with the growth factor, whereas prodomain elements N- and C-terminal to the arm associate differently with the growth factor and may compete with one another to regulate latency and stepwise displacement by type I and II receptors. Sequence conservation suggests that pro-BMP9 can adopt both cross-armed and open-armed conformations. We propose that interactors in the matrix stabilize a cross-armed pro-BMP conformation and regulate transition between cross-armed, latent and open-armed, nonlatent pro-BMP conformations.

scholarly journals USP15 targets ALK3/BMPR1A for deubiquitylation to enhance bone morphogenetic protein signalling

Open Biology ◽  
2014 ◽  
Vol 4 (5) ◽  
pp. 140065 ◽  
Author(s):  
Lina Herhaus ◽  
Mazin A. Al-Salihi ◽  
Kevin S. Dingwell ◽  
Timothy D. Cummins ◽  
Lize Wasmus ◽  
...  
Keyword(s):  
Bone Morphogenetic Protein ◽  
Osteoblast Differentiation ◽  
Target Genes ◽  
Bone Morphogenetic Protein Signalling ◽  
Morphogenetic Protein ◽  
Bmp Pathway ◽  
Bmp Signalling ◽  
Myoblast Cells ◽  
Mouse Myoblast ◽  
Transcriptional Target

Protein kinase ALK3/BMPR1A mediates bone morphogenetic protein (BMP) signalling through phosphorylation and activation of SMADs 1/5/8. SMAD6, a transcriptional target of BMP, negatively regulates the BMP pathway by recruiting E3 ubiquitin ligases and targeting ALK3 for ubiquitin-mediated degradation. Here, we identify a deubiquitylating enzyme USP15 as an interactor of SMAD6 and ALK3. We show that USP15 enhances BMP-induced phosphorylation of SMAD1 by interacting with and deubiquitylating ALK3. RNAi -mediated depletion of USP15 increases ALK3 K48-linked polyubiquitylation, and reduces both BMP-induced SMAD1 phosphorylation and transcription of BMP target genes. We also show that loss of USP15 expression from mouse myoblast cells inhibits BMP-induced osteoblast differentiation. Furthermore, USP15 modulates BMP-induced phosphorylation of SMAD1 and transcription during Xenopus embryogenesis.

scholarly journals The Bone Morphogenetic Protein Type Ib Receptor Is a Major Mediator of Glial Differentiation and Cell Survival in Adult Hippocampal Progenitor Cell Culture

2004 ◽  
Vol 15 (8) ◽  
pp. 3863-3875 ◽  
Author(s):  
A. Brederlau ◽  
R. Faigle ◽  
M. Elmi ◽  
A. Zarebski ◽  
S. Sjöberg ◽  
...  
Keyword(s):  
Cell Survival ◽  
Bone Morphogenetic Protein ◽  
Cell Fate ◽  
Bone Morphogenetic Proteins ◽  
Bmp Signaling ◽  
Dominant Negative ◽  
Type I ◽  
Protein Receptor ◽  
Morphogenetic Protein ◽  
Mediate Cell

Bone morphogenetic proteins (BMPs) act as growth regulators and inducers of differentiation. They transduce their signal via three different type I receptors, termed activin receptor-like kinase 2 (Alk2), Alk3, or bone morphogenetic protein receptor Ia (BMPRIa) and Alk6 or BMPRIb. Little is known about functional differences between the three type I receptors. Here, we have investigated consequences of constitutively active (ca) and dominant negative (dn) type I receptor overexpression in adult-derived hippocampal progenitor cells (AHPs). The dn receptors have a nonfunctional intracellular but functional extracellular domain. They thus trap BMPs that are endogenously produced by AHPs. We found that effects obtained by overexpression of dnAlk2 and dnAlk6 were similar, suggesting similar ligand binding patterns for these receptors. Thus, cell survival was decreased, glial fibrillary acidic protein (GFAP) expression was reduced, whereas the number of oligodendrocytes increased. No effect on neuronal differentiation was seen. Whereas the expression of Alk2 and Alk3 mRNA remained unchanged, the Alk6 mRNA was induced after impaired BMP signaling. After dnAlk3 overexpression, cell survival and astroglial differentiation increased in parallel to augmented Alk6 receptor signaling. We conclude that endogenous BMPs mediate cell survival, astroglial differentiation and the suppression of oligodendrocytic cell fate mainly via the Alk6 receptor in AHP culture.

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