ALK2/3 are components of the immune synapse crucial for T cell activation and death
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE292407 | GEO | 2025/05/30
REPOSITORIES: GEO
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Project description:Implantation of an embryo in the uterus is a multistep process tightly controlled by an intricate regulatory network of interconnected ovarian, uterine, and embryonic factors. Bone morphogenetic protein (BMP) ligands and receptors are expressed in the pregnant uterus, and BMP2 has been shown to be a key regulator of implantation. In this study, we investigated the roles of the BMP type 1 receptor, activin-like kinase 2 (ALK2), during mouse pregnancy by producing uterine-specific Alk2 conditional knockout (cKO) mice. In the absence of ALK2, embryos can invade the uterine epithelium and stroma, but stromal cells cannot undergo uterine decidualization, resulting in sterility. Mechanistically, microarray analysis revealed that CCAAT/enhancer-binding protein β (Cebpb) expression is suppressed during decidualization in Alk2 cKO females. These findings and the similar phenotypes of Cebpb cKO and Alk2 cKO mice lead to the hypothesis that BMPs act upstream of C/EBPβ to regulate decidualization. To test this hypothesis, we knocked down ALK2 in human uterine stromal cells (HESC) and discovered that ablation of ALK2 alters HESC decidualization and suppresses CEBPB mRNA and protein levels. Chromatin immunoprecipitation (ChIP) analysis of decidualizing HESC confirmed that BMP signaling protein, SMAD1, directly regulates expression of CEBPB by binding a distinct regulatory sequence in the CEBPB promoter; C/EBPβ, in turn, regulates the expression of progesterone receptor (PGR). Our work clarifies the conserved mechanisms through which BMPs regulate embryo implantation in rodents and primates and, for the first time, uncovers a linear pathwayof BMP signaling through ALK2 to regulate CEBPB and, subsequently, PGR during decidualization. gene expression profiling of two groups: control mice and Alk2 cKO mice
2014-01-07 | E-GEOD-46689 | biostudies-arrayexpress
Project description:Implantation of an embryo in the uterus is a multistep process tightly controlled by an intricate regulatory network of interconnected ovarian, uterine, and embryonic factors. Bone morphogenetic protein (BMP) ligands and receptors are expressed in the pregnant uterus, and BMP2 has been shown to be a key regulator of implantation. In this study, we investigated the roles of the BMP type 1 receptor, activin-like kinase 2 (ALK2), during mouse pregnancy by producing uterine-specific Alk2 conditional knockout (cKO) mice. In the absence of ALK2, embryos can invade the uterine epithelium and stroma, but stromal cells cannot undergo uterine decidualization, resulting in sterility. Mechanistically, microarray analysis revealed that CCAAT/enhancer-binding protein β (Cebpb) expression is suppressed during decidualization in Alk2 cKO females. These findings and the similar phenotypes of Cebpb cKO and Alk2 cKO mice lead to the hypothesis that BMPs act upstream of C/EBPβ to regulate decidualization. To test this hypothesis, we knocked down ALK2 in human uterine stromal cells (HESC) and discovered that ablation of ALK2 alters HESC decidualization and suppresses CEBPB mRNA and protein levels. Chromatin immunoprecipitation (ChIP) analysis of decidualizing HESC confirmed that BMP signaling protein, SMAD1, directly regulates expression of CEBPB by binding a distinct regulatory sequence in the CEBPB promoter; C/EBPβ, in turn, regulates the expression of progesterone receptor (PGR). Our work clarifies the conserved mechanisms through which BMPs regulate embryo implantation in rodents and primates and, for the first time, uncovers a linear pathwayof BMP signaling through ALK2 to regulate CEBPB and, subsequently, PGR during decidualization.
2014-01-07 | GSE46689 | GEO
Project description:Stress-induced phosphoprotein 1 (STIP1) is a co-chaperone that regulates other chaperone proteins that was recently shown to be secreted by ovarian cancer cells to induce cell proliferation. In this study, we found that STIP1 induced the phosphorylation of endogenous SMAD1/5, and knockdown of SMAD1/4/5 blocked STIP1-activated ID3 expression. Inhibition of ALK2, a serine/threonine kinase receptor, with siRNA or the specific inhibitor LDN193189, blocked STIP1-induced phosphorylation of SMAD1/5 and inhibited STIP1-related cell proliferation. The signaling pathway was found to involve binding of secreted STIP1 to ALK2, phosphorylation of SMAD, and activation of ID3 to induce cell proliferation was identified not only by in vitro immunofluorescent microscopy and biochemical identification of complex formation, but also by in vivo immunohistochemical analyses of ovarian cancer tissues. MDAH2774 cell treated with rhSTIP1 MDAH2774 cell treated without rhSTIP1 MDAH2774 cell treated with rhSTIP1-2 MDAH2774 cell treated without rhSTIP1-2
2012-03-03 | E-GEOD-27654 | biostudies-arrayexpress
Project description:Runx1 is highly expressed in osteoblasts, however, its function in osteogenesis is unclear. We generated mesenchymal progenitor-specific (Runx1f/fTwist2-Cre) and osteoblast-specific (Runx1f/fCol1α1-Cre) conditional knockout (Runx1 CKO) mice. The mutant CKO mice with normal skeletal development displayed a severe osteoporosis phenotype at postnatal and adult stages. Runx1 CKO resulted in decreased osteogenesis and increased adipogenesis. RNA-sequencing analysis, Western blot, and qPCR validation of Runx1 CKO samples showed that Runx1 regulates BMP signaling pathway and Wnt/β-catenin signaling pathway. ChIP assay revealed direct binding of Runx1 to the promoter regions of Bmp7, Alk3, and Atf4, and promoter mapping demonstrated that Runx1 upregulates their promoter activity through the binding regions. Bmp7 overexpression rescued Alk3, Runx2, and Atf4 expression in Runx1-deficient BMSCs. Runx2 expression was decreased while Runx1 was not changed in Alk3 deficient osteoblasts. Atf4 overexpression in Runx1-deficient BMSCs did not rescue expression of Runx1, Bmp7, and Alk3. Smad1/5/8 activity was vitally reduced in Runx1 CKO cells, indicating Runx1 positively regulates the Bmp7/Alk3/Smad1/5/8/Runx2/ATF4 signaling pathway. Notably, Runx1 overexpression in Runx2-/- osteoblasts rescued expression of Atf4, OCN, and ALP to compensate Runx2 function. Runx1 CKO mice at various osteoblast differentiation stages reduced Wnt signaling and caused high expression of C/ebpα and Pparγ and largely increased adipogenesis. Co-culture of Runx1-deficient and wild-type cells demonstrated that Runx1 regulates osteoblast−adipocyte lineage commitment both cell-autonomously and non-autonomously. Notably, Runx1 overexpression rescued bone loss in OVX-induced osteoporosis. This study focused on the role of Runx1 in different cell populations with regards to BMP and Wnt signaling pathways and in the interacting network underlying bone homeostasis as well as adipogenesis, and has provided new insight and advancement of knowledge in skeletal development. Collectively, Runx1 maintains adult bone homeostasis from bone loss though up-regulating Bmp7/Alk3/Smad1/5/8/Runx2/ATF4 and WNT/β-Catenin signaling pathways, and targeting Runx1 potentially leads to novel therapeutics for osteoporosis. Using unbiased genome-wide RNA-seq data from Runx1f/fCol1α1-Cre, Runx1ffTwist2-cre, Runx1f/f;Col2α1-Cre and their control osteoblasts, we examined Runx1-mediated transcriptional targets that could account for osteoblast differentiation defects and increased adipocytes.
2022-09-26 | GSE213930 | GEO
Project description:Stress-induced phosphoprotein 1 (STIP1) is a co-chaperone that regulates other chaperone proteins that was recently shown to be secreted by ovarian cancer cells to induce cell proliferation. In this study, we found that STIP1 induced the phosphorylation of endogenous SMAD1/5, and knockdown of SMAD1/4/5 blocked STIP1-activated ID3 expression. Inhibition of ALK2, a serine/threonine kinase receptor, with siRNA or the specific inhibitor LDN193189, blocked STIP1-induced phosphorylation of SMAD1/5 and inhibited STIP1-related cell proliferation. The signaling pathway was found to involve binding of secreted STIP1 to ALK2, phosphorylation of SMAD, and activation of ID3 to induce cell proliferation was identified not only by in vitro immunofluorescent microscopy and biochemical identification of complex formation, but also by in vivo immunohistochemical analyses of ovarian cancer tissues.
2012-03-03 | GSE27654 | GEO
Project description:The tightly controlled BMP-Smad1 pathway is essential for embryonic development and postnatal tissue homeostasis. Dysfunction of BMP-Smad1 signaling also leads to tumor development such as juvenile polyposis and Cowden syndromes and various tumors in mouse models, with unknown pathological mechanisms. Here we establish a link between the BMP-Smad pathway and the prominent tumor suppressor Atm-p53 pathway. We identify activated nuclear Smad1 as an Atm substrate under genotoxic stress. Atm-mediated Smad1 S239 phosphorylation disrupts Smad1 interaction with protein phosphatase PPM1A and enhances Smad1 activation and up-regulation, which not only turns on target genes including Cdk1nc but also interacts with p53 and inhibits Mdm2-mediated p53 ubiquitination, leading to p53 stabilization. Functionally, Smad1 acts like a tumor suppressor in DNA damage response, cell transformation and tumorigenesis in a p53-dependent manner. Sequencing of the gastric cancer samples revealed that Smad1 is frequently mutated, with S239 as mutational hotspot. This study thus establishes the BMP-Smad1 pathway as an integral part of DNA damage response, which can suppresses tumorigenesis via p53. Transformed MEFs (Smad1f/f, Smad1f/f Cre) treated with 50ng/ml BMP2, 1 ug/ml doxorubincin, or both for different periods of time. The mRNA levels of all genes were compared using microarray analysis.
2012-12-31 | E-GEOD-36843 | biostudies-arrayexpress
Project description:The tightly controlled BMP-Smad1 pathway is essential for embryonic development and postnatal tissue homeostasis. Dysfunction of BMP-Smad1 signaling also leads to tumor development such as juvenile polyposis and Cowden syndromes and various tumors in mouse models, with unknown pathological mechanisms. Here we establish a link between the BMP-Smad pathway and the prominent tumor suppressor Atm-p53 pathway. We identify activated nuclear Smad1 as an Atm substrate under genotoxic stress. Atm-mediated Smad1 S239 phosphorylation disrupts Smad1 interaction with protein phosphatase PPM1A and enhances Smad1 activation and up-regulation, which not only turns on target genes including Cdk1nc but also interacts with p53 and inhibits Mdm2-mediated p53 ubiquitination, leading to p53 stabilization. Functionally, Smad1 acts like a tumor suppressor in DNA damage response, cell transformation and tumorigenesis in a p53-dependent manner. Sequencing of the gastric cancer samples revealed that Smad1 is frequently mutated, with S239 as mutational hotspot. This study thus establishes the BMP-Smad1 pathway as an integral part of DNA damage response, which can suppresses tumorigenesis via p53.
2012-12-31 | GSE36843 | GEO
Project description:Bone morphogenetic proteins (BMPs) are transforming growth factor β (TGFβ) family members that regulate the post-implantation and mid-gestation stages of pregnancy. In this study we discovered that signaling via activin-like kinase 3 (ALK3/BMPR1A), a BMP type 1 receptor, is necessary for blastocyst attachment. To understand the role of ALK3 in the luminal uterine epithelium, we obtained the gene expression profiles of isolated luminal uterine epithelium from 3.5dpc control and Alk3 cKO mice. Gene expression profiling of isolated luminal uterine epithelium from control and Alk3 cKO mice. two group comparison
2016-01-04 | E-GEOD-73717 | biostudies-arrayexpress
Project description:The dorsoventral gradient of BMP signaling plays an essential role in embryonic patterning, with high BMP signal activating ventral-lateral mesoderm markers directly, and low BMP signal inducing neural tissues. The Zinc finger SWIM domain-containing protein 4 (zswim4) is expressed in the dorsal blastopore lip at the onset of Xenopus gastrula and then enriched at the forming neuroectoderm at mid-gastrula stages. Overexpression of zswim4 in Xenopus embryos causes inhibition of the anterior axis and shortened, curved body, and knockdown or knockout of zswim4 disturbed embryonic body axis formation and head development. The expression of ventral-lateral mesoderm marker genes was reduced after zswim4 overexpression and increased in embryos with zswim4 knockdown. Neural marker genes were repressed in zswim4 morphant. Mechanistically Zswim4 attenuates BMP signal through reducing protein stability of Smad1 in both Xenopus embryos and HEK293T cells. Zswim4 interacts with Smad1 and promotes ubiquitination of Smad1 in HEK293T cells. To identify the interaction partner of Zswim4 in regulating Smad1 stability, we performed SILAC based IP in HEK293T cells, and the precipitates were analyzed by Mass Spectrometry.
2024-05-22 | PXD035207 | Pride
Project description:Stress-induced phosphoprotein 1 (STIP1), a co-chaperone that organizes other chaperones- heat shock proteins (HSP), was recently shown to be secreted by human ovarian cancer cells to induce cell proliferation. In neuronal tissues, binding to prion protein was required for STIP1 to activate the ERK (extracellular regulated MAP kinase) signaling pathways. However, in this study, we found that STIP1 stimulated cell proliferation of ovarian cancer via a bone morphogenetic protein (BMP) signaling pathway, not through the prion-ERK pathway. The STIP1 binding to a BMP receptor, ALK2 (activin A receptor, type II-like kinase 2), was necessary and sufficient to stimulate cancer cell proliferation. The binding of STIP1 to ALK2 activated the SMAD signaling pathway, leading to transcriptional activation of ID3 (inhibitor of DNA binding 3) that promotes cell proliferation. In conclusion, ovarian cancer tissues secrete STIP1 into the local environment and eventually into blood circulation of patients. In an autocrine and/or paracrine fashion, secreted STIP1 stimulates cancer cell proliferation by binding to ALK2 and activating the SMAD-ID3 signaling pathways. Elucidation of the mechanism by which STIP1 stimulates cancer cell proliferation may pave the way for developing novel therapeutic strategies for treatment of ovarian cancer. SKOV3 cell,treated without rhSTIP1 SKOV3 cell,treated with rhSTIP1 SKOV3 cell,treated without rhSTIP1-2 SKOV3 cell,treated with rhSTIP1-2
2013-03-09 | E-GEOD-36383 | biostudies-arrayexpress