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https://www.readbyqxmd.com/read/28298490/aberrant-caveolin-1-mediated-smad-signaling-and-proliferation-identified-by-analysis-of-adenine-474-deletion-mutation-c-474dela-in-patient-fibroblasts-a-new-perspective-in-the-mechanism-of-pulmonary-hypertension
#1
Glenn Marsboom, Zhenlong Chen, Yang Yuan, Yanmin Zhang, Chinnaswamy Tiruppathi, James E Loyd, Eric D Austin, Roberto F Machado, Richard D Minshall, Jalees Rehman, Asrar B Malik
A heterozygous Caveolin-1 c.474delA mutation has been identified in a family with heritable pulmonary arterial hypertension (PAH). This frameshift mutation leads to caveolin-1 protein that contains all known functional domains but has a change only in the final 20 amino acids of the C terminus. Here we studied how this mutation alters caveolin-1 function using patient-derived fibroblasts. Transmission electron microscopy showed that fibroblasts carrying the c.474delA mutation formed typical caveolae. Expression of mutated caveolin-1 in caveolin-1-null mouse fibroblasts failed to induce formation of caveolae due to retention of the mutated protein in the endoplasmic reticulum...
March 15, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28120026/-blast-like-tumor-tissue-in-cervical-lymph-node-with-expression-of-placental-alkaline-phosphatase
#2
C Fellbaum, S Kircher, U Oehler, R Blessing, A Rosenwald
We report a case of ALK1-positive anaplastic large cell lymphoma with expression of placental alkaline phosphatase (PLAP) in many tumor cells. Initially, due to the positivity of tumor cells for CD30 and PLAP, lymph node metastasis of a germ cell neoplasm was discussed. Anaplastic large cell lymphomas of T‑cell lineage form a group of rare non-Hodgkin lymphomas with heterogeneous morphological and immunohistochemical appearance. They may imitate other neoplasms, such as large cell B‑cell lymphomas, metastasis of a carcinoma, melanoma, embryonal carcinoma or seminoma, rhabdomyosarcoma and inflammatory myofibroblastic tumor...
January 24, 2017: Der Pathologe
https://www.readbyqxmd.com/read/28103025/identification-of-the-first-selective-activin-receptor-like-kinase-1-inhibitor-a-reversible-version-of-l-783277
#3
Hanna Cho, Sandip Sengupta, Sean S H Jeon, Wooyoung Hur, Hwan Geun Choi, Hong-Seog Seo, Byung Joo Lee, Jeong Hun Kim, Minhwan Chung, Noo Li Jeon, Nam Doo Kim, Taebo Sim
We synthesized 1 (San78-130), a reversible version of L-783277, as a selective and potent ALK1 inhibitor. Our study showed that 1 possesses great kinase selectivity against a panel of 342 kinases and more potent activity against ALK1 than L-783277. Among the six ALK isotypes (ALK1-6), ALK1 is most significantly inhibited by compound 1. Compound 1 suppresses the BMP9-induced Smad1/5 pathway by mainly inhibiting ALK1 in C2C12 cells. Our molecular dynamics simulations suggest that H-bonding interaction between the C-4' hydroxyl group of 1 and Arg334 of ALK1 substantially contributes to the ALK1 inhibition...
February 6, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28031424/the-dart-study-results-from-the-dose-escalation-and-expansion-cohorts-evaluating-the-combination-of-dalantercept-plus-axitinib-in-advanced-renal-cell-carcinoma
#4
Martin H Voss, Rupal S Bhatt, Elizabeth R Plimack, Brian I Rini, Robert S Alter, J Thaddeus Beck, Dawn Wilson, Xiaosha Zhang, Musa Mutyaba, Chad Glasser, Kenneth M Attie, Matthew L Sherman, Shuchi S Pandya, Michael Atkins
PURPOSE: Activin receptor-like kinase 1 (ALK1) is a novel target in angiogenesis. Concurrent targeting of ALK1 and vascular endothelial growth factor (VEGF) signaling results in augmented inhibition of tumor growth in renal cell carcinoma (RCC) xenograft models. Dalantercept is an ALK1 receptor-fusion protein that acts as a ligand trap for bone morphogenetic proteins (BMP) 9 and 10. The DART Study evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of dalantercept plus axitinib in patients with advanced RCC and determined the optimal dose for further testing...
December 28, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27902739/degenerative-suspensory-ligament-desmitis-dsld-in-peruvian-paso-horses-is-characterized-by-altered-expression-of-tgf%C3%AE-signaling-components-in-adipose-derived-stromal-fibroblasts
#5
Wei Luo, John Sandy, Katie Trella, Daniel Gorski, Shuguang Gao, Jun Li, Sabrina Brounts, Jorge Galante, Anna Plaas
Equine degenerative suspensory ligament desmitis (DSLD) in Peruvian Paso horses typically presents at 7-15 years and is characterized by lameness, focal disorganization of collagen fibrils, and chondroid deposition in the body of the ligament. With the aim of developing a test for disease risk (that can be used to screen horses before breeding) we have quantified the expression of 76 TGFβ-signaling target genes in adipose-derived stromal fibroblasts (ADSCs) from six DSLD-affected and five unaffected Paso horses...
2016: PloS One
https://www.readbyqxmd.com/read/27897192/pi3-kinase-inhibition-improves-vascular-malformations-in-mouse-models-of-hereditary-haemorrhagic-telangiectasia
#6
Roxana Ola, Alexandre Dubrac, Jinah Han, Feng Zhang, Jennifer S Fang, Bruno Larrivée, Monica Lee, Ana A Urarte, Jan R Kraehling, Gael Genet, Karen K Hirschi, William C Sessa, Francesc V Canals, Mariona Graupera, Minhong Yan, Lawrence H Young, Paul S Oh, Anne Eichmann
Activin receptor-like kinase 1 (ALK1) is an endothelial serine-threonine kinase receptor for bone morphogenetic proteins (BMPs) 9 and 10. Inactivating mutations in the ALK1 gene cause hereditary haemorrhagic telangiectasia type 2 (HHT2), a disabling disease characterized by excessive angiogenesis with arteriovenous malformations (AVMs). Here we show that inducible, endothelial-specific homozygous Alk1 inactivation and BMP9/10 ligand blockade both lead to AVM formation in postnatal retinal vessels and internal organs including the gastrointestinal (GI) tract in mice...
November 29, 2016: Nature Communications
https://www.readbyqxmd.com/read/27874028/a-mouse-model-of-hereditary-hemorrhagic-telangiectasia-generated-by-transmammary-delivered-immunoblocking-of-bmp9-and-bmp10
#7
Santiago Ruiz, Haitian Zhao, Pallavi Chandakkar, Prodyot K Chatterjee, Julien Papoin, Lionel Blanc, Christine N Metz, Fabien Campagne, Philippe Marambaud
Hereditary hemorrhagic telangiectasia (HHT) is a potentially life-threatening genetic vascular disorder caused by loss-of-function mutations in the genes encoding activin receptor-like kinase 1 (ALK1), endoglin, Smad4, and bone morphogenetic protein 9 (BMP9). Injections of mouse neonates with BMP9/10 blocking antibodies lead to HHT-like vascular defects in the postnatal retinal angiogenesis model. Mothers and their newborns share the same immunity through the transfer of maternal antibodies during lactation...
November 22, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27869117/genome-wide-rnai-screen-reveals-alk1-mediates-ldl-uptake-and-transcytosis-in-endothelial-cells
#8
Jan R Kraehling, John H Chidlow, Chitra Rajagopal, Michael G Sugiyama, Joseph W Fowler, Monica Y Lee, Xinbo Zhang, Cristina M Ramírez, Eon Joo Park, Bo Tao, Keyang Chen, Leena Kuruvilla, Bruno Larriveé, Ewa Folta-Stogniew, Roxana Ola, Noemi Rotllan, Wenping Zhou, Michael W Nagle, Joachim Herz, Kevin Jon Williams, Anne Eichmann, Warren L Lee, Carlos Fernández-Hernando, William C Sessa
In humans and animals lacking functional LDL receptor (LDLR), LDL from plasma still readily traverses the endothelium. To identify the pathways of LDL uptake, a genome-wide RNAi screen was performed in endothelial cells and cross-referenced with GWAS-data sets. Here we show that the activin-like kinase 1 (ALK1) mediates LDL uptake into endothelial cells. ALK1 binds LDL with lower affinity than LDLR and saturates only at hypercholesterolemic concentrations. ALK1 mediates uptake of LDL into endothelial cells via an unusual endocytic pathway that diverts the ligand from lysosomal degradation and promotes LDL transcytosis...
November 21, 2016: Nature Communications
https://www.readbyqxmd.com/read/27866969/overexpression-of-cd109-in-the-epidermis-differentially-regulates-alk1-versus-alk5-signaling-and-modulates-extracellular-matrix-synthesis-in-the-skin
#9
Joshua Vorstenbosch, Christopher M Nguyen, Shufeng Zhou, You Jung Seo, Aya Siblini, Kenneth W Finnson, Albane A Bizet, Simon D Tran, Anie Philip
Transforming growth factor-β (TGF-β) is a multifunctional growth factor involved in many physiological processes including wound healing and inflammation. Excessive TGF-β signaling in the skin has been implicated in fibrotic skin disorders such as keloids and scleroderma. We previously identified CD109 as a TGF-β co-receptor and inhibitor of TGF-β signaling and have shown that transgenic mice overexpressing CD109 in the epidermis display decreased scarring. In certain cell types, in addition to the canonical type I receptor, ALK5, which activates Smad2/3, TGF-β can signal through another type I receptor, ALK1, which activates Smad1/5...
March 2017: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/27865758/bone-morphogenetic-protein-2-and-transforming-growth-factor-%C3%AE-1-inhibit-the-expression-of-the-proinflammatory-cytokine-il-34-in-rheumatoid-arthritis-synovial-fibroblasts
#10
Marguerite Chemel, Regis Brion, Aude-Isabelle Segaliny, Audrey Lamora, Celine Charrier, Benedicte Brulin, Yves Maugars, Benoit Le Goff, Dominique Heymann, Franck Verrecchia
IL-34 is a proinflammatory cytokine implicated in rheumatoid arthritis (RA). The current study aimed to assess the IL-34 expression in response to two members of the transforming growth factor (TGF)-β family, TGF-β1 and bone morphogenetic protein (BMP)-2, in synovial fibroblasts from RA patients. IL-34, TGF-β1, and BMP-2 productions were measured in patient synovial fluids by enzyme-linked immunosorbent assay. IL-34 mRNA levels were quantified by real-time quantitative PCR in human synovial fibroblasts and murine mesenchymal stem cells...
January 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/27848974/differential-expression-of-tgf-%C3%AE-superfamily-members-and-role-of-smad1-5-9-signalling-in-chondral-versus-endochondral-chondrocyte-differentiation
#11
Verena Dexheimer, Jessica Gabler, Katharina Bomans, Tanja Sims, Georg Omlor, Wiltrud Richter
Proteins of the transforming-growth-factor-β (TGF-β)-superfamily have a remarkable ability to induce cartilage and bone and the crosstalk of TGF-β - and BMP-signalling pathways appears crucial during chondrocyte development. Aim was to assess the regulation of TGF-β-superfamily members and of Smad2/3- and Smad1/5/9-signalling during endochondral in vitro chondrogenesis of mesenchymal stromal cells (MSC) relative to chondral redifferentiation of articular chondrocytes (AC) to adjust chondrocyte development of MSC towards a less hypertrophic phenotype...
November 16, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27748860/bone-morphogenetic-protein%C3%A2-9-promotes-the-differentiation-of-mouse-spleen-macrophages-into-osteoclasts-via-the-alk1-receptor-and-erk-1-2-pathways-in%C3%A2-vitro
#12
Hai Li, Dahang Zhao, Shengjing Wang, Jing Ding, Li Zhao
It has been confirmed that bone morphogenetic protein-9 (BMP-9) promotes the differentiation of osteoblasts. However, the ways in which BMP‑9 exerts its effects on the differentiation of osteoclasts and bone resorption remain to be elucidated. The present study was designed to investigate the roles and the molecular mechanism of BMP‑9 on the proliferation and differentiation of osteoclast precursors in vitro. Mouse spleen macrophages (RAW 264.7 cells) were cultured in the presence of receptor activator for nuclear factor‑κb ligand (RANKL) in vitro...
November 2016: Molecular Medicine Reports
https://www.readbyqxmd.com/read/27742676/correction-endothelial-alk1-is-a-therapeutic-target-to-block-metastatic-dissemination-of-breast-cancer
#13
(no author information available yet)
No abstract text is available yet for this article.
October 15, 2016: Cancer Research
https://www.readbyqxmd.com/read/27741515/compound-genetically-engineered-mouse-models-of-cancer-reveal-dual-targeting-of-alk1-and-endoglin-as-a-synergistic-opportunity-to-impinge-on-angiogenic-tgf-%C3%AE-signaling
#14
Nikolas M Eleftheriou, Jonas Sjölund, Matteo Bocci, Eliane Cortez, Se-Jin Lee, Sara I Cunha, Kristian Pietras
Angiogenesis occurs early in tumor development, sustains primary tumor growth and provides a route for metastatic escape. The TGF-β family receptors modulate angiogenesis via endothelial-cell specific pathways. Here we investigate the interaction of two such receptors, ALK1 and endoglin, in pancreatic neuroendocrine tumors (PanNET). Independently, ALK1 and endoglin deficiencies exhibited genetically divergent phenotypes, while both highly correlate to an endothelial metagene in human and mouse PanNETs. A concurrent deficiency of both receptors synergistically decreased tumor burden to a greater extent than either individual knockdown...
December 20, 2016: Oncotarget
https://www.readbyqxmd.com/read/27731483/immunolocalization-of-the-tgfb1-system-in-submandibular-gland-fibrosis-after-experimental-periodontitis-in-rats
#15
Candela R González, Mariano Ar Amer, Alfredo D Vitullo, Silvia I González-Calvar, María I Vacas
Saliva is the first barrier to entry of bacteria and viruses into the body. The submandibular glands (SMG) contribute to the maintenance of oral health and regulation of immune/ inflam matory responses. Previous studies suggest that transforming growth factor beta 1 (TGFB1) may contribute to salivary gland fibrosis but the expression of the TGFB1 system in the SMG has not been elucidated. Thus, the aim of this study was to analyze in rat SMG the immunolocalization of TGFB1 and its specific receptors ALK5 (profibrotic) and ALK1 (proproliferative) and the coreceptor endoglin (EDG) in a bilateral experimental periodontitis (EP) model (cotton thread ligature around the neck of the first lower molars) for 1 and 6 weeks...
September 2016: Acta Odontológica Latinoamericana: AOL
https://www.readbyqxmd.com/read/27688842/expression-of-tgf-%C3%AE-signaling-regulator-rbpms-rna-binding-protein-with-multiple-splicing-is-regulated-by-il-1%C3%AE-and-tgf-%C3%AE-superfamily-members-and-decreased-in-aged-and-osteoarthritic-cartilage
#16
S Shanmugaapriya, A van Caam, L de Kroon, Elly L Vitters, B Walgreen, H van Beuningen, E Blaney Davidson, Peter M van der Kraan
OBJECTIVE: RNA-binding protein with multiple splicing (RBPMS) has been shown to physically interact with Smads and enhance transforming growth factor-β (TGF-β)-mediated Smad2/3 transcriptional activity in mammalian cells. Objective of this study was to examine whether expression of RBPMS is regulated by interleukin-1β (IL)-1β and TGF-β superfamily growth factors and whether expression of RBPMS is altered during aging and experimental osteoarthritis. METHODS: Expression of RBPMS protein was investigated in chondrocyte cell lines of murine (H4) and human (G6) origin using Western blot analysis...
October 2016: Cartilage
https://www.readbyqxmd.com/read/27686567/anaplastic-lymphoma-kinase-positive-large-b-cell-lymphoma-literature-review-and-report-of-an-endoscopic-fine-needle-aspiration-case-with-tigroid-backgrounds-mimicking-seminoma
#17
Hany Sakr, Michael Cruise, Prabhleen Chahal, Claudiu Cotta, James Cook, Sricharan Chalikonda, Steven Rosenblatt, Fatima Hamadeh, Omar Al-Nourhji, Charles D Sturgis
Anaplastic lymphoma kinase-positive large B-cell lymphoma (ALK+ LBCL) is a rare distinct type of non-Hodgkin's lymphoma that arises in association with alterations of the ALK gene. This distinct disease entity is typically associated with an aggressive clinical course and appears in light microscopic preparations as a monomorphic population of large, immunoblast-like cells. In this report, we describe a case of ALK+ LBCL diagnosed by transgastric endoscopic ultrasound-guided fine needle aspiration (EUS FNA) of splenic hilar lymph nodes...
February 2017: Diagnostic Cytopathology
https://www.readbyqxmd.com/read/27672213/blood-flow-boosts-bmp-signaling-to-keep-vessels-in-shape
#18
Claudio A Franco, Holger Gerhardt
Bone morphogenic proteins (BMPs) and blood flow regulate vascular remodeling and homeostasis. In this issue, Baeyens et al. (2016. J. Cell Biol http://dx.doi.org/10.1083/jcb.201603106) show that blood flow sensitizes endothelial cells to BMP9 signaling by triggering Alk1/ENG complexing to suppress cell proliferation and to recruit mural cells, thereby establishing endothelial quiescence.
September 26, 2016: Journal of Cell Biology
https://www.readbyqxmd.com/read/27648727/a-phase-2-study-of-dalantercept-an-activin-receptor-like-kinase-1-ligand-trap-in-patients-with-recurrent-or-metastatic-squamous-cell-carcinoma-of-the-head-and-neck
#19
Antonio Jimeno, Marshall R Posner, Lori J Wirth, Nabil F Saba, Roger B Cohen, Elizabeta C Popa, Athanassios Argiris, Kenneth F Grossmann, Ammar Sukari, Dawn Wilson, Xiaosha Zhang, Jade Sun, Chad Glasser, Kenneth M Attie, Matthew L Sherman, Susan S Pandya, Jared Weiss
BACKGROUND: Patients with platinum-refractory, recurrent or metastatic squamous cell carcinoma of the head and neck (RM-SCCHN) have limited options. Activin receptor-like kinase 1 (ALK1) is a type I receptor of the transforming growth factor β superfamily expressed on activated endothelial cells. Dalantercept is an ALK1 receptor fusion protein that acts as a ligand trap to block signaling through ALK1 and inhibits stages of angiogenesis involved in blood vessel maturation and stabilization...
September 20, 2016: Cancer
https://www.readbyqxmd.com/read/27646277/defective-fluid-shear-stress-mechanotransduction-mediates-hereditary-hemorrhagic-telangiectasia
#20
Nicolas Baeyens, Bruno Larrivée, Roxana Ola, Brielle Hayward-Piatkowskyi, Alexandre Dubrac, Billy Huang, Tyler D Ross, Brian G Coon, Elizabeth Min, Maya Tsarfati, Haibin Tong, Anne Eichmann, Martin A Schwartz
Morphogenesis of the vascular system is strongly modulated by mechanical forces from blood flow. Hereditary hemorrhagic telangiectasia (HHT) is an inherited autosomal-dominant disease in which arteriovenous malformations and telangiectasias accumulate with age. Most cases are linked to heterozygous mutations in Alk1 or Endoglin, receptors for bone morphogenetic proteins (BMPs) 9 and 10. Evidence suggests that a second hit results in clonal expansion of endothelial cells to form lesions with poor mural cell coverage that spontaneously rupture and bleed...
September 26, 2016: Journal of Cell Biology
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