Context-Dependent Functions of Angiopoietin 2 Are Determined by the Endothelial Phosphatase VEPTP

Total Page:16

File Type:pdf, Size:1020Kb

Context-Dependent Functions of Angiopoietin 2 Are Determined by the Endothelial Phosphatase VEPTP Context-dependent functions of angiopoietin 2 are determined by the endothelial phosphatase VEPTP Tomokazu Soumaa,b,1, Benjamin R. Thomsona,b,1, Stefan Heinenc,1, Isabel Anna Carotaa,b, Shinji Yamaguchia,b, Tuncer Onaya,b, Pan Liua,b, Asish K. Ghosha, Chengjin Lid, Vera Ereminad, Young-Kwon Honge, Aris N. Economidesf, Dietmar Vestweberg, Kevin G. Petersh, Jing Jina,b, and Susan E. Quaggina,b,2 aFeinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL 60611; bDivision of Nephrology/ Hypertension, Northwestern University Feinberg School of Medicine, Chicago, IL 60611; cHurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, ON MN4 3M5, Canada; dLunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada; eKeck School of Medicine, University of Southern California, Los Angeles, CA 90033; fRegeneron Pharmaceuticals, Tarrytown, NY 10591; gMax Planck Institute of Molecular Biomedicine, 48149 Münster, Germany; and hAerpio Therapeutics, Cincinnati, OH 45242 Edited by Kari Alitalo, Wihuri Research Institute and University of Helsinki, Helsinki, Finland, and approved December 20, 2017 (received for review August 20, 2017) The angiopoietin (ANGPT)–TIE2/TEK signaling pathway is essential for outcomes (2, 19). Developmental mouse models provide further blood and lymphatic vascular homeostasis. ANGPT1 is a potent TIE2 support for ANGPT2-mediated antagonism of ANGPT1–TIE2 ac- activator, whereas ANGPT2 functions as a context-dependent agonist/ tivation in blood vessels (1, 3, 4). Deletion of either Angpt1 or Tie2 antagonist. In disease, ANGPT2-mediated inhibition of TIE2 in blood results in embryonic lethality at embryonic day (E) 10.5 due to severe vessels is linked to vascular leak, inflammation, and metastasis. Using defects in cardiovascular development (7–11). This phenotype is conditional knockout studies in mice, we show TIE2 is predominantly reproduced by endothelial overexpression of Angpt2, supporting an activated by ANGPT1 in the cardiovascular system and by ANGPT2 in antagonistic role for ANGPT2 in the blood endothelium (12). the lymphatic vasculature. Mechanisms underlying opposing actions In contrast to its antagonistic role in the blood vasculature, of ANGPT2 in blood vs. lymphatic endothelium are poorly understood. ANGPT2 functions as a TIE2 agonist in the lymphatic endo- Here we show the endothelial-specific phosphatase VEPTP (vascular thelium (1, 3, 21). Angpt2 knockout mice display lymphatic de- endothelial protein tyrosine phosphatase) determines TIE2 response fects, including chylous ascites, as well as a sprouting defect in CELL BIOLOGY to ANGPT2. VEPTP is absent from lymphatic endothelium in mouse the retinal blood vascular capillaries (22–24). Intriguingly, only in vivo, permitting ANGPT2/TIE2-mediated lymphangiogenesis. Inhibi- the lymphatic phenotypes were rescued by the obligate TIE2 tion of VEPTP converts ANGPT2 into a potent TIE2 activator in blood agonist ANGPT1, supporting an agonistic role for ANGPT2 endothelium. Our data support a model whereby VEPTP functions as a specific to the lymphatic endothelium (22–24). rheostat to modulate ANGPT2 ligand effect on TIE2. Two recent papers have suggested that TIE2 is not required for lymphatic function in vivo, raising questions about the mechanism angiopoietin–TIE2 pathway | VEPTP | angiogenesis | lymphangiogenesis | tyrosine kinase of ANGPT2-mediated lymphangiogenesis (25, 26). However, here we report that LEC-specific loss of TIE2 phenocopies the lym- phatic defects observed in Angpt2 knockout mice, confirming that he angiopoietin–TIE2 (tyrosine kinase with Ig and EGF TIE2 is required for lymphatic development. Based on these data, Thomology domains, also known as TEK) receptor tyrosine kinase pathway regulates vascular homeostasis, maturation, and remodeling, and has been described as the “gatekeeper” of vascular Significance quiescence (1–4). TIE2 phosphorylation enhances vascular stability by promoting endothelial cell survival, reducing responsiveness to Reducing vascular leakage and stabilizing the endothelium inflammatory stimuli, and strengthening cellular junctions in ma- through activation of the angiopoietin (ANGPT)–TIE2 receptor ture vessels (5–10). The primary TIE2 agonist, angiopoietin 1 tyrosine kinase pathway is a promising therapeutic strategy for (ANGPT1), is secreted from perivascular cells, acting in a paracrine vascular diseases. ANGPT2 is one of two major ligands for the manner (7, 11). A second ligand, ANGPT2, has been described as a TIE2 receptor. Uniquely, ANGPT2 possesses an agonistic role in context-dependent agonist/antagonist, despite having similar re- lymphatic endothelium, but acts as a competitive antagonist in ceptor affinity as the agonistic ligand ANGPT1 (12–14). Unlike blood endothelium. The molecular basis for the opposing actions ANGPT1, ANGPT2 is secreted by endothelial cells and acts on the of ANGPT2 in these two vascular beds is poorly understood. Here TIE2 receptor in an autocrine manner (15). we demonstrate that the absence of VEPTP expression in the The ANGPT–TIE2 pathway has attracted attention due to lymphatic endothelium confers an agonist function of ANGPT2 on strong associations and causal links with human diseases, in- TIE2 receptor, but VEPTP expression in blood endothelium abro- cluding rare genetic disorders, such as hereditary vascular mal- gates its activity. Our findings provide mechanistic insights formations and primary congenital glaucoma (16–18), as well as needed to advance therapeutic targeting of this pathway. common diseases, such as sepsis, cancer, diabetes, and cardio- vascular disease (7, 19, 20). Vigorous efforts have been made to Author contributions: T.S., B.R.T., S.H., J.J., and S.E.Q. designed research; T.S., B.R.T., S.H., I.A.C., S.Y., T.O., P.L., A.K.G., C.L., and V.E. performed research; Y.-K.H., A.N.E., D.V., understand and translate this pathway to the clinic. However, a K.G.P., and J.J. contributed new reagents/analytic tools; T.S., B.R.T., S.H., J.J., and S.E.Q. major question remains: why does ANGPT2 display opposing analyzed data; and T.S., B.R.T., S.H., J.J., and S.E.Q. wrote the paper. context-dependent roles in different vascular beds (14)? In blood Conflict of interest statement: A.N.E. is an employee of Regeneron Pharmaceuticals. endothelial cells (BECs), ANGPT2 is described as an antagonist K.G.P. is an employee of Aerpio Therapeutics. of ANGPT1-mediated TIE2 activation (1, 3, 12, 14), while the This article is a PNAS Direct Submission. situation is reversed in lymphatic endothelial cells (LECs), where This open access article is distributed under Creative Commons Attribution-NonCommercial- ANGPT2 serves as the primary TIE2 agonist (21). NoDerivatives License 4.0 (CC BY-NC-ND). In the blood endothelium, where TIE2 signaling plays an im- 1T.S., B.R.T., and S.H. contributed equally to this work. portant role in vascular stability, elevated levels of circulating 2To whom correspondence should be addressed. Email: [email protected]. ANGPT2 in vascular diseases, such as sepsis, result in TIE2 in- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. hibition, leading to increased capillary leakiness and poor clinical 1073/pnas.1714446115/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1714446115 PNAS Early Edition | 1of6 Downloaded by guest on September 25, 2021 we hypothesize that the context-dependent agonist/antagonist function of ANGPT2 and its opposing effects on TIE2 in different vascular beds (i.e., LEC vs. BEC) might be explained by differ- ential expression of molecular components of the pathway, in- cluding negative regulators, such as the endothelial specific phosphatase, vascular endothelial protein tyrosine phosphatase (VEPTP) (27–30). To elucidate the molecular basis of opposing functions of ANGPT2 in LECs vs. BECs, we generated a series of gene- modified mouse lines and determined a critical cell-autonomous role for TIE2 signaling in lymphangiogenesis. We found that VEPTP is absent from LECs but abundant in BECs, and then used cell-biologic and proteomic-based approaches to explore the effect of VEPTP on ANGPT2–TIE2 activity. Our results show that VEPTP functions as a molecular “rheostat,” modulating re- ceptor sensitivity to enable discrimination between ANGPT li- gands, and provide a molecular mechanism to explain the opposing roles of ANGPT2 in blood and lymphatic vasculature. Results ANGPT2–TIE2 Signaling Is Essential for Embryonic Lymphangiogenesis. To identify the molecular basis of the differential functions of ANGPT2 in LECs and BECs, we characterized the role of ANGPT2–TIE2 signaling in lymphatic development, where ANGPT2 has a well-defined agonistic role (22–24). As expected, whole-body Tie2 deletion from conception using the Rosa26rtTA; tetOCre bitransgenic system in mice harboring a Tie2 conditional Δ by inversion (COIN) allele (Tie2WB E0) resulted in embryonic lethality between E9.5 and E10.5 (17, 18). However, embryos in- duced at E12.5 were found to survive until late gestation, allowing analysis of the lymphatic vasculature. At E16.5, all embryos were found alive. However, subcutaneous edema was observed in Fig. 1. ANGPT2–TIE2 signaling is essential for dermal lymphatic develop- Δ Tie2WB E12.5 knockout embryos, which was never observed in Tie2 ment. (A and B) Subcutaneous edema was observed following genetic de- wild-type or heterozygous controls (Fig. 1A). This result was re- letion of Tie2. Gross view of
Recommended publications
  • Epha4/Tie2 Crosstalk Regulates Leptomeningeal Collateral Remodeling Following Ischemic Stroke
    EphA4/Tie2 crosstalk regulates leptomeningeal collateral remodeling following ischemic stroke Benjamin Okyere, … , John B. Matson, Michelle H. Theus J Clin Invest. 2019. https://doi.org/10.1172/JCI131493. Research In-Press Preview Neuroscience Vascular biology Leptomeningeal anastomoses or pial collateral vessels play a critical role in cerebral blood flow (CBF) restoration following ischemic stroke. The magnitude of this adaptive response is postulated to be controlled by the endothelium, although the underlying molecular mechanisms remain under investigation. Here we demonstrated that endothelial genetic deletion, using EphA4f/f/Tie2-Cre and EphA4f/f/VeCahderin-CreERT2 mice and vessel painting strategies, implicated EphA4 receptor tyrosine kinase as a major suppressor of pial collateral remodeling, CBF and functional recovery following permanent middle cerebral artery occlusion. Pial collateral remodeling is limited by the cross talk between EphA4-Tie2 signaling in vascular endothelial cells, which is mediated through p-Akt regulation. Furthermore, peptide inhibition of EphA4 resulted in acceleration of the pial arteriogenic response. Our findings demonstrate EphA4 is a negative regulator of Tie2 receptor signaling which limits pial collateral arteriogenesis following cerebrovascular occlusion. Therapeutic targeting of EphA4 and/or Tie2 represents an attractive new strategy for improving collateral function, neural tissue health and functional recovery following ischemic stroke. Find the latest version: https://jci.me/131493/pdf 1 EphA4/Tie2
    [Show full text]
  • The Interplay Between Angiopoietin-Like Proteins and Adipose Tissue: Another Piece of the Relationship Between Adiposopathy and Cardiometabolic Diseases?
    International Journal of Molecular Sciences Review The Interplay between Angiopoietin-Like Proteins and Adipose Tissue: Another Piece of the Relationship between Adiposopathy and Cardiometabolic Diseases? Simone Bini *,† , Laura D’Erasmo *,†, Alessia Di Costanzo, Ilenia Minicocci , Valeria Pecce and Marcello Arca Department of Translational and Precision Medicine, Sapienza University of Rome, Viale del Policlinico 155, 00185 Rome, Italy; [email protected] (A.D.C.); [email protected] (I.M.); [email protected] (V.P.); [email protected] (M.A.) * Correspondence: [email protected] (S.B.); [email protected] (L.D.) † These authors contributed equally to this work. Abstract: Angiopoietin-like proteins, namely ANGPTL3-4-8, are known as regulators of lipid metabolism. However, recent evidence points towards their involvement in the regulation of adipose tissue function. Alteration of adipose tissue functions (also called adiposopathy) is considered the main inducer of metabolic syndrome (MS) and its related complications. In this review, we intended to analyze available evidence derived from experimental and human investigations highlighting the contribution of ANGPTLs in the regulation of adipocyte metabolism, as well as their potential role in common cardiometabolic alterations associated with adiposopathy. We finally propose a model of ANGPTLs-based adipose tissue dysfunction, possibly linking abnormalities in the angiopoietins to the induction of adiposopathy and its related disorders. Keywords: adipose tissue; adiposopathy; brown adipose tissue; ANGPTL3; ANGPTL4; ANGPTL8 Citation: Bini, S.; D’Erasmo, L.; Di Costanzo, A.; Minicocci, I.; Pecce, V.; Arca, M. The Interplay between 1. Introduction Angiopoietin-Like Proteins and Adipose tissue (AT) is an important metabolic organ and accounts for up to 25% of Adipose Tissue: Another Piece of the healthy individuals’ weight.
    [Show full text]
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
    Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated.
    [Show full text]
  • Single-Cell RNA Sequencing Demonstrates the Molecular and Cellular Reprogramming of Metastatic Lung Adenocarcinoma
    ARTICLE https://doi.org/10.1038/s41467-020-16164-1 OPEN Single-cell RNA sequencing demonstrates the molecular and cellular reprogramming of metastatic lung adenocarcinoma Nayoung Kim 1,2,3,13, Hong Kwan Kim4,13, Kyungjong Lee 5,13, Yourae Hong 1,6, Jong Ho Cho4, Jung Won Choi7, Jung-Il Lee7, Yeon-Lim Suh8,BoMiKu9, Hye Hyeon Eum 1,2,3, Soyean Choi 1, Yoon-La Choi6,10,11, Je-Gun Joung1, Woong-Yang Park 1,2,6, Hyun Ae Jung12, Jong-Mu Sun12, Se-Hoon Lee12, ✉ ✉ Jin Seok Ahn12, Keunchil Park12, Myung-Ju Ahn 12 & Hae-Ock Lee 1,2,3,6 1234567890():,; Advanced metastatic cancer poses utmost clinical challenges and may present molecular and cellular features distinct from an early-stage cancer. Herein, we present single-cell tran- scriptome profiling of metastatic lung adenocarcinoma, the most prevalent histological lung cancer type diagnosed at stage IV in over 40% of all cases. From 208,506 cells populating the normal tissues or early to metastatic stage cancer in 44 patients, we identify a cancer cell subtype deviating from the normal differentiation trajectory and dominating the metastatic stage. In all stages, the stromal and immune cell dynamics reveal ontological and functional changes that create a pro-tumoral and immunosuppressive microenvironment. Normal resident myeloid cell populations are gradually replaced with monocyte-derived macrophages and dendritic cells, along with T-cell exhaustion. This extensive single-cell analysis enhances our understanding of molecular and cellular dynamics in metastatic lung cancer and reveals potential diagnostic and therapeutic targets in cancer-microenvironment interactions. 1 Samsung Genome Institute, Samsung Medical Center, Seoul 06351, Korea.
    [Show full text]
  • 4 Transcription and Secretion Novel Regulator of Angiopoietin-Like Protein A
    Acute-Phase Protein α1-Antitrypsin−−A Novel Regulator of Angiopoietin-like Protein 4 Transcription and Secretion This information is current as Eileen Frenzel, Sabine Wrenger, Stephan Immenschuh, of September 28, 2021. Rembert Koczulla, Ravi Mahadeva, H. Joachim Deeg, Charles A. Dinarello, Tobias Welte, A. Mario Q. Marcondes and Sabina Janciauskiene J Immunol 2014; 192:5354-5362; Prepublished online 23 April 2014; Downloaded from doi: 10.4049/jimmunol.1400378 http://www.jimmunol.org/content/192/11/5354 Supplementary http://www.jimmunol.org/content/suppl/2014/04/23/jimmunol.140037 http://www.jimmunol.org/ Material 8.DCSupplemental References This article cites 56 articles, 25 of which you can access for free at: http://www.jimmunol.org/content/192/11/5354.full#ref-list-1 Why The JI? Submit online. by guest on September 28, 2021 • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2014 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Acute-Phase Protein a1-Antitrypsin—A Novel Regulator of Angiopoietin-like Protein 4 Transcription and Secretion Eileen Frenzel,* Sabine Wrenger,* Stephan Immenschuh,† Rembert Koczulla,‡ Ravi Mahadeva,x H.
    [Show full text]
  • Angiocrine Endothelium: from Physiology to Cancer Jennifer Pasquier1,2*, Pegah Ghiabi2, Lotf Chouchane3,4,5, Kais Razzouk1, Shahin Rafi3 and Arash Rafi1,2,3
    Pasquier et al. J Transl Med (2020) 18:52 https://doi.org/10.1186/s12967-020-02244-9 Journal of Translational Medicine REVIEW Open Access Angiocrine endothelium: from physiology to cancer Jennifer Pasquier1,2*, Pegah Ghiabi2, Lotf Chouchane3,4,5, Kais Razzouk1, Shahin Rafi3 and Arash Rafi1,2,3 Abstract The concept of cancer as a cell-autonomous disease has been challenged by the wealth of knowledge gathered in the past decades on the importance of tumor microenvironment (TM) in cancer progression and metastasis. The sig- nifcance of endothelial cells (ECs) in this scenario was initially attributed to their role in vasculogenesis and angiogen- esis that is critical for tumor initiation and growth. Nevertheless, the identifcation of endothelial-derived angiocrine factors illustrated an alternative non-angiogenic function of ECs contributing to both physiological and pathological tissue development. Gene expression profling studies have demonstrated distinctive expression patterns in tumor- associated endothelial cells that imply a bilateral crosstalk between tumor and its endothelium. Recently, some of the molecular determinants of this reciprocal interaction have been identifed which are considered as potential targets for developing novel anti-angiocrine therapeutic strategies. Keywords: Angiocrine, Endothelium, Cancer, Cancer microenvironment, Angiogenesis Introduction of blood vessels in initiation of tumor growth and stated Metastatic disease accounts for about 90% of patient that in the absence of such angiogenesis, tumors can- mortality. Te difculty in controlling and eradicating not expand their mass or display a metastatic phenotype metastasis might be related to the heterotypic interaction [7]. Based on this theory, many investigators assumed of tumor and its microenvironment [1].
    [Show full text]
  • The Angiopoietin-2 and TIE Pathway As a Therapeutic Target for Enhancing Antiangiogenic Therapy and Immunotherapy in Patients with Advanced Cancer
    International Journal of Molecular Sciences Review The Angiopoietin-2 and TIE Pathway as a Therapeutic Target for Enhancing Antiangiogenic Therapy and Immunotherapy in Patients with Advanced Cancer Alessandra Leong and Minah Kim * Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY 10032, USA; afl[email protected] * Correspondence: [email protected] Received: 26 September 2020; Accepted: 13 November 2020; Published: 18 November 2020 Abstract: Despite significant advances made in cancer treatment, the development of therapeutic resistance to anticancer drugs represents a major clinical problem that limits treatment efficacy for cancer patients. Herein, we focus on the response and resistance to current antiangiogenic drugs and immunotherapies and describe potential strategies for improved treatment outcomes. Antiangiogenic treatments that mainly target vascular endothelial growth factor (VEGF) signaling have shown efficacy in many types of cancer. However, drug resistance, characterized by disease recurrence, has limited therapeutic success and thus increased our urgency to better understand the mechanism of resistance to inhibitors of VEGF signaling. Moreover, cancer immunotherapies including immune checkpoint inhibitors (ICIs), which stimulate antitumor immunity, have also demonstrated a remarkable clinical benefit in the treatment of many aggressive malignancies. Nevertheless, the emergence of resistance to immunotherapies associated with an immunosuppressive tumor microenvironment has restricted therapeutic response, necessitating the development of better therapeutic strategies to increase treatment efficacy in patients. Angiopoietin-2 (ANG2), which binds to the receptor tyrosine kinase TIE2 in endothelial cells, is a cooperative driver of angiogenesis and vascular destabilization along with VEGF. It has been suggested in multiple preclinical studies that ANG2-mediated vascular changes contribute to the development and persistence of resistance to anti-VEGF therapy.
    [Show full text]
  • Stromal Cell Interactions Mediated by Hypoxia-Inducible Factors Promote Angiogenesis, Lymphangiogenesis, and Metastasis
    Oncogene (2013) 32, 4057–4063 & 2013 Macmillan Publishers Limited All rights reserved 0950-9232/13 www.nature.com/onc REVIEW Cancer–stromal cell interactions mediated by hypoxia-inducible factors promote angiogenesis, lymphangiogenesis, and metastasis GL Semenza Interactions between cancer cells and stromal cells, including blood vessel endothelial cells (BECs), lymphatic vessel endothelial cells (LECs), bone marrow-derived angiogenic cells (BMDACs) and other bone marrow-derived cells (BMDCs) play important roles in cancer progression. Intratumoral hypoxia, which affects both cancer and stromal cells, is associated with a significantly increased risk of metastasis and mortality in many human cancers. Recent studies have begun to delineate the molecular mechanisms underlying the effect of intratumoral hypoxia on cancer progression. Reduced O2 availability induces the activity of hypoxia- inducible factors (HIFs), which activate the transcription of target genes encoding proteins that play important roles in many critical aspects of cancer biology. Included among these are secreted factors, including angiopoietin 2, angiopoietin-like 4, placental growth factor, platelet-derived growth factor B, stem cell factor (kit ligand), stromal-derived factor 1, and vascular endothelial growth factor. These factors are produced by hypoxic cancer cells and directly mediate functional interactions with BECs, LECs, BMDACs and other BMDCs that promote angiogenesis, lymphangiogenesis, and metastasis. In addition, lysyl oxidase (LOX) and LOX-like proteins,
    [Show full text]
  • Human Epidermal Growth Factor Receptor 2 Regulates Angiopoietin-2 Expression in Breast Cancer Via AKT and Mitogen-Activated Protein Kinase Pathways Guilian Niu and W
    Research Article Human Epidermal Growth Factor Receptor 2 Regulates Angiopoietin-2 Expression in Breast Cancer via AKT and Mitogen-Activated Protein Kinase Pathways Guilian Niu and W. Bradford Carter Don and Erika Wallace Comprehensive Breast Program, H. Lee Moffitt Cancer Center and Research Institute, Department of Interdisciplinary Oncology, University of South Florida College of Medicine, Tampa, Florida Abstract signaling pathways. None of the ligands bind HER2, but HER2 is Abnormal activation of human epidermal growth factor the preferred dimerization partner for all of the ErbB receptors. receptor 2 (HER2; ErbB-2) in breast tumors results in The role of HER2 as an important predictor of patient outcome increased metastasis and angiogenesis, as well as reduced and response to various therapies in breast cancer has been clearly survival.Here, we show that angiopoietin-2 (Ang-2) expression established (2, 5–7). Patients with HER2-overexpressing breast correlates with HER2 activity in human breast cancer cell tumors have an increased incidence of metastasis and a poorer lines.Inhibiting HER2 activity with anti-HER2 monoclonal survival rate when compared with patients whose tumors express antibody trastuzumab (Herceptin) or HER2 short interfering HER2 at normal levels. The angiopoietins (Ang) are novel endothelial growth factors, RNA in tumor cells down-regulates Ang-2 expression.Consis- tent with the important roles of AKT and mitogen-activated found to be ligands for the endothelium-specific tyrosine receptor protein kinase in the HER2 signaling pathway, AKT and ERK Tie-2 (8, 9). Ang-1 plays a role in maintaining and stabilizing mitogen-activated protein kinase (MAPK) kinase activity is mature vessels by promoting the interaction between endothelial necessary for Ang-2 up-regulation by HER2.Moreover, over- cells and the surrounding support cells (10–12).
    [Show full text]
  • Altiratinib Inhibits Tumor Growth, Invasion, Angiogenesis, and Microenvironment-Mediated Drug Resistance Via Balanced Inhibition of MET, TIE2, and VEGFR2 Bryan D
    Published OnlineFirst August 18, 2015; DOI: 10.1158/1535-7163.MCT-14-1105 Small Molecule Therapeutics Molecular Cancer Therapeutics Altiratinib Inhibits Tumor Growth, Invasion, Angiogenesis, and Microenvironment-Mediated Drug Resistance via Balanced Inhibition of MET, TIE2, and VEGFR2 Bryan D. Smith1, Michael D. Kaufman1, Cynthia B. Leary1, Benjamin A. Turner1, Scott C. Wise1, Yu Mi Ahn1, R. John Booth1, Timothy M. Caldwell1, Carol L. Ensinger1, Molly M. Hood1, Wei-Ping Lu1, Tristan W. Patt1, William C. Patt1, Thomas J. Rutkoski1, Thiwanka Samarakoon1, Hanumaiah Telikepalli1, Lakshminarayana Vogeti1, Subha Vogeti1, Karen M. Yates1, Lawrence Chun2, Lance J. Stewart2, Michael Clare1, and Daniel L. Flynn1,3 Abstract Altiratinib (DCC-2701) was designed based on the rationale of wild-type and mutated forms, in vitro and in vivo. Through its engineering a single therapeutic agent able to address multiple balanced inhibitory potency versus MET, TIE2, and VEGFR2, hallmarks of cancer (1). Specifically, altiratinib inhibits not only altiratinib provides an agent that inhibits three major evasive mechanisms of tumor initiation and progression, but also drug (re)vascularization and resistance pathways (HGF, ANG, and resistance mechanisms in the tumor and microenvironment VEGF) and blocks tumor invasion and metastasis. Altiratinib through balanced inhibition of MET, TIE2 (TEK), and VEGFR2 exhibits properties amenable to oral administration and exhibits (KDR) kinases. This profile was achieved by optimizing binding substantial blood–brain barrier penetration, an attribute of into the switch control pocket of all three kinases, inducing type II significance for eventual treatment of brain cancers and brain inactive conformations. Altiratinib durably inhibits MET, both metastases. Mol Cancer Ther; 14(9); 1–12.
    [Show full text]
  • The Metabolic Effects of Angiopoietin-Like Protein 8 (ANGPLT8) Are Differentially Regulated By
    bioRxiv preprint doi: https://doi.org/10.1101/734954; this version posted August 15, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. The Metabolic Effects of Angiopoietin-like protein 8 (ANGPLT8) are Differentially Regulated by Insulin and Glucose in Adipose Tissue and Liver and are Controlled by AMPK Signaling Lu Zhang1, Chris E. Shannon1, Terry M. Bakewell1, Muhammad A. Abdul-Ghani1, Marcel Fourcaudot1, and Luke Norton1* Affiliations: 1Diabetes Division, University of Texas Health Science Center, San Antonio, TX Key words: ANGPTL8, Insulin, Lipid, Adipose Tissue, Liver, Transcription factor Running title: Regulation and function of ANGPTL8 Word Count (main): 3,493 Word Count (abstract): 249 Figures and Tables: 6 Figures, 3 Tables, 4 Supplementary Figures *Address all correspondence to: Luke Norton, PhD Email: [email protected] bioRxiv preprint doi: https://doi.org/10.1101/734954; this version posted August 15, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Abstract Objective: The angiopoietin-like protein (ANGPTL) family represents a promising therapeutic target for dyslipidemia, which is a feature of obesity and type 2 diabetes (T2DM). The aim of the present study was to determine the metabolic role of ANGPTL8 and to investigate its nutritional, hormonal and molecular regulation in key metabolic tissues.
    [Show full text]
  • Cardiovascular Disease Products
    Cardiovascular Disease Products For more information, visit: www.bosterbio.com Cardiovascular Disease Research Cardiovascular disease is the leading cause of death in developed nations. Boster Bio aims to supply researchers with high-quality antibodies and ELISA kits so they can make new discoveries and help save lives. In this catalogue you will find a comprehensive list of high-affinity Boster antibodies and high sensitivity Boster ELISA kits targeted at proteins associated with cardiovascular disease. Boster: The Fastest Growing About Bosterbio Antibody Company In 2015 Boster is an antibody manufacturer founded in 1993 by histologist Steven Xia. Over the past two decades, Boster and its products have been cited in over 20,000 publications and counting. The firm specializes in developing antibodies and ELISA kits that feature high affinity, Boster Bio received the CitaAb award for high specificity at affordable the greatest increase in number of prices. citations during 2015 than any other antibody manufacturer. Table of Contents Boster Cardiovascular Disease Related Antibodies…………..………..... 2 Boster Cardiovascular Disease Related ELISA Kits……………………..…. 9 1 High Affinity Boster Antibodies Boster supplies only the highest quality antibodies. Our high-affinity polyclonal and monoclonal antibodies are thoroughly validated by Western Blotting, Immunohistochemistry and ELISA. This is our comprehensive catalog of our antibody products related to cardiovascular disease, sorted in alphabetical order by target gene name. Catalog No Product Name
    [Show full text]