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Tissue Factor Regulation, Signaling and Functions Beyond Coagulation with a Focus on Diabetes

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Tissue Factor Regulation, Signaling and Functions Beyond Coagulation with a Focus on Diabetes Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 1626 Tissue Factor regulation, signaling and functions beyond coagulation with a focus on diabetes DESIRÉE EDÉN ACTA UNIVERSITATIS UPSALIENSIS ISSN 1651-6206 ISBN 978-91-513-0842-5 UPPSALA urn:nbn:se:uu:diva-399599 2020 Dissertation presented at Uppsala University to be publicly examined in Enghoffsalen, Akademiska sjukhuset, ing. 50, Uppsala, Friday, 21 February 2020 at 13:15 for the degree of Doctor of Philosophy (Faculty of Medicine). The examination will be conducted in Swedish. Faculty examiner: Docent, Universitetslektor Sofia Ramström (Örebro Universitet, Institutionen för medicinska vetenskaper). Abstract Edén, D. 2020. Tissue Factor regulation, signaling and functions beyond coagulation with a focus on diabetes. Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 1626. 65 pp. Uppsala: Acta Universitatis Upsaliensis. ISBN 978-91-513-0842-5. Background: Tissue factor (TF) is a 47 kDa transmembrane glycoprotein best known for initiating the coagulation cascade upon binding of its ligand FVIIa. Apart from its physiological role in coagulation, TF and TF/FVIIa signaling has proved to be involved in diseases such as diabetes, cancer and cardiovascular diseases. Biological functions coupled to TF/FVIIa signaling include diet-induced obesity, apoptosis, angiogenesis and migration. Aim: The aim of this thesis was to investigate the role of TF/FVIIa in cells of importance in diabetes, to further investigate the mechanism behind TF/FVIIa anti-apoptotic signaling in cancer cells and lastly to examine the regulation of TF expression in monocytes by micro RNAs (miRNA). Results: In paper I we found that TF/FVIIa signaling augments cytokine-induced beta cell death and impairs glucose stimulated insulin secretion from human pancreatic islets. In paper II the relevance of TF/FVIIa in isolated human primary adipocytes was investigated. Adipocytes are a target cell for insulin and diabetics typically have increased lipolysis and impaired glucose uptake. No evidence was found for a role of TF/FVIIa in lipolysis or glucose uptake in adipocytes. However, adipocytes were found to express TF and FVII. The FVII produced was sufficient to initiate coagulation in the adipocytes. In paper III an anti-apoptotic TF/FVIIa induced signaling pathway in prostate and breast cancer cells was investigated in depth. Previous research has shown that TF/FVIIa signaling results in transactivation of insulin-like growth factor 1 receptor (IGF-1R) leading to subsequent protection from apoptosis induced by TNF- related apoptosis inducing ligand (TRAIL). The current results propose a mechanism where IGF-1R transactivation by TF/FVIIa is dependent on integrin β1 (ITGβ1) signaling. TF/FVIIa/ ITGβ1 signaling was found to result in phosphorylation of src and subsequent phosphorylation of caveolin 1 (Cav1). Once phosphorylated, the inhibitory effect of Cav1 on IGF-1R is cancelled, resulting in IGF-1R activation. In paper IV the role of miRNA regulation of TF expression in monocytic cells was investigated. The miRNA miR-223-3p was identified to be differentially expressed in U937 cells undergoing differentiation to a more monocyte-like phenotype and an anti-parallel correlation between TF and miR-223-3p expression in monocytes was proved. Hence, miR-223-3p regulates the inducible expression of TF in monocytes. Conclusions: The work in this thesis furthers the knowledge of molecular mechanisms behind TF regulation and TF/FVIIa signaling and some functional consequences as well as their biological relevance in diabetes. Keywords: Tissue factor, diabetes, cell signaling, coagulation, beta cells, adipocytes, apoptosis, lipolysis, micro RNA Desirée Edén, Department of Medical Sciences, Akademiska sjukhuset, Uppsala University, SE-75185 Uppsala, Sweden. © Desirée Edén 2020 ISSN 1651-6206 ISBN 978-91-513-0842-5 urn:nbn:se:uu:diva-399599 (http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-399599) Till Leila, Jan och Robert List of Papers This thesis is based on the following papers, which are referred to in the text by their Roman numerals. I Edén D, Siegbahn A, Mokhtari D. (2015) Tissue factor/factor VIIa signalling promotes cytokine-induced beta cell death and impairs glu- cose-stimulated insulin secretion from human pancreatic islets. Dia- betologia, 58(11):2563–72 II Edén D, Panagiotou G, Mokhtari D, Eriksson JW, Åberg M, Sieg- bahn A. (2019) Adipocytes express tissue factor and FVII and are procoagulant in a TF/FVIIa-dependent manner. Upsala Journal of Medical Sciences, 124(3):158-167 III Åberg M, Edén D, Siegbahn A. Activation of β1 integrins and caveo- lin-1 by TF/FVIIa promotes IGF-1R signaling and cell survival. Manuscript IV Alfredsson J, Edén D, Christersson C, Åberg M, Siegbahn A. miR- 223-3p regulates post-transcriptional tissue factor gene expression in human monocytic cells. Manuscript Reprints were made with permission from the respective publishers. Contents Introduction ................................................................................................... 11 Tissue factor and FVIIa ................................................................................. 13 Background ............................................................................................... 13 TF/FVIIa initiation of the coagulation process ......................................... 13 Blood borne tissue factor .......................................................................... 14 TF expression ........................................................................................... 15 miRNA ................................................................................................. 16 TF/FVIIa intracellular signaling ............................................................... 18 PAR signaling ...................................................................................... 19 RTK signaling ...................................................................................... 20 Integrin signaling ................................................................................. 21 Diabetes ......................................................................................................... 23 Background ............................................................................................... 23 The immune system and cytokines ........................................................... 24 Classification of diabetes .......................................................................... 24 T1D and T2D ....................................................................................... 25 Adipocyte function and malfunction in T2D ............................................ 26 TF and FVIIa in diabetes .......................................................................... 28 Methods ......................................................................................................... 29 Cell culture and isolated cells ................................................................... 29 Protein expression and cell signaling ....................................................... 30 Western blot ......................................................................................... 30 Flow cytometry .................................................................................... 30 Protein proximity ligation (PLA) ......................................................... 30 Gene expression ........................................................................................ 31 siRNA gene silencing .......................................................................... 31 qRT-PCR .............................................................................................. 31 RT-PCR ................................................................................................ 31 Functional studies ..................................................................................... 32 Apoptosis ............................................................................................. 32 Glucose stimulated insulin secretion (GSIS) ....................................... 32 Lipolysis ............................................................................................... 32 Glucose uptake ..................................................................................... 33 TF coagulation activity ........................................................................ 33 Aims .............................................................................................................. 34 Results and Discussion .................................................................................. 35 Paper I ....................................................................................................... 35 Background .......................................................................................... 35 Results and discussion ......................................................................... 35 Paper II ..................................................................................................... 37 Background .......................................................................................... 37 Results and discussion ......................................................................... 37 Paper III .................................................................................................... 39 Background .........................................................................................
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