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Diversification of TGF-Β Signaling in Homeostasis and Disease

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Diversification of TGF-Β Signaling in Homeostasis and Disease To my grandparents . If I have a thousand ideas and only one turns out to be good, I am satisfied -Alfred Nobel Anyone who has never made a mistake has never tried anything new -Albert Einstein List of Papers This thesis is based on the following papers, which are referred to in the text by their Roman numerals. I Niimi, H.*, Pardali, K.*, Vanlandewijck, M., Heldin, C-H., Moustakas, A. Notch signaling is necessary for epithelial growth arrest by TGF- . The Journal of Cell Biology (2007), 176(5):695-707. II Kowanetz, M.*, Lönn, P.*, Vanlandewijck, M., Kowanetz, K., Heldin, C-H, Moustakas, A. TGF- induces SIK to negatively regulate receptor type I kinase signaling. The Journal of Cell Biology (2008), 182(4):655-662. III Lönn, P.*, Vanlandewijck, M.*, Kowanetz, M., Kowanetz, K., Heldin, C-H., Moustakas, A. SIK and Smurf2 cooperate to downregulate the TGF- type I receptor. Manuscript. IV Vanlandewijck, M., Lomnytska, M., Busch, C., Heldin, C-H., Moustakas, A. SIK phosphorylates and degrades Par3 to me- diate tight junction disassembly during epithelial-mesenchymal transition. Manuscript. * Indicates that these authors contributed equally to the work Reprints were made with permission from the respective publishers. Contents Introduction ................................................................................................... 11 Signaling pathways ....................................................................................... 12 Notch signaling ........................................................................................ 12 The Notch signaling cascade from receptor to nucleus ....................... 12 Modulation of the Notch signaling pathway ........................................ 14 Notch Signaling in cancer .................................................................... 16 TGF- signaling ....................................................................................... 19 Ligands of the TGF- superfamily ...................................................... 19 Receptors of the TGF- superfamily ................................................... 20 Canonical TGF- signaling: Smads as signal transducers ................... 21 Non-canonical TGF- signaling .......................................................... 24 Negative regulation of TGF- signaling .............................................. 26 TGF- signaling in cancer ................................................................... 27 Crosstalk between pathways .................................................................... 30 The Wnt signaling pathway ................................................................. 30 Convergence of Notch and TGF- signaling on p53 ........................... 31 Direct crosstalk between Notch and TGF- ........................................ 32 Salt-inducible kinase ................................................................................ 33 Epithelial polarity and plasticity ................................................................... 35 Epithelial junctions ................................................................................... 35 Epithelial polarity complexes ................................................................... 38 Epithelial to mesenchymal transition ....................................................... 40 Present investigation ..................................................................................... 43 Aim ........................................................................................................... 43 Paper I ...................................................................................................... 43 Paper II ..................................................................................................... 44 Paper III .................................................................................................... 45 Paper IV ................................................................................................... 46 Future perspectives ....................................................................................... 48 Acknowledgements… ................................................................................... 52 References ..................................................................................................... 54 Abbreviations ADAM A disintegrin and metalloproteinase domain AJ Adherens junction ALK Activin receptor-like kinase AMP Adenosine 5’ –monophosphate AMPK AMP activated protein kinase bHLH Basic helix-loop-helix BMP Bone morphogenetic protein CA Constitutively active CBP CREB binding protein Cdc Cell division cycle CDK Cyclin dependent kinase CK Casein kinase CREB cAMP response element binding protein CSL CBF1/RBPj /Su (H)/Lag-1 CTGF Connective tissue growth factor DLG Disk large DSL Delta/Serrate/LAG-2 DOS Delta and OSM-11-like proteins ECM Extracellular matrix EGF Epidermal growth factor EMT Epithelial to mesenchymal transition ERK Extracellular signal related kinase Evi-1 Ecotropic viral integration site 1 FBXW7 F-box and WD40 domain protein 7 FoxH1 Forkhead box H1 GDF Growth and differentiation factor GFP Green fluorescent protein GEF Guanine exchange factor GS Glycine-Serine GSK-3 Glycogen synthase kinase-3 HaCaT Human keratinocytes cell line HD Heterodimerization HDAC Histone deacetylase HNF4 Hepatocyte nuclear factor 4 alpha JAM Junctional adhesion molecule JPS Juvenile Polyposis Syndrome LAP Latency associated peptide Lfng Lunatic Fringe LLC Large latency complex LTBP Latent TGF- binding protein Mad Mothers against decapentaplegic MAGUK Membrane associated guanylate kinase MAML Mastermind/Lag-3 MAPK Mitogen activated protein kinase MDM2 Mouse double minute 2 homologue MH Mad homology MIS Müllerian inhibiting substance MMP Matrix-metalloprotease Myc Avian Myelocytoma viral oncogene homologue NECD Notch extracellular domain NES Nuclear export signal NET1 Neuroepithelial cell transforming gene 1 NF B Nuclear factor kappa B NICD Notch intracellular domain NLS Nuclear localization signal NMuMG Namru murine mammary gland NRK Normal rat kidney NT N-terminal NTICD Notch transmembrane and intracellular domain NRR Negative regulatory region O-Fut O-fucosyl transferase PALS1 Protein associated with Lin seven 1 PATJ PALS1 associated TJ protein Par Partitioning defective PDP Pyruvate dehydrogenase phosphatase PEST Proline/glutamic acid/serine/threonine PI3 Phosphatidylinositol-3 PKA Protein kinase A PKC Protein kinase C PP2a Protein phosphatase 2a PPM1A Protein phosphatase magnesium dependent 1A PTEN Protein tyrosine phosphate and Tensin homologue RAM RBPj associated module Ran Ras related nuclear protein RhoA RAS homologue gene family, member A ROCK Rho-associated coiled-coil-containing protein kinase ROS Reactive oxygen species SARA Smad anchor for receptor activation SBE Smad binding element SCP Small C-terminal domain phosphatase SHARP SMART/HDAC1-associated repressor protein SIK Salt inducible kinase siRNA Small interfering RNA SKI V-ski avian sarcoma viral oncogene homologue SKP S phase kinase associated protein SLC Small latency complex Smurf Smad ubiquitination regulatory factor SNO Ski related novel gene TACE Tumor necrosis factor alpha converting enzyme TAK1 TGF- activated kinase 1 T-ALL T-cell acute lymphoblastic leukemia TGF- Transforming growth factor beta TGIF TGF- induced factor Tiam T-cell lymphoma invasion and metastasis TIF1 Transcription intermediate factor 1 TORC Transducer of regulated CREB activity TSP Thrombospondin TJ Tight junction UBA Ubiquitin associated YY1 Ying Yang 1 ZEB Zinc finger E-box binding homeobox ZO Zona occludens ZONAB ZO-1 associated nucleic acid binding protein Introduction Although cancer is one of the most well studied diseases, the long term sur- vival of patients is still poor. One of the major reasons cancer is so deadly is because of metastasis from the primary tumor into different organs, with poor prognosis for the patient. The exact molecular mechanism of metastasis is currently heavily studied, but not yet fully clarified. Transforming Growth Factor (TGF- ) is an important regulator of many biological processes during embryogenesis and in the adult organism. TGF- is known to play an important role in cell proliferation, differentiation, cell motility, apoptosis and many other cellular processes. This growth factor also plays an important role during tumor formation and metastasis. In early stages of tumorigenesis TGF- acts as a tumor suppressor by preventing cell growth. However, during more advanced stages of tumor development, TGF- acts as a tumor promoter by enhancing tumor cell differentiation into a more invasive type of cells. Since the discovery of the TGF- 1 cytokine 25 years ago, many research groups all over the world have contributed to understanding the molecular biology of this signaling pathway. Although the complete mechanism of how TGF- influences tissue homeostasis, tumor formation and cancer progres- sion remains to be elucidated, it became clear that many of the physiological effects of TGF- are mediated through crosstalk with other pathways, allow- ing for diverse context-specific responses to TGF- signaling activation. The aim of the research here presented is to uncover novel mechanisms al- lowing for diversification of TGF- signaling. 11 Signaling pathways Notch signaling Almost a century ago, T.H Morgan’s group described a strain of Drosophila with notches at the margins of their wing blades. In accordance with the phenotype, this mutation was named Notch1. Roughly twenty years
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