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Irhom2 in Skin Disease and Oesophageal Cancer Etheridge, Sarah

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Irhom2 in Skin Disease and Oesophageal Cancer Etheridge, Sarah iRHOM2 in skin disease and oesophageal cancer Etheridge, Sarah For additional information about this publication click this link. http://qmro.qmul.ac.uk/jspui/handle/123456789/8037 Information about this research object was correct at the time of download; we occasionally make corrections to records, please therefore check the published record when citing. For more information contact [email protected] iRHOM2 in skin disease and oesophageal cancer Sarah Louise Etheridge A Thesis presented for the degree of Doctor of Philosophy 2015 Supervisor: Professor David Kelsell Centre for Cutaneous research The Blizard Institute Barts and the London School of Medicine and dentistry Queen Mary, University of London Abstract Mutations in RHBDF2, the gene encoding inactive rhomboid protein iRHOM2, result in the dominantly inherited condition Tylosis with oesophageal cancer (TOC). TOC causes plamoplantar keratoderma, oral precursor lesions and up to a 95 % life-time risk of oesophageal squamous cell carcinoma (SCC). The role of iRHOM2 in the epidermis is not well characterised, although we previously showed dysregulated epidermal growth factor receptor (EGFR) signalling and accelerated migration in TOC keratinocytes, and a role for iRHOM2 was shown in trafficking the metalloproteinase ADAM17. Substrates of ADAM17 include EGFR ligands and adhesion molecules. iRHOM2 localisation and function were investigated in frozen sections and keratinocyte cell lines from control and TOC epidermis. Although iRHOM2 was predicted to be an ER- membrane protein, it showed cell-surface expression in control epidermis, with variable localisation in TOC. Increased processing and activation of ADAM17 was seen in TOC keratinocytes compared with control cells, suggesting that increased ADAM17-mediated processing of EGFR ligands may cause the changes in EGFR signalling. Downstream of iRHOM2-ADAM17, Eph/Ephrin and NOTCH signalling also appeared affected. Additionally, desmosomes in TOC epidermis lacked the electron-dense midline of the mature desmosomes seen in normal skin; this was accompanied by increased processing of desmoglein 2, a substrate of ADAM17. Expression and localisation of iRHOM2 was also investigated in TOC and sporadic SCC. iRHOM2 expression varied between SCC cell lines, and appeared to correlate with ADAM17 and NOTCH1 expression in oesophageal SCC and head and neck SCC cells. In summary, iRHOM2 mutations in TOC appear to be gain-of-function in nature, resulting in increased ADAM17 processing and enhanced EGFR signalling. Questions remaining include the reason why iRHOM2 is found at the plasma membrane. Future study of the iRHOM2-ADAM17 pathway may provide additional insight into the mechanism of epidermal wound healing and the pathogenesis of oesophageal SCC. 1 Table of Contents Table of Contents .............................................................................................. 2 Figures and Tables ......................................................................................... 10 Statement of Originality ................................................................................. 15 Collaborations and publications ................................................................... 16 Acknowledgements ........................................................................................ 18 List of Abbreviations ...................................................................................... 20 Chapter 1: Introduction .................................................................................. 25 1.1 The Skin ..................................................................................................... 25 1.1.1 The Epidermis ................................................................................................ 25 1.1.1.1 Expression of keratins .............................................................................. 26 1.1.1.2 Differentiation ........................................................................................... 28 1.1.1.3 Terminal differentiation and formation of the stratum corneum ................. 28 1.2 Cell-cell adhesion and communication in the skin ................................ 29 1.2.1 Gap junctions ................................................................................................. 29 1.2.2 Tight junctions ................................................................................................ 30 1.2.3 Adherens junctions ......................................................................................... 31 1.2.4 Desmosomes ................................................................................................. 34 1.2.4.1 Desmosomal Cadherins ........................................................................... 35 1.2.4.2 Armadillo proteins .................................................................................... 36 1.2.4.3 Desmoplakin ............................................................................................ 38 1.2.4.4 Other desmosomal proteins ..................................................................... 38 1.2.4.5 Desmosome assembly ............................................................................. 39 1.2.4.6 Desmosomal signalling ............................................................................ 41 1.3 Inherited Skin Diseases ............................................................................ 41 1.3.1 Mutations in desmosomal proteins ................................................................. 42 1.3.2 Mutations causing defects in protein folding ................................................... 43 1.3.3 Ichthyoses, including Harlequin Ichthyosis ..................................................... 44 1.3.4 Mutations in proteases and their inhibitors ...................................................... 45 1.3.5 Tylosis with oesophageal cancer .................................................................... 46 2 1.4 Rhomboid proteins ................................................................................... 46 1.4.1 The Inactive Rhomboids ................................................................................. 47 1.4.2 Rhomboid Proteases ...................................................................................... 49 1.4.2.1 RHBDL2 .................................................................................................. 49 1.4.2.1.1 RHBDL2 substrates - Thrombomodulin ............................................. 50 1.4.2.1.2 RHBDL2 substrates – Ephrin B3 ....................................................... 50 1.4.2.1.3 RHBDL2 substrates - EGF ................................................................ 50 1.4.3 iRHOM protein signalling ................................................................................ 51 1.5 ADAM17 ..................................................................................................... 53 1.5.1 ADAM17 structure and expression ................................................................. 53 1.5.2 iRHOMs traffick ADAM17 from ER to Golgi .................................................... 54 1.5.3 ADAM17 substrates ....................................................................................... 55 1.5.3.1 Tumour Necrosis Factor-α (TNF-α) .......................................................... 55 1.5.3.2 Adhesion molecules ................................................................................. 57 1.5.3.3 EGFR ligands .......................................................................................... 57 1.5.3.3.1 Amphiregulin ..................................................................................... 57 1.5.3.3.2 Transforming Growth Factor Alpha .................................................... 58 1.6 EGF receptor signalling............................................................................ 58 1.6.1 The EGFR / ErbB family of receptor tyrosine kinases ..................................... 59 1.6.2 Signalling Pathways downstream of EGFR activation..................................... 59 1.6.2.1 MAPK/ERK signalling .............................................................................. 60 1.6.2.2 The PI3K-Akt cell survival pathway .......................................................... 60 1.6.2.3 Cross-talk between the PI3K-Akt and Ras-MAPK/ERK pathways ............ 61 1.6.2.4 PLCγ activation of PKC ............................................................................ 62 1.7 NOTCH signalling ..................................................................................... 64 1.7.1 NOTCH receptor Structure and Function ........................................................ 64 1.7.2 The NOTCH Signalling Pathway .................................................................... 65 1.7.2.1 Canonical and non-canonical NOTCH signalling ...................................... 65 1.7.3 Is S2 cleavage mediated by ADAM10 or ADAM17? ....................................... 66 1.7.4 Regulation of NOTCH..................................................................................... 67 1.7.4.1 NOTCH endocytosis and trafficking ......................................................... 68 3 1.7.5 NOTCH signalling in the skin and gastrointestinal tract .................................. 70 1.7.5.1 NOTCH signalling in the epidermis .......................................................... 70 1.7.5.2 NOTCH signalling in oesophageal differentiation ....................................
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