Novel Functions of the Neurofibromatosis 2 Tumour Suppressor Protein Merlin

.............................................................................................................. 9 REVIEW OF THE LITERATURE............................................................................. 11 1. THE CELL DIVISION CYCLE......................................................................................................11 2. CANCER GENES.............................................................................................................................12 2.1 Oncogenes ....................................................................................................................................12 2.2 Tumour suppressor genes .............................................................................................................13 3. THE ACTIN CYTOSKELETON....................................................................................................13 3.1 The actin cytoskeleton in disease..................................................................................................14 4. THE BAND 4.1 PROTEIN SUPERFAMILY ................................................................................14 4.1 The ERM protein family...............................................................................................................15 4.1.1 The ERM proteins..................................................................................................................16 4.1.1.1 Structure of the ERM proteins ........................................................................................17 4.1.2 The NF2 protein, merlin ........................................................................................................17 4.1.3 Ezrin and merlin in neoplasia ...............................................................................................19 4.1.3.1 Neurofibromatosis 2, NF2 ..............................................................................................19 5. MOLECULAR INTERACTIONS AND FUNCTIONS OF MERLIN AND EZRIN..................20 5.1 Association with the cytoskeleton.................................................................................................20 5.2 Association with the plasma membrane........................................................................................22 5.3 Cell adhesion and cell-cell communication ..................................................................................23 5.4 Cell proliferation ..........................................................................................................................24 6. REGULATION OF MERLIN AND EZRIN ..................................................................................26 6.1 Phosphorylation............................................................................................................................26 6.2 RHO GTPases ..............................................................................................................................29 6.3 Homotypic and heterotypic binding..............................................................................................30 6.4 Other mechanisms of regulation ...................................................................................................30 AIMS OF THE STUDY ............................................................................................ 32 METHODS .............................................................................................................. 33 RESULTS AND DISCUSSION................................................................................ 34 1. HETEROTYPIC AND HOMOTYPIC INTERACTIONS OF MERLIN AND EZRIN (I) .......34 1.1 Heterotypic interactions................................................................................................................34 1.2 Homotypic interactions.................................................................................................................35 1.3 Merlin N-ERMAD and C-ERMAD..............................................................................................36 1.4 Regulation of the dormant and active states .................................................................................37