John Eriksson Department of Biosciences Åbo Akademi University Turku, Finland.

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1 John Eriksson Department of Biosciences Åbo Akademi University Turku, Finland

2 Three cytoskeletal polymer systems Intermediate filaments Mikrotubuli Mikrofilaments or actin filaments

3 The challenges of being a cell Nutrients Nutrients Mechanical forces Nutrients Cellular interactions Cell polarity Stresses Mobility Stresses and orientation Mobility and orientation Tissue integration and integrity Stresses

4 Figure 16-5 Molecular Biology of the Cell ( Garland Science 2008)

5 Different forms of intermediate filaments INTERMEDIATE FILAMENTS CYTOPLASMIC NUCLEAR Type I, II Type III Type IV Type V Keratins I, II Vimentin, desmin, GFAP, peripherin Neurofilaments, nestin, a-internexin, synemin Nuclear lamins In epithelia In connective tissue, muscle cells, neuroglia cells, peripheral neurons Neuronal cells, muscle cells In all nucleated cells

6 Intermediate filament assembly IFs

7 Association of intermediate filaments with signaling molecules Integrins, adhesion molecules Intermediate filaments P-buffer Akt TSC1/2 Death receptors Kinase scaffolds Raf Cdc25 Rheb mtor Cell migration Cell survival Cell growth Cell division Cell size Pallari and Eriksson, Science STKE 2006 (review)

8 o INTERMEDIATE FILAMENTS - THE PERFECT SIGNALING ORGANIZERS/SCAFFOLDS o o o o o Large family of genes with highly specific expression patterns and properties Allows tissue-specific organization and functions of signaling systems Numerous different binding motifs Highly organized structures Phosphorylation-based regulation

9 Vimentin, PKCs and integrins Stimulus Signal Molecule B Adhesion Migration Invasion Signal molecule Signal molecule Vimentin Cell shape cues Inactive Active

10 Figure Molecular Biology of the Cell ( Garland Science 2008)

11 Figure Molecular Biology of the Cell ( Garland Science 2008)

12 Figure 19-60b Molecular Biology of the Cell ( Garland Science 2008)

13 Figure Molecular Biology of the Cell ( Garland Science 2008)

14 Figure Molecular Biology of the Cell ( Garland Science 2008)

15 IF PROTEINS AT THE CROSSROADS OF WOUND HEALING

16 Inhibited wound re-epithelialization during late stage of wound healing of VIM-/- mice.

17 The inhibited wound re-epithelialization is associated with hampered collagen deposition in VIM-/- wounds VIM-/- WT Apical Surface focal adhesions EMT collagen collagen pan-keratin pan-keratin Day 15 post injury

18 VIMENTIN REGULATES FIBROBLAST PROLIFERATION

19 Fibroblast vimentin is involved in TGFb-Slug-EMT signaling in keratinocytes Epidermis Injury Dermis EMT program

20 Vimentin, Slug and ERK participate in cell invasion

21 Vimentin and EMT TGF-b Inactive Active Slug pslug EMT ERK perk Vimentin Cell shape cues Inactive Active

22 Vimentin acts as a meta-level organizer in EMT Vimentin Vimentin Injury Fibroblast proliferation TGFb-Slug signaling Keratinocyte activation Migration and re-epithelialization Collagen deposition Wound healing

23 Clinical implications of regulating imentin for proper wound healing

24 IF-centric view of the world Various stimuli Signaling molecule Cell shape cues Intercellular interactions Signaling molecule IF protein Organization and polymerization state Material structure and stiffness Process Cell stress

25 Post-doctoral fellows Fang Cheng Claire Hyder Senthil Kumar Preethy Paul Graduate students Josef Gullmets Alia Joko Kimmo Isoniemi Julia Lindqvist Ponnuswamy Mohanasundaram Erik Niemelä Elin Torvaldson Cytoskeletal and survival signaling Dept. of Biosciences, Åbo Akademi University & Turku Centre for Biotechnology Alumni Tomoko Asaoka Aurelie dethonel Tao He Tim Holmström Saima Ferraris Marko Kallio Aura Kaunisto Vitaly Kochin Annika Meinander Andrey Mikhailov Mikko Nieminen Hanna-Mari Pallari Emilia Peuhu Minna Poukkula Adolfo Rivero-Muller Cecilia Sahlgren Andrzey Stepulak Thomas Söderström Diana Toivola Collaborators and contributors Robert Goldman, Northwestern Univ., USA Johanna Ivaska, Univ. of Turku, Finland Sirpa Jalkanen, Univ. of Turku, Finland Tor Ny, Univ. of Umeå, Sweden Karen Ridge, Northwestern Univ., USA Funding - The Academy of Finland - Sigrid Jusélius Foundation - The Finnish Cancer Foundations - Technological Development Agency of Finland - Åbo Akademi Univ. Foundation

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