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Cellular Architecture and Cytoskeletal Structures Involved In CELLULAR ARCHITECTURE AND CYTOSKELETAL STRUCTURES INVOLVED IN CELL HAPTOTAXIS Surya P. Amarachintha A Dissertation submitted to the graduate college of Bowling Green State University in partial fulfillment of the requirement for the degree of DOCTOR OF PHILOSOPHY May 2012 Committee: Carol A. Heckman, PhD. Advisor Howard C. Cromwell, PhD. Graduate faculty representative Carmen F. Fioravanti, PhD. Michael E. Geusz, PhD. Wendell Griffith, PhD. ii ABSTRACT Carol A Heckman, Advisor Filopodia play a sensory role in directing motility during embryonic development and axon pathfinding. They also show a low prevalence in cancer cells. Here, I determined whether cultured cells from a rat tracheal epithelial line used filopodia to sense adhesive gradients. Cells exhibited haptotaxis (movement toward the more adhesive surface) when plated on tantalum (Ta) and platinum (Pt) metallic gradients. The gradients were created on glass, and high (H), middle (M), and low (L) positions defined along the gradient. Cell counts in randomly selected fields confirmed that the cells recognized the gradient. To determine whether the prevalence of protrusions differed at the H, M, and L locations, the values of latent factors 4 (filopodia), 5, and 7 were determined. Factor 4 values were high at H and significantly lower at M and L (p<0.05). Cells’ ability to form larger protrusions, represented by factors 5 (lamellar distribution) and 7 (nascent neurites), was unaltered across the Ta gradient. The directional cues also appeared to be interpreted within a cell, as shown by analyzing the cells’ top (T) side, i.e. the side oriented toward H location, from the bottom (B) side. Factor 4 values at H-T significantly exceed those at M-B and L-T. Trend analysis confirmed a decrease in factor 4 over the gradient with significance of P<0.001 (Ta) and P<0.023 (Pt). On Pt only, factor 5 increased (P<0.0001) as the metal content of the substrate declined. Cdc42 (cell division cycle 42) plays a crucial role in establishing polarity, and is also involved in filopodia formation, cell motility, and directional migration. Since there is some loss of polarity in preneoplastic lesions, the role of Cdc42 in filopodia-mediated sensing was of interest. To determine whether Cdc42 was implicated in reconstruction of cellular architecture and rearrangement of cytoskeletal structures, I tested the role of Cdc42 effectors in gradient iii sensing. While most effectors bind to Cdc42 at multiple regions, there is usually a short linear stretch of residues that is critical for binding. Peptides representing such stretches of Cdc42 were designed to model its surface and thereby inhibit effector-Cdc42 binding. Using filopodia trend analysis to determine the effect of each peptide, I found that ACK, IQGAP, and Par6 were essential for directional pointing of filopodia. A sequence blocking PKCε interaction with its docking site also prevented pointing activity. Although WASP binds directly to Cdc42, the peptide designed to block this interaction did not affect directional pointing of the filopodia. Introduction of the peptide against PAK gave a paradoxical result. Directional identification mechanisms were intact but the direction of filopodia pointing was reversed. I also studied the relationship between filopodia and ruffles on any given cell, in order to understand the complex processes of cell motility and directional persistence. Ruffle frequency and filopodia were inversely related, and this relationship was independent of the location on the gradient or the peptide introduced into the cells. On tantalum, sites at HT, MT, and LT and on platinum sites at HT, MT, and both LT and LB showed ruffling interacting with filopodia, with a level of significance P<0.025. Despite the tendency for ruffling activity to increase toward the less adhesive end of the gradient, none of the ruffling variables showed a statistically significant trend. However, the data suggest that cells make ruffles at the expense of filopodia regardless of substrate to which they are attached. This inverse relationship was stronger at the top of the cell than at the bottom. Thus it can be confirmed that ruffles and filopodia are inversely related, but ruffling is unlikely to be a mechanism of gradient sensing. iv ACKNOWLEDGEMENTS I sincerely thank Dr. Carol Heckman for her continuous guidance and support in finishing this project successfully. I thank Drs. Carmen Fioravanti, Michael Geusz, Wendell Griffith, and Graduate faculty representative Dr. Howard Cromwell for their help in being excellent advisors and guiding me all through my studies. My sincere thanks to Drs. Nancy Boudreau and Kenneth Ryan from department of applied statistics for their tremendous contribution in statistical analysis of my data. My thanks also go to Dr. Marylin Cayer for her help in some of my experiments. I also would like to acknowledge my lab mates Mita Varghese, Andrew Roholt, and Congyingzi Zhang for their cooperation in the lab and friends Mahesh, Ashapurna, and Vishal for sharing their thoughts. Lastly and most importantly I wish to thank Sylvia Lindinger and my family members for their continuous encouragement, love, and support. v TABLE OF CONTENTS CHAPTER 1. BACKGROUND 1.1 Introduction .................................................................................................................. 1 1.2. Barriers to further progress ......................................................................................... 2 1.3. Transmembrane receptors ........................................................................................... 4 1.3.1. Integrins and intracellular constituents of focal contacts ................................ 6 1.3.2. The actin-integrin linkage ............................................................................... 6 1.3.3. Importance of integrin signaling in migrating cells’ adhesion and protrusion ..................................................................... 9 1.3.4. Additional components of focal signal transduction machinery ..................... 9 1.3.4A. Integrin-Linked Kinase .................................................................... 9 1.3.4B. The adaptors ..................................................................................... 11 1.3.4C. Parvins .............................................................................................. 11 1.3.4D. Paxillin ............................................................................................. 12 1.4. Systems biology and cell motility ............................................................................... 13 1.5. Major structures involved in cell migration ................................................................ 14 1.5.1. Lamellipodia ................................................................................................... 14 1.5.2. Filopodia ......................................................................................................... 17 1.5.2A. Proteins involved in actin regulation or filopodia formation ........... 17 1.5.3. Focal adhesions ............................................................................................... 20 1.5.4. Lamella ........................................................................................................... 22 1.5.5. Ruffles ............................................................................................................ 22 1.6. Factors.............. ........................................................................................................... 23 vi CHAPTER 2. FILOPODIA RESPOND TO THE METAL GRADIENT 2.1. INTRODUCTION ...................................................................................................... 25 2.1.1. Haptotaxis ....................................................................................................... 25 2.1.2. Filopodia as mechanosensors .......................................................................... 26 2.2. MATERIALS AND METHODS ................................................................................ 28 2.2.1. Preparation of metal gradient .......................................................................... 28 2.2.2. Statistics used in this study ............................................................................. 30 2.3. RESULTS ................................................................................................................... 32 2.3.1. Features of cells on a tantalum steep gradient ................................................ 32 2.3.2. Gradient effects on features resolved by directionality on tantalum .............. 33 2.3.3. Results of ANOVA or GLM on tantalum ....................................................... 34 2.3.4. Pearson correlation coefficients on tantalum .................................................. 36 2.3.5. Trend analysis on tantalum ............................................................................. 37 2.3.6. Features of cells on platinum shallow gradient ............................................... 39 2.3.7. Gradient effects on features resolved by directionality on platinum .............. 40 2.3.8. Results of ANOVA or GLM on platinum ....................................................... 41 2.3.9. Pearson correlation coefficients on platinum .................................................. 42 2.3.10. Trend analysis on platinum ........................................................................... 45 2.4. DISCUSSION ............................................................................................................
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