CHAPTER FIVE Mechanotransduction Pathways Linking the Extracellular Matrix to the Nucleus Zeinab Jahed, Hengameh Shams, Mehrdad Mehrbod, Mohammad R.K. Mofrad 1 Molecular Cell Biomechanics Laboratory, Departments of Bioengineering and Mechanical Engineering, University of California at Berkeley, Berkeley, California, USA 1 Corresponding author: e-mail address: mofrad@berkeley.edu Contents 1. Introduction 172 2. ECM Molecules 173 2.1 Fibrinogen 174 2.2 Fibronectin 175 3. Integrins 176 3.1 Bidirectional signaling by integrins 178 3.2 Integrin activation 178 4. Integrin–Actin Linkers: Focal Adhesion Formation 180 4.1 Talin 180 4.2 Kindlin 182 4.3 Vinculin 184 4.4 a-Actinin 186 4.5 Filamin 188 4.6 FAK: Signaling protein focal adhesion kinase 191 5. Integrins Team Up (Integrin Clustering) 195 6. Missing LINC: Linkers of Nucleoskeleton and Cytoskeleton 199 6.1 Nesprin and SUN 199 7. Conclusions 202 8. Future Research Directions 207 Acknowledgments 209 References 209 Abstract Cells contain several mechanosensing components that transduce mechanical signals into biochemical cascades. During cell–ECM adhesion, a complex network of molecules mechanically couples the extracellular matrix (ECM), cytoskeleton, and nucleoskeleton. The network comprises transmembrane receptor proteins and focal adhesions, which International Review of Cell and Molecular Biology, Volume 310 # 2014 Elsevier Inc. ISSN 1937-6448 All rights reserved. http://dx.doi.org/10.1016/B978-0-12-800180-6.00005-0 171