Letter From the Guest Editor

Focal adhesions (FAs) are dynamic integrin-actin links and consist in highly-organized multimolecular submembrane complexes forming mechanical connections between the cytoskeleton machinery and the extracellular matrix. FAs are composed of more than 50 different proteins forming structured scaffold at adhesion sites and involved in the dynamic association with the actin-microfilament bundles. The molecular arsenal at cytoskeleton-FA interface governs intracellular contractile forces and generates various integrin-signaling processes required for cell survival, differentiation and migration. The last decade, many research teams have attempted to provide a more comprehensive analysis of temporal and spatial molecular events controlling the range of protein:protein interactions and the hierarchy of protein recruitment/removal within these submembrane plaques. The molecular mechanisms involved appear every day more and more complex and, despite extensive studies, many exciting questions remained still enigmatic. For example, how can the short-lived focal complex structures may either disassemble or develop into mature FA? How are regulated the specific molecular interplays at the FA sites? What physical and mechanical forces are required for efficient FA dynamics? How do components from the extracellular matrix trigger only specific intracellular signaling through FA? How podosomes and FAs exhibit so different structural and functional properties and what extracellular or intracellular signals activate the dynamics of these specialized structures? What can instigate FAs to generate podosomes?

In this special issue, the papers selected through a strict peer-reviewed process highlight recent major discoveries and proposed attractive molecular models in the field of FA dynamics. In this regard, the paper by Truong and Danen stresses the importance and the complexity of the integrin adhesome network. The authors describe how a single switch in integrin composition within adhesion sites may induce dramatic changes in intracellular signaling pathways, cytoskeleton organization, FA dynamics and finally cell mobility. In the second paper in this issue, Wagner and Sabourin reveal the key role of the microtubule-associated Ste20-like kinase (SLK) in the control of adhesion turnover and cell migration. The authors proposed a speculative model describing the molecular bases of SLK activation and recruitment at the leading edge of migrating cells. In this model, the FAK/Src-mediated activation of SLK leads to local alteration in cytoskeleton network and/or destabilization of FA through a still unidentified mechanism. The manuscript presented by Dr. Goetz provides in turn new information in the understanding of the molecular bases of FA turnover and identifies two novel actors, i.e. the Mgat5/galectin-3 lattice and tyrosine-phosphorylated caveolin-1. The proposed model is really exciting and supports the concept of a transmembrane crosstalk between the galectin lattice and caveolin-1 leading to integrin clustering and activation, RhoGTPase activation and finally increased FAK/paxilin location within FA sites. These succeeding molecular events lead to FA maturation, disassembly and to increased cell migration. According to the author, such mechanism could also be highly involved during tumor progression. The paper by Mohseni and Chishti focuses on the little-known actin-binding protein dematin. The experimental data recently published by the authors revealed a key functional role for this protein in the control of cell morphology, adhesion and migration. In this issue, the authors proposed an elegant molecular model in which dematin functions as a novel upstream negative regulator of the RhoA activation, thus leading to the regulation of cytoskeleton reorganization and FA dynamics. Podosome-type adhesions are filamentous actin-rich structures associated with extracellular matrix proteolysis and found in both migrating and invasive cells. Despite their physiological and pathological importance, the molecular bases of podosome formation remain poorly characterized. In their paper, Oikawa and Takenawa review current knowledge on the mechanism of podosome formation and report a critical role of the rare phosphoinositide PtdIns(3,4) P2 in the recruitment of a protein complex containing Tks5/FISH, Grb2 and N-WASP. This molecular structure appears Src-dependent and is required for actin nucleation at podosome sites.

In the frame of the study of the molecular mechanisms of FA formation and dynamics, the papers selected in this issue expose remarkable and significant discoveries in a very complementary angle. The molecular models proposed by the authors help to improve our understanding of how integrin-based adhesion complex dynamics is regulated and stress the fascinating complexity of the cellular system. Decoding such molecular mechanisms is a really exciting challenge that will continue to attract much attention of many scientists all over the world for the next decades.

About Dr. Dedieu

Dr. Stéphane Dedieu is Associate Professor at the University of Reims (France) and is member of the French National Center for Scientific Research (Unit 6237). Dr. Dedieu recieved his Ph.D. in 2003 in the field of Biochemistry and Molecular Biology at the University of Bordeaux. At this date, he studied the involvement of the calpain-dependent proteolysis during myoblast migration. Then he did a post-doc at the French National Institute of Health and Medical Research (Unit 459) at the Henry Warembourg Faculty of Medicine at the University of Lille, in the team of Dr. P. Lefebvre. He joined his current position in 2005. Now, he heads a research group interested in identifying molecular markers of cancer progression and developing alternative anti-tumor strategies. His staff mainly focuses on two molecular targets, i.e. the endocytic receptor LRP-1 and extracellular matrix protein thrombospondin, and investigates their involvement in cancer cell adhesion, migration, apoptosis and signaling.