Molecular Cell Biology
The cytoskeleton is responsible for the mechanical stabilisation of the cell and its outer shape, for the movement of the cell as a whole as well as for movement and transportation within the cell. The research group "XY" focusses on one specific part of the cytoskeleton: the aktincytoskeleton. Which plays a role in giving an effective immune response as well as a target for pathogens. Understanding the molecular mechanisms underlining the construction and destruction of the actin structure is one of the main goals of Klemens Rottner and his teams.
Our group is mainly interested in understanding the molecular mechanisms that drive the reorganization of different actin structures in cells. The actin cytoskeleton is responsible for building a diverse array of structures with multiple functions, ranging from contractile actin/myosin filament bundles in skeletal and heart muscle to the very transient actin accumulations accompanying endo- or phagocytosis or the dynamic protrusive organelles such as lamellipodia and filopodia. Moreover, specific types of cell-cell or cell-substrate adhesions are frequently built and regulated by the actin cytoskeleton, and have decisive functions for normal physiology and disease, such as the invadopodia of cancer cells. Actin-dependent motility processes are equally important for effective immune responses and metastasis in cancer. In addition, the actin cytoskeleton is frequently usurped by viral or bacterial pathogens, in order to invade into or hide and spread within their host cells. In previous years, we mostly focused on the molecular mechanisms of actin filament assembly and reorganization, especially at the plasma membrane, and how these processes are abused by bacterial pathogens.
Actin filament assembly involves both nucleation and elongation. In the meantime, the field distinguishes between three classes of nucleators: (i) Arp2/3 complex and activators, (ii) the family of formins and (iii) the third class comprising Spir, cobl and leiomodin.
The Arp2/3-complex harbours seven subunits, including the two actin-related proteins Arp2 and Arp3. The complex is mostly inactive in the absence of so called nucleation promoting factors (NPFs), the founding member of which is known as WASP, mutated in the rare, X-linked immunodeficiency Wiskott Aldrich Syndrome. The family in mammals comprises as classical members haematopoietic WASP, the more ubiquitous and neuronally enriched N-WASP and three WAVE isoforms (1,2,3). More recently, additional family members have appeared on the scene, termed WASH, WHAMM and JMY.
In addition, WASP/N-WASP and WAVEs are direct or indirect effectors of small Rho (Ras homology) - family GTPases, prominent members of which are able to stimulate actin-based cell protrusions. It is generally agreed today that small GTPases of the Rac subfamily drive lamellipodia protrusion by connecting to WAVE mediating Arp2/3 complex activation. In spite of the commonly accepted, essential function of Rac/WAVE and Arp2/3 complex for lamellipodial actin filament assembly, more recent work reveals an additional contribution of other Rho-GTPase signalling pathways. For instance, we were recently able to show how Cdc42 supports the protrusion of lamellipodia through activation of the formin family member FMNL2.
Another group of Arp2/3 complex interactors is called type II NPFs, and in mammals comprises the Src-substrate cortactin and its haematopoietic counterpart HS1. Both proteins accumulate at sites of dynamic actin assembly, and show a great degree of co-localization in cells with Arp2/3-complex. In our group, we have generated a murine, conditional cortactin mutant model, which allows dissecting cortactin function in specific processes and tissues.
Our work benefits from numerous, fruitful national and international collaborations, for instance with the labs of Jan Faix (Hannover), Cord Brakebusch (Kopenhagen, Denmark), Marie-France Carlier (Gif-sur-Yvette, France), Michael Schnoor (Mexico City) or Walter Witke (Bonn). In a new project funded by the Deutsche Forschungsgemeinschaft (DFG), molecular manipulation will be combined with atomic force microscopy (AFM) measurements (Josef Käs, Leipzig) and mathematical modelling (Martin Falcke, Berlin). At the Biocenter and HZI, we will build on already established collaborations, such as with Martin Korte und Kristin Michaelsen-Preusse (Biozentrum) or Theresia Stradal (HZI).