Our group is interested in the cytoskeleton of primary human cells, especially of monocytic and endothelial cells. We study the dynamic regulation of the actin and tubulin cytoskeletons in the context of cell adhesion, migration, invasion and phagocytosis. These cellular functions are based on closely regulated and spatially restricted reorganization of the cytoskeleton, and play critical roles during physiological or pathological processes such as diapedesis, wound healing, metastasis, or uptake of pathogens.A detailed study of the molecular mechanisms underlying cytoskeletal dynamics is, therefore, essential for a better understanding of these processes and for the development of specific tools for their therapeutic modulation. Our projects focus on various model systems, which address different aspects of cell adhesion, migration, invasion or phagocytosis, and are all critically regulated by actin and tubulin turnover.

Podosomes in a human marcrophage
(F-actin in red, supervillin in green) ©Photo AG Linder

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Macrophage adhesion and migration

Influence of actin-associated proteins in the turnover of podosomal adhesions.

Podosomes are actin-rich adhesions of macrophages and other cell types that play important roles in cell migration and invasion. Podosomes are multifunctional organelles that impact on multiple cell functions such as adhesion, matrix degradation, or rigidity and topology sensing. Comparable to other adhesion structures, the podosome proteome is highly complex, with over 200 potential components. We study the role of selected proteins on formation, architecture and dynamics of podosomes in primary human macrophages.

Podosomes and microtubules in a macrophage
(f-actin in red, beta-tubulin in green) ©Photo AG Linder

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Cytoskeletal cooperation at podosomes

Dynamic regulation of actin-dependent podosomes by microtubules and molecular motor proteins.

Formation and turnover of podosomes depends on the localized delivery of components and regulators by microtubule-based transport processes. Podosomes are thus an ideal system to study the interconnection between the actin and microtubule cytoskeletons. We are particularly interested in the impact of various motor proteins of the kinesin protein family that all regulate different aspects of podosome biology.

Matrix degradation by podosomes
(gelatin matrix in red, F-actin in blue) ©Photo AG Linder

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Regulation of cell invasion

Intracellular trafficking of matrix metalloproteinases and their influence on extracellular matrix degradation.

Invasive migration is a key ability of cells in both physiological and pathological scenarios, including migration of immune cells to sites of infection and dissemination of cancer cells during metastasis. Matrix metalloproteinases (MMPs) are important enzymes that mediate proteolysis-based invasion of cells. In this project, we study the intracellular trafficking pathways of MMPs and the effect of trafficking regulators on MMP-based degradation of the extracellular matrix. For this, we use both 2D and 3D models of cell invasion.

Macrophage capturing Borrelia spirochete
(F-actin in red, GFP in green) ©Photo AG Linder

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Processing of pathogens by immune cells

Uptake and intracellular processing of Borrelia burgdorferi by human macrophages and dendritic cells.

Borrelia burgdorferi is the causative agent of Lyme disease, a multisystemic disorder affecting skin, joints and nervous system. Macrophages and dendritic cells are among the first immune cells to encounter infecting borreliae in the body. Internalization and elimination of borreliae by these cells is thus decisive for the outcome of a respective infection. We study the uptake and intracellular processing of borreliae by immune cells, aiming for a better understanding of the respective molecular processes.

Impaired endothelial monolayer
(F-actin in red, Arp2/3 complex in green) ©Photo AG Linder

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Regulation of endothelial integrity

Role of RhoGTPase effectors and actin-associated proteins in the dynamic formation of cell-cell contacts.

The integrity of the endothelial monolayer is essential for the maintenance of the blood-vessel barrier. Opening and closure of contacts between endothelial cells regulate the efflux of fluid and transmigration of blood cells into surrounding tissues. Fine-tuned control of cell junction dynamics by regulating the interplay of constituent proteins is therefore essential for endothelial functions. We study the role of actin-based processes proteins in the dynamic regulation of cell-cell contacts in both physiological and pathological settings.

More detailed information on our projects can be found at the Linder Lab website

Current research activities are funded by the Deutsche Forschungsgemeinschaft (LI 925/3-2, LI925/2-2, LI952/4-1 and GRK 1459),

and the Wilhelm Sander-Stiftung

The Invadosome Consortium is an open network of laboratories interested in cell adhesion and tissue invasion.The Tissue Transmigration Training Network is a consortium of European labs, which is funded by the 7th Framework Program of the European Commission. The network is focused on the training of young researchers in innvovative methods and topics in invasive cell migration.