Contact

PD Dr. Tanja Maritzen
phone +49 30 94793 - 214 (office)/ -368 (lab)
maritzen(at)fmp-berlin.de

Maritzen Lab Research

Cytoskeletal Dynamics and Cellular Motility

Cellular movement is dependent on the coordinated interplay between membrane traffic, actin cytoskeleton dynamics, and focal adhesion turnover. One focus of our group is to study proteins that connect these processes, as these are likely nodes of integration at which signals elicited by internal or external cues converge to regulate cell motility.

We have identified Gadkin as one such connecting node that acts at the interface between membrane traffic and actin dynamics, thereby modulating cell motility. Gadkin facilitates microtubule-dependent transport of AP-1 positive endosomal vesicles (Schmidt et al., PNAS, 2009) and directly binds to the ARP2/3 complex, a key actin nucleator organizing branched actin filament networks during membrane protrusion formation. In the absence of pro-migratory signaling Gadkin sequesters Arp2/3 on intracellular vesicles thereby preventing Arp2/3 action at lamellipodial protrusions and inhibiting cell spreading and cell migration of melanoma cells (Maritzen et al., PNAS, 2012).

Cell migration is not only important for cancer cells, but also crucial for the function of numerous types of immune cells which have to quickly migrate through the organism to organize the host defense against invading pathogens. A prominent example are dendritic cells (DCs) which act as sentinels of our immune system. Stationed in peripheral tissues, immature DCs continuously sample antigens. Upon encounter of pathogens they mature and migrate to lymph nodes to activate T cells. Thus, efficient DC migration is crucial for the adaptive immune response. To understand and possibly manipulate DC migration is not only of academic interest, but likely also of therapeutic value since keeping DCs from reaching and priming T cells is a potential avenue to treat autoimmune diseases like multiple sclerosis.
Being upregulated and phosphorylated in DCs upon their maturation, Gadkin likely contributes to DC functions. Consistent with Gadkin´s role as inhibitor of Arp2/3, we observed a higher amount of filamentous actin in DCs derived from Gadkin deficient mice. However, while the loss of Gadkin increased the velocity of melanoma cells, it impaired the in vitro migration of DCs (Schachtner et al., PlosOne, 2015). This result makes sense in the light of recent findings from the lab of Ana-Maria Lennon-Duménil which showed that Arp2/3-dependent actin polymerization is not driving DC motility, but rather diminishing the actin pool needed for mDia-mediated fast DC migration.
Thus the divergent consequences of loss of Gadkin in motile cells illustrates the high degree of plasticity in the mechanisms that underlie cell migration in different cell types. In the future we want to investigate additional endocytic and actin regulatory molecules in DCs to gain a more comprehensive picture of the molecular players shaping their migratory behaviour.

A: Hypothetical model of the dual role of Gadkin in membrane transport and modulation of actin dynamics.

B: Gadkin colocalizes with the actin nucleating ARP2/3 complex (visualized with antibodies against the subunit ARPC2) in B16F1 cells plated on Matrigel (Maritzen, PNAS, 2012).

C: Mouse embryonic fibroblasts migrating into a wound (courtesy of Fabian Feutlinske).

Leibniz-Forschungsinstitut für Molekulare Pharmakologie im Forschungsverbund Berlin e.V. (FMP)
Campus Berlin-Buch
Robert-Roessle-Str. 10
13125 Berlin, Germany
+4930 94793 - 100 
+4930 94793 - 109 (Fax)
info(at)fmp-berlin.de

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