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Amtliche Mitteilungen der Technischen Universität Dortmund Nr. 2/2025
(Technische Universität Dortmund, 2025-01-22)
Digital platforms for social inclusion: the case of an information platform for refugees
(2024-12) Schreieck, Maximilian; Wiesche, Manuel; Usachova, Olga; Krcmar, Helmut
The number of people fleeing their home countries has increased drastically in recent years. Host countries such as Germany are striving for the social inclusion of refugees. From a neoliberalist view, social inclusion comprises access to social resources, such as the labor market. The social justice view goes further, interpreting social inclusion as the participation of refugees as equal members of society. Digital platforms can contribute to social inclusion through their mechanisms of openness, generativity, and network effects. Drawing on the case of Integreat, an information platform for refugees in Germany, we show how these digital platform mechanisms supported the access and participation aspects of social inclusion. The case study serves as a starting point for research at the intersection of the literature streams of digital platforms and social inclusion and, more broadly, informs the use of digital platforms for social causes.
The role of LIPG in regulating cholesterol homeostasis in cancer
(2024) Mahmoud, Zhwan; Hengstler, Jan G.; Thriel, Christoph van
The endothelilal lipase or lipase G (LIPG) is expressed in cancer cells and high LIPG expression is shown to be associated with shorter metastasis free survival in untreated woman with node-negative breast cancer. LIPG is a cell surface associated lipase with multifaceted roles. It displays phospholipase A1 activity towards phosphatidylcholine in high-density lipoproteins (HDL), thereby releasing lysophosphatidylcholine (LPC) and free fatty acids, which can be used by the cells. In addition, LIPG has a non-enzymatic bridging function, enhancing the docking of lipoproteins to the cell surface. This could influence cholesterol exchange between cells and lipoproteins. Despite the important role of cholesterol tumor progression, the contribution of LIPG in tumor cholesterol homeostasis has not been studied so far. Thus, this study addresses the impact of LIPG on cholesterol metabolism in cancer cells.
Mechanistic principles of Rho GTPase patterning
(2024) Weiß, Yannic; Bastiaens, Philippe; Mutschler, Hannes
Rho GTPases are regulators of morphogenesis in all eukaryotic cells. These peripheral membrane proteins spatially control actin cytoskeleton dynamics by locally concentrating at the plasma membrane in polarized activity patterns. However, the biochemical mechanisms by which Rho GTPases enrich at specific membrane sites where they are subsequently activated remain unknown. Here, I use in vitro reconstitution in model membrane systems to evaluate the relationship between the membrane-cytosolic shuttling of Rho GTPases and their activity state. I established a minimal system of templated Rho GTPase activity patterns that fully recapitulates the catalytic and spatial cycles of Rho GTPases. By utilizing this system, I demonstrate that effector proteins selectively stabilize active Rho GTPases on membrane surfaces. This stabilization is achieved through an avidity-driven mechanism that increases membrane retention of active Rho GTPases and decreases their diffusivity on the membrane. Together, the results show that effector proteins couple the catalytic and spatial cycles of Rho GTPases, thereby actively contributing to their spatial polarization. These findings are vital in our reconstitution of a synthetic Rho GTPase signaling network capable of spontaneous and stable polarization. To this end, I biochemically engineered and purified synthetic proteins, mediating regulatory feedback between distinct Rho GTPases based on direct recruitment. This linear feedback can promote the autonomous formation of stable Rho GTPase activity patterns, as shown by theory. I established a pipeline of biochemical assays to characterize these synthetic proteins, demonstrating their capacity to interact with active Rho GTPases and modulate their activity. Hence, I successfully created synthetic regulators of Rho GTPase activity that are directly recruited by active Rho GTPases. This paves the way for the implementation of regulatory feedback in an experimental system and is the first step toward a complete reconstitution of a minimal system that promotes the stable polarization of Rho GTPase activity.
The relationship between oncogenic KRas and wild-type Ras activity and signaling
(2024) Kewagamang, Kitso Ata; Bastiaens, Philippe; Hengstler, Jan
Ras proteins play an important role in various signaling cascades, transducing external signals into phenotypic and behavioral responses. In many cancers, however, Ras-mediated signaling is dysregulated, with mutated, constitutively active KRas proteins being the most pervasive in pancreatic ductal carcinoma and colorectal cancer.
The mechanisms driving this dysregulation are complex. Wild-type Ras isoforms, including the cognate wild-type Ras counterpart to the oncogenic Ras, are thought to play distinct roles in how they mediate Ras signaling and alter cell behavior in cancerous cells. Moreover, overexpressed oncogenic Ras proteins can cause senescence when heterogeneously expressed with wild-type Ras isoforms. The molecular mechanism of this oncogene-induced senescence is not fully understood, although the involvement of tumor suppressor proteins such as p53 has been shown. Whether an interaction between oncogenic and wild-type Ras also plays a role here remains unclear.
To investigate how oncogenic KRas activity affects wild-type Ras activity and subsequent signaling, a two-component chemical genetic approach was developed. This technique allows bioorthogonal chemical control of the amount of KRas oncoproteins at the plasma membrane. It leverages the important feature of plasma membrane localization of Ras proteins in signal transduction.
The results herein show that a reversible, chemically-induced dimerization system can effectively control plasma membrane localization of ectopically expressed KRas in cells. Using this approach, we found that cytosolic oncogenic KRas (possessing G12V or G12D mutations) has higher GTP-loading compared to wild-type KRas, providing further evidence for its constitutive activity. We also show that acutely enriching overexpressed wild-type KRas and oncogenic KRas at the plasma membrane resulted in transient activation of endogenous wild-type Ras and the downstream signaling effectors ERK and AKT. As Epidermal Growth Factor (EGF) – mediated-Ras signaling is often dysregulated in cancer, an investigation into the effects of plasma membrane localization of oncogenic KRas on this network was performed by way of EGF dose-response experiments. Results suggest that accumulation of oncogenic KRas proteins at the plasma membrane causes an ultrasensitive response in endogenous wild-type Ras activity and downstream effectors at lower EGF doses, compared to wild-type cells. Additionally, clonogenic assays revealed that over-expressed KRas G12V and G12D oncoproteins were associated with reduced proliferation, regardless of whether they were localized in the cytosol or at the plasma membrane.
Collectively, these findings indicate that KRas oncoproteins have an activating interaction with the wild-type Ras proteins at the plasma membrane and initiate downstream signaling. Furthermore, oncogenic Ras may increase the sensitivity of transformed cells to growth factor stimulation by this interaction with wild-type Ras. However, these effects alone are likely insufficient to drive tumorigenesis when oncogenic KRas is overexpressed, as proliferation was suppressed. Thus, further mechanisms may be required for cancer formation. Altogether, these results help to explain some of the changes in signaling responses to growth factors in KRas-driven carcinogenesis.