UNNAMEd-2 · Unraveling the conceptional novel ADAM17 regulation by PP2A in metastasis formation.

Unraveling the conceptional novel ADAM17 regulation by PP2A in metastasis formation.

Cancer research has made great progress during the last decades, resulting in significantly improved prognostic tools and treatment options. However, in addition to severe illness many patients experience resistance to therapy. Additionally, almost half of the patients develop metastasis, which are responsible for about 90% of all cancer related death. Cancer development is a multi-step process that requires the orchestration between the cancer cell and the cells in the environment. One factor that is known to influence cancer development and metastasis by releasing signaling molecules from the cancer cell surface is ADAM17. It sits as a pair of molecular scissors in the cell's outer membrane and cleaves other proteins from the cell surface. Studies trying to inhibit ADAM17 and thereby tumor progression however failed due to the low specificity of the drug to ADAM17. Furthermore, ADAM17 produced on other cells of the tumor environment is crucial for tumor growth inhibition and blocking of ADAM17 activity on these cells enhances tumor growth. The activity of ADAM17 is highly regulated as well as the expression of it substrates. Another strategy to inhibit the pro-tumorigenic function of ADAM17 is by targeting molecules known to regulate ADAM17 activity, or by blocking the shedding of specific substrates. The group of our collaborator Prof. Jakob Nielsson identified a novel binding partner of ADAM17, namely the protein phosphatase PP2A. Phosphorylation’s serves often as a molecular switch to activate or switch “ON” enzymes. They can also initiate the destruction of the protein, the binding to other proteins or the translocation to another part of the cells. Phosphatases in turn remove these phosphate groups and therefore switch the protein “OFF”. Prof. Nielssons team identified a novel binding motif for a specific isoform of PP2A, B56, and found that this binding motif is present in the intracellular part of ADAM17. We therefore hypothesized, that PP2A is a negative regulator of ADAM17. The objectives of your study was therefore to: - Understand whether and how the function of ADAM17 is regulated by PP2A. - Determine the molecular mechanisms of the regulation and its impact in cancer development

Data: CORDIS, © European Union