Taspase 1 and its sphere of activity – novel target proteins and influence on cell cycle progression
Final Report Abstract
The protease Threonine aspartase 1 (Taspase1) is involved in cancerogenesis by proteolytic processing of several target proteins including MLL (mixed lineage leukemia) proteins and transcription factor TFIIA. This proposal sought to gain novel insights into Taspase1’s sphere of activity and its overarching function. First, this project has broadened the degradome of Taspase1: Among others, the unconventional Myosin1f (Myo1f) was identified as a bona fide substrate of Taspase1 and the project results of WP1 also revealed that Myo1f is able to induce filopodia resulting in increased cellular adhesion and migration. Taspase1 impairs this function of Myo1f, because cleavage removes the N-terminal ATP-binding site, rendering the main Myo1f cleavage fragment incapable of inducing or elongating filopodia. As Tasp1 and Myo1f inversely correlate in immune cell differentiation, it was postulated that Tasp1-mediated proteolysis of Myo1f is a mechanism to fine-tune filopodia formation, relevant particularly for maturation of hematopoietic stem cell-derived monocytes into macrophages, and thus for the innate immune response. Furthermore, the second work package of this project has not only unraveled new binding partners of Taspase1, but made also important contributions to the fundamental understanding of this development- and cancer-relevant protease: Topoisomerase II was identified as a new interactor and the interplay of both proteins enhances Topoisomerase IIβ-induced DNA double-strand breaks that are a precondition for stimulus-driven gene transcription. This was confirmed by Taspase1 depletion studies which led to a decrease in the expression of estrogen-regulated genes. Moreover, it could be demonstrated that the protease alters the H3K4 epigenetic signature upon estrogenstimulus, presumably by cleavage of the chromatin modifying enzyme MLL. Taken together, the project results demonstrated for the first time, that Taspase1’s sphere of activity covers the cellular estrogen signalling pathway. Consequently, Taspase1 can now be categorized as a multimodal co-activator of estrogen-stimulated transcription.
Publications
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The Taspase1/Myosin1f-axis regulates filopodia dynamics. iScience, 25(6), 104355.
Hensel, Astrid; Stahl, Paul; Moews, Lisa; König, Lena; Patwardhan, Rutuja; Höing, Alexander; Schulze, Nina; Nalbant, Perihan; Stauber, Roland H. & Knauer, Shirley K.
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Taspase1 Facilitates Topoisomerase IIβ-Mediated DNA Double-Strand Breaks Driving Estrogen-Induced Transcription. Cells, 12(3), 363.
Oelschläger, Lisa; Stahl, Paul; Kaschani, Farnusch; Stauber, Roland H.; Knauer, Shirley K. & Hensel, Astrid
