Publikationsserver der Universitätsbibliothek Marburg
Titel:Charakterisierung von DYRK1A als nicht-kanonischer Modulator des Hedgehog-Signalwegs
Autor:Schneider, Philipp
Weitere Beteiligte: Lauth, Matthias (Dr.)
Veröffentlicht:2014
URI:https://archiv.ub.uni-marburg.de/diss/z2014/0651
DOI: https://doi.org/10.17192/z2014.0651
URN: urn:nbn:de:hebis:04-z2014-06513
DDC: Medizin
Titel (trans.):Characterization of DYRK1A as a non-canonical modulator of the Hedgehog signaling pathway
Publikationsdatum:2015-04-15
Lizenz:https://rightsstatements.org/vocab/InC-NC/1.0/

Dokument

Schlagwörter:
Forschung, Krebs <Medizin>, Krebsforschung, Medizin, DYRK1A, Biologie, Down-Syndrom, Hedgehog

Zusammenfassung:
Der Hedgehog (HH)-Signalweg spielt eine besondere Rolle während der Embryonalentwicklung. Im adulten Stadium ist er bis auf wenige Ausnahmen inaktiv und eine ektopische Reaktivierung kann zur Entstehung von Krebs führen. 30 % aller Tumorerkrankungen zeigen eine gesteigerte Aktivität des HH-Signalwegs. Neben der kanonischen Aktivierung des Signalwegs durch einen HH-Liganden existieren auch alternative Routen, die in erhöhter Aktivität der Transkriptionsfaktoren der GLI-Krüppel-Familie GLI1, GLI2 und GLI3 resultieren. Hierbei deutet sich eine besondere Rolle für die „Dual specificity tyrosine-phosphorylation regulated“ Kinasen (DYRKs) an. DYRK1B und DYRK2 sind als Gegenspieler des HH-Signalwegs beschrieben. Die Literatur beschreibt DYRK1A als positiven Faktor für GLI1 durch direkte Phosphorylierung abhängig vom N Terminus von GLI1, was aktivierende Funktionen, wie etwa eine Anreicherung von GLI1 im Zellkern, hat. Die Aufklärung dieses Mechanismus ist ein lohnendes Ziel, denn Proteinkinasen bieten ideale Zielstrukturen für hochpotente Pharmazeutika. Diese Arbeit bestätigt den positiven Effekt von transient überexprimiertem DYRK1A auf GLI1. Die Serine 102, 104, 130 und 132 sind dabei von Bedeutung, was eine Phosphorylierung dieser Aminosäuren nahelegt. Jeweils die Serine 102 und 104 sowie 130 und 132 bilden zusammen mit einem Prolin ein allgemeines Kerntranslokalisationssignal. Außerdem wurde in dieser Arbeit gezeigt, dass DYRK1A den SUFU-GLI1-Komplex in Abhängigkeit seiner Kinaseaktivität, nicht jedoch der oben genannten Serine, auflösen kann, was auf weitere Regulationsmechanismen von GLI1 durch DYRK1A hinweist. Weitere Experimente zeigten abhängig von Zelltyp und Zustand des HH-Signalwegs unterschiedliche Funktionen von DYRK1A, die vom erwarteten stimulierenden Effekt bis hin zu einer Inhibition des Signalwegs reichten. Ein von der Gruppe durchgeführter in vitro Kinase „Screen“ zeigte das AKTIN-bindende LIM Protein 1 (ABLIM1) als Phosphorylierungsziel von DYRK1A und weitere Untersuchungen zeigten ABLIM1 (und ABLIM2) sowie die „downstream“ wirkenden Proteine MKL1 („Megakaryoblastic leukemia 1“) und KDM3A (Lysin-spezifische Demethylase 3A) als positive Faktoren für den HH-Signalweg. Wir vermuten, dass DYRK1A ABLIM-Proteine phosphorylieren kann und so von AKTIN-Filamenten löst. Die daraus resultierende Erhöhung des G AKTIN-Pools führt zur Inhibition von MKL1 und so kann dieses nicht mehr in Kombination mit KDM3A bei der Expression von HH-Zielgenen mitwirken. Dies zeigt einen bisher unbekannten nicht-kanonischen Mechanismus der Regulation des HH-Signalwegs durch DYRK1A, der die beobachtete inhibitorische Rolle der Kinase erklären kann. Die Verknüpfung des HH-Signalwegs mit dem Feld der MKL1-regulierten Zielgentranskription ermöglicht eine Vernetzung mit einer Reihe anderer zellulärer Vorgänge. Die in dieser Arbeit gewonnenen neuartigen Erkenntnisse tragen weiter zur Aufklärung der komplexen Modulation des HH-Signalwegs bei und sind damit ein wichtiger Schritt für die zielgerichtete Entwicklung von Therapieansätzen bezüglich Tumorerkrankungen, die aus einer Deregulation des HH-Signalwegs resultieren.

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