Der ALK-Rezeptor in zellulären Modellen des humanen Neuroblastomkrebses: Aktivierung und Signalisierung

Der ALK-Rezeptor in zellulären Modellen des humanen Neuroblastomkrebses: Aktivierung und Signalisierung

The ALK receptor in cellular models of human neuroblastoma cancer: activation and signaling

Laura Jacqueline Aksak

Doctoral thesis

Date of Examination: 2018-01-31

Date of issue: 2018-01-08

Advisor: Wouters-Bunt, Freddy Prof. Dr.

Referee: Kube, Dieter Prof. Dr.

Referee: Schön, Margarete Prof. Dr.

Persistent Address: http://hdl.handle.net/11858/00-1735-0000-002E-E315-E

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Abstract

English

This thesis is about different mutations of the tyrosine kinase ALK and their role in the human neuroblastoma cancer. The ALK subtypes wildtype, F1174L, R1275Q, Y1604F and I1250T have been investigated in a laboratory projekt using neuroblastoma cells, fluorescence markers and microscopy. On the one hand, different behaviour of the subtypes could be shown when it comes to activation and activation thresholds, measured by displaying phosphotyrosine as a marker of ALK activation, taking the amount of ALK receptors into account. This behaviour could be reflected in FRET measurements. In addition, the ALK-subtypes showed typical cytomorphology, that was partiallly first described and compared. On the other hand, the downstream signaling of the ALK subtypes was analyzed by using sandwich immuno assays, thereby prooving a leading role of the Akt pathway. The Ras/Raf/MEK/ERK pathway was found to play a minor role in the ALK downstream signaling, which was additionally confirmed using an ERK1/2 inhibitor on neuroblastoma cells, that showed no effect on the amount and distribution of phosphotyrosine, the marker of ALK activation.

Keywords: neuroblastoma; alk

Schlagwörter: Neuroblastom; ALK