Lehrstuhl für Experimentelle Medizin II
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  Wnt Signal Transduction Pathway
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Research Overview

Tumour Suppressor APC

Amer Family of Proteins

Conductin in Cancer

Activin B and renal cell carcinoma


T E R M I N E


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J O B S

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Praktika / Diplom

Molecular oncology of the Wnt signal transduction pathway

Overview of Research Activities 

Our main goal is to investigate the molecular mechanisms of tumour development and progression by cell and molecular biological methods as well as mouse models, to find new ways for diagnosis, prognosis and therapy.         

The Wnt signalling pathway regulates various processes during embryonic development and can lead to cancer. Wnts are secreted glycoproteins, which induce the accumulation of b-catenin in the cytoplasm and nucleus by binding to frizzled and LRP receptors. b-Catenin interacts with TCF transcription factors and activates target genes. The destruction of b-catenin is induced by phosphorylation in a multi-protein complex, which consists of the scaffold components axin and conductin/axin2, the serine/threonine kinase GSK3b and the tumour suppressor APC (Adenomatous Polyposis Coli). The Wnt signal inhibits phosphorylation of b-catenin and thereby leads to its stabilisation. In colorectal tumours, mutations of APC or conductin, or mutations of the serine/threonine phosphorylation sites in b-catenin lead to stabilization of b-catenin and trigger constitutive signalling to the nucleus. Such b-catenin mutations are also found in a multitude of other tumour types suggesting that aberrant activation of Wnt signalling is a key mechanism of oncogenic transformation. Our research has contributed to the field by identifying b-catenin as a transcription factor through binding to TCF/LEF and identification of conductin, which in turn aided in describing the mechanisms of b-catenin regulation by the multiprotein destruction complex.


simplified scheme of the Wnt-pathway (J. Hülsken)

Recent work in our lab has dealt with the consequences of APC mutations on Wnt signalling in tumours, and we have identified a new family of proteins whose first member, Amer1, interacts with and recruits APC to the plasma membrane. In addition, work carried in our lab has identified a role for conductin and aberrant Wnt siganling in the generation of Chromosomal Instability (CIN), which is a hallmark of colorectal cancers and is thought to be involved in the generation and progression of tumours. Through our work on conductin we have discovered that components of the Wnt signalling can localize to the mitotic spindle and centrosomes and can regulate the spindle checkpoint, which oversees successful progression through mitosis. A further focus of our studies is the regulation and consequences of b-catenin dependent transcription and its relationship to cell cycle regulation. Moreover, work undertaken in the lab deals with functional genomics of renal cell carcinomas with special focus on the role of Activin B in regulating adhesion of renal cell carcinoma cells to extracellular matrix and promoting invasion of tumour cells.



 
Wnt a bit more complex