Project group leader Eva M. Wenzel Wnt signalling in physiology and disease
The Wnt signalling pathway is central during developmental processes, tissue repair and disease. Inappropriate activity of this pathway results in a variety of human cancers, for example colon cancer. The central molecule of the canonical Wnt signalling pathway is β-catenin, which drives the expression of mitogenic genes, leading to an increased cell proliferation. The protein levels of β-catenin are usually under tight control by the so-called β-catenin destruction complex, which leads to the constitutive degradation of this proto-oncogene in non-proliferative tissue. β-catenin is thereby recruited into a multiprotein destruction complex which includes the structural proteins adenomatous polyposis coli (APC) and axis inhibition protein 1 and 2 (AXIN1/2), and the kinases casein kinase 1α (CK1α) and glycogen synthase kinase 3 (GSK3). The resulting phosphorylation of β-catenin serves as a recognition site for the E3-ligase β-TrCP, which leads to an ubiquitination of β-catenin followed by degradation in the proteasome.
However, the exact interplay of the destruction complex components and the molecular interactions required to process β-catenin remain elusive. For example, the role of APC in the degradation of β-catenin remains poorly understood, but must be significant, as mutations in the APC gene are the most frequent cause of colon cancer. The main goal of our project group is to elucidate the role of the β-catenin destruction complex in cancer development by molecularly dissecting its composition, structure, function and regulation.
Cover of November edition of Molecular Cancer Research 2015 by Thorvaldsen, Pedersen, Wenzel et al.
3D structured illumination micrograph of SW480 colon carcinoma cells showing Tankyrase-inhibitor induced degradasomes.
Wenzel EM, Schultz SW, Schink KO, Pedersen NM, Nähse V, Carlson A, Brech A, Stenmark H, Raiborg C. Concerted ESCRT and clathrin recruitment waves define the timing and morphology of intraluminal vesicle formation. Nat Commun 2018, 9 (1), 2932
Raiborg C, Wenzel EM, Pedersen NM, Olsvik H, Schink KO, Schultz SW, Vietri M, Nisi V, Bucci C, Brech A, Johansen T, Stenmark H. Repeated ER-endosome contacts promote endosome translocation and neurite outgrowth. Nature 2015, 520 (7546), 234-8
Thorvaldsen TE, Pedersen NM, Wenzel EM, Schultz SW, Brech A, Liestøl K, Waaler J, Krauss S, Stenmark H. Structure, Dynamics, and Functionality of Tankyrase Inhibitor-Induced Degradasomes. Mol Cancer Research 2015, 13(11):1487-501
- Cover on November edition of Molecular Cancer Research
Schneikert J, Ruppert JG, Behrens J, Wenzel EM, Different Roles of Axin Interacting with the SAMP and Second Twenty Amino Acid Repeats of Adenomatous Polyposis Coli. PLoS One. 2014, 9(4):e94413
- This article was recommended by the Faculty of 1000: http://f1000.com/prime/718346651
Kohler EM, Chandra SH, Behrens J, Schneikert J, Beta-catenin degradation mediated by the CID domain of APC provides a model for the selection of APC mutations in colorectal, desmoid and duodenal tumours. Hum Mol Genet 2010, 18(2): 213-226
Kohler EM, Brauburger K, Behrens J, Schneikert J, Contribution of the 15 amino acid repeats of truncated APC to beta-catenin degradation and selection of APC mutations in colorectal tumours from FAP patients. Oncogene 2009, 29(11): 1663-1671
Kohler EM, Derungs A, Daum G, Behrens J, Schneikert J, Functional definition of the mutation cluster region of adenomatous polyposis coli in colorectal tumours. Hum Mol Genet 2008, 17(13): 1978-1987
Our research is supported by:
Eva M. Wenzel, Department of Molecular Cell Biology, Institute for Cancer Research
Oslo University Hospital,The Norwegian Radium Hospital,0379 Oslo, Norway
Phone +47 22 78 18 19