The Wnt Signaling Pathway (β Catenin )

1. The Wnt Signaling Pathway ( β -Catenin ) Jonathan Fletcher Dr. Amanda Dickinson’s Developmental Biology Fall 2011

2. Normal Cellular Conditions Wnt ligand is not present Dishevelled is inactive GSK3 destruction complex prevents the dissociation of β -Catenin Β-TrCP then targets β -Catenin for proteosomal destruction No transcription of Wnt genes occur under normal conditions

3. Normal Conditions (Wnt - ) FRZ Β -TrCP DSH

4. Presence of Wnt ligand Wnt Ligand is present and interacts with Frizzled transmembrane receptors (Logan and Nusse 2004 ) LRP associates with the Wnt/Frizzled protein complex. LRP is required for signaling in many Wnt pathways. (Wehrli et al. 2000) Frizzled then activates Dishevelled (Logan and Nusse 2004) Once activated Dishevelled inhibits the GSK3 destruction complex enzyme (Logan and Nusse 2004) β -Catenin is now free to dissociate from the APC protein and enter the nucleus (Behrans et al. 1996) Once in the nucleus β -Catenin can associate with an LEF or TCF DNA-Binding protein, becoming a transcription factor (Behrans et al. 1996) This complex binds to and activates the Wnt responsive genes (Behrans et al. 1996; Cadigan and Nusse 1997)

5. Conditions with Wnt present ( Wnt + ) Wnt LEF/TCF B-Cat Wnt –responsive genes DSH FRZ LRP

6. Things can go wrong: Cancer! The APC protein also functions as a tumor suppressor (Korinek et al 1997) Colon cancer may occur when APC genes are mutated (Korinek et al 1997) APC can no longer keep β -Catenin out of the nucleus (Korinek et al. 1997; He et al. 1998) Once inside the nucleus β -Catenin can bind with other proteins including SMADs, CtBP, Groucho and CBP to upregulate proteins for cell division. This can lead to uncontrolled proliferation Ultimately can lead to tumor formation, more mutations, invasion and metastasis.

7. If APC is mutated (Oncogenes) TCF B-Cat Cyclins, c-Myc, Pro-tumorigenic genes APC Groucho CtBP1 CBP SMAD FRZ DSH When APC is mutated the Gsk3 complex becomes unlinked from Wnt Signaling (Does not matter if Wnt is present or not… It will still release B-Catenin)

8. Wnt Role In Development Wnt proteins now recognized as a major developmentally important family of proteins. (Cadigan and Nusse 1997) They are important in embryonic induction (Cadigan and Nusse 1997) They are extremely important in the generation of cell polarity (Cadigan and Nusse 1997) They also function in the specification of the cells fate(Cadigan and Nusse 1997)

9. Legend DSH- Dishevelled Protein FRZ- Frizzled Receptor CBP- CREB binding Protein Wnt- Wingless/Integrated protein Groucho-Non-DNA binding co-repressor ( named after comedian) SMAD- The name is a combination of the drosophila protein, mothers against decapentaplegic (MAD) and the C. elegans protein SMA. CtBP-1-Carboxyl terminal binding protein c-MYC- myelocytomatosis oncogene LEF- Lymphoid Enhancer Factor TCF- DNA binding protein APC- Adenomatous polyposis coli GSK-3- Glycogen synthase kinase 3 LRP- arrow Axin-Negative regulator of Wnt β-Cat- Beta Catenin Protein Β-TrCP-beta transduction repeat containing protein

10. References www.familyguy.wikia.com/wiki/peter_griffin http://www.ccalliance.org/colorectal_cancer/staging.html www.bioportal.kobic.re.kr/Pdcase/pathway.jsp?pathway=h_wntPathway Jürgen Behrens, Boris-Alexander Jerchow, Martin Würtele, Jan Grimm, Christian Asbrand, Ralph Wirtz, Michael Kühl, Doris Wedlich and Walter Birchmeier. Functional Interaction of an Axin Homolog, Conductin, with β-Catenin, APC, and GSK3β. Science 24 April 1998: Vol. 280 no. 5363 pp. 596-599 Logan CY, Nusse R. The Wnt signaling pathway in development and disease. Annual Review Cell Development Biology. 2004:20:781-810 Cadigan KM, Nusse R.Wnt signaling: a common theme in animal development. Genes Dev. 1997 Dec 15:11 (24) 3286- 305 Wehrli M, Dougan ST, Caldwell K, O’Keefe L. Schwartz S, Vaizel-Ohayon D, Schejter E, Tomlinson A, DiNardo S. Arrow encodes an LDL-receptor-related protein essential for Wingless signaling. Nature. 2000. 407 (6803): 527- 530 Vladmir Korinek, Nick Barker, Patrice J. Morin, Dick Van Wichen, Roel de Weger, Kenneth W. Kinzler, Bert Vogelstein and Hans Clever. 1997. Constituitive Transcriptional Activation by a Beta-catenin- Tcf Complex in APC -/- Colon Carcinoma. Science 21 Vol. 275 No. 5307 pp. 1784-1787

11. Brownies!!! The Wnt Way!!!!! Wnt FRZ Cell Membrane DSH Inhibition APC GSk3 Β -Catenin Axin LEF/TCF Transcription Active

12. Thank You!!! Dr. Amanda Dickinson, PhD Ryan Lab for not eating these delicious brownies before I could get them down the hall!