The document describes the Wnt signaling pathway under normal and Wnt ligand present conditions, noting that in the presence of the Wnt ligand, β-catenin is stabilized and translocates to the nucleus to activate Wnt responsive genes. It also discusses how mutations in APC can lead to uncontrolled cell proliferation and cancer by dysregulating the Wnt pathway and allowing β-catenin to accumulate in the nucleus. Finally, it briefly outlines the important roles of the Wnt pathway in development.

1. 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
DSH
Β-TrCP

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
LRP
FRZ
DSH
LEF/TCF
B-Cat Wnt –responsive genes

6. Things can go wrong: Cancer!
 The APC protein also functions  This can lead to uncontrolled
as a tumor suppressor (Korinek proliferation
et al 1997)  Ultimately can lead to tumor
 Colon cancer may occur when formation, more
APC genes are mutated (Korinek mutations, invasion and
et al 1997) metastasis.
 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.

7. If APC is mutated (Oncogenes)
FRZ
When APC is
mutated the Gsk3
APC complex becomes
DSH unlinked from Wnt
Signaling (Does not
matter if Wnt is
present or not… It
will still release B-
Catenin)
CtBP TCF
1
B-Cat Cyclins, c-Myc, Pro-tumorigenic genes
SMAD

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
againstdecapentaplegic (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
Cell FRZ
Membrane
APC DSH Active
Inhibition
GSk3
Β-Catenin Axin
Transcription
LEF/TCF

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