Wnt-signaling (+colorectal cancer development) Flashcards
Describe the canonical Wnt signaling pathway with and without Wnt signal. Explain what Wnt proteins are. Use the following terms: Frizzled, Dishevelled, axin, LEF1/TCF.
Wnt proteins are secreted signal molecule.
Canonical wnt pathway = wnt/b-catenin pathway:
- Wnt binds Frizzles (7-pass trans-membrane cell surface receptor) + co-receptor LDL-receptor related protein (LRP)
- Activated Frizzled recruits scaffold protein Dishevelled + promotes phosphorylation of LRP receptor by kinases GSK3 and CK1.
- Axin is brought to receptor complex and inactivated, disrupting b-catenin degradation complex in the cytoplasm.
- Preventing phosphorylation and degradation of b-catenin.
- Unphosphorylated b-catenin accumulates and translocates to nucleus, alters gene transcription pattern
Absence of wnt:
Wnt-responsive genes are kept silent by inhibitory complex of transcription regulatory proteins, including LEF1/TCF bound to Groucho.
In response to Wnt-signal, b-catenin enters nucleus and binds LEF1/TCF proteins, displacing Groucho.
What is the consequence if APC is mutated in the Wnt signaling pathway?
Mutations in APC inhibits APC’s ability to bind b-catenin. B-catenin accumulates and stimulates gene transcription even in absence of wnt-signaling. Resulting in uncontrolled cell growth and proliferation, promoting the development of cancer.
How does Wnt signaling play a role in oncogenesis?
Mutations in the Wnt signaling pathway, such as in APC. Can cause accumulation and stimulation of gene transcription by b-catenin even in absence of Wnt. Wnt target genes include for example Myc which is a regulator for cell growth. Transcription of Myc even in absence of wnt can cause uncontrolled cell growth and proliferation, promoting the development of cancer.
Wnt plays an important role in the homeostasis of intestinal epithelium. How does the degree of Wnt signaling change along the crypt-villus axis for the normal pathway and an APC mutated pathway?
Stem cells are present in crypts, daughter cells will move upwards and differentiate along the crypt-villus axis where proliferation stops. The wnt signaling (proliferating signal) decreases along the crypt-villus axis. (termination of Wnt signaling stops cell division as cells leave the crypts).
In an APC mutated pathway, wnt-signaling is permanently activated. Resulting in high expression levels of Wnt target genes which promote proliferation. In APC-mutated cells, the degree of wnt-signaling is equal across the entire crypt-villus axis.
What makes LGR5 so important in stem cell colorectal cancer research?
Intestinal epithelium stem cells, which lay in the intestinal crypts, have a high expression of Lgr5. Lgr5+ stem cells are multipotent and immortal (can produce new stem cells). A mini-gut can be made from a single Lgr5+ cell in the suitable environment. Which provides a lot of possibilities in colorectal cancer research.
