Wnt/beta-catenin Signaling Pathway with Resulting Condition: Adenomatous Polyposis Coli

00:00 One other interesting pathway, and there are a couple others that we're not gonna even cover, but I just want you to see this one, because this does lead to disease.

00:10 So, this is the Wnt/beta-catenin signaling pathway.

00:15 And this has to do with proliferation, largely of epithelium, and very commonly, in the gastrointestinal tract epithelium.

00:22 So, wnt is a ligand, and there is a receptor on the surface of cells shown there at the top, in that green box, that is composed of the LRP proteins and the F2 protein.

00:36 And that will form a receptor.

00:39 And in the absence of wnt, the associated blue blobs in the cytoplasm below it are not activated.

00:49 So, those have a certain conformation.

00:52 And when everything is -- when there's no wnt, then that complex will target for degradation, the beta-catenin.

01:03 So, the important molecule for targeting is APC.

01:07 It stands for adenomatous polyposis coli.

01:11 It's a protein that's part of that blue blob complex, and in the absence of wnt, it says to the proteasome, "Degrade and complete destroy beta-catenin." And it does. It breaks it down to little, tiny fragments. Okay? That's the normal pathway and that keeps any activation from happening.

01:32 Okay, now let's add the ligand. Let's add wnt.

01:34 Now, wnt comes in, and when it binds to its receptor, there's a conformational change, and we recruit a lot of the blue blobs that were originally holding beta-catenin in a conformation where it would be degraded.

01:48 And we recruit those blue blobs and beta-catenin is free to go about its business without degradation.

01:55 An elevated level of beta-catenin will then get into the nucleus and were often running in terms of transcription into, including proliferation of the epithelial cells that are there. Cool.

02:07 And we want this to happen.

02:09 Wnt is a normal good guy, and the LRP and the F2 proteins, normal good guys.

02:14 And APC, normal good guy. But what happens if one of these gets mutated? Now, if we get mutations in an important gene, the adenomatous polyposis coli, the APC gene, that original complex no longer exists, and beta-catenin is free to go about its business without being degraded, even in the absence of ligand. So, as shown on the left-hand side, there's no wnt, but there's also no APC. And so, the beta-catenin is free, and it will then go into the nucleus and drive transcription.

02:49 So, if you have mutations in APC, you will get a disease called adenomatous polyposis coli, which looks like this.

02:58 And you get innumerable, innumerable polyps throughout the colon, and you are a lifetime risk of pretty much 90% of developing colon cancer, because of this unregulated proliferation.

03:12 Just because of a mutation in the APC, allowing beta-catenin to go wild.

03:17 So, an interesting example of disease associated with signaling.