The question is from my oncology(cancer biology) class.. \"Explain in detail abo

Question

The question is from my oncology(cancer biology) class..

"Explain in detail about wnt-beta-catenin signaling pathway and its contribution to cell proliferation"

My professor wants a very long, detailed explaination for each assignment... and I seriously have no idea, and didn't even start studying the cell signaling part.

I will really really appreciate it if you could explain in detail, including what wnt signliang pathway is, what it is composed of, etc, etc. Please explain it in detail and long explanation!

p.s. The textbook for this course is cancer biology written by Robert. A. Weinburg

Explanation / Answer

Wnt signaling was first identified for its role in carcinogenesis. The Wnt proteins are a family of secreted growth factors that bind to receptors of the Frizzled and LRP family, which a re related to Smoothened.

Frizzled (FZD) family receptors span the plasma membrane and constitute a distinct family of G-protein coupled receptors and lipoprotein receptor-related proteins (LRP) act as co-receptors.

Signaling from LRP and FZH leads to activation of a cytoplasmic protein called Dishevelled (DSH), and inhibition of a complex of the negative Wnt regulator, axin, APC, and the protein kinase GSK-3. Within this complex, GSK-3 phosphorylates -catenin, leading to its ubiquitination and degradation but after its inhibition, GSK3 can no longer phosphorylate -catenin. This allows -catenin enter the nucleus, where it is able to activate a transcription factor of the TCF/LEF (T-cell factor/lymphoid enhancer factor) thus trigger the transcription of genes that were until then repressed. Among the genes that are thus transcribed are MYC, which encodes a transcription factor involved in cell proliferation, and cyclin D1(CCND1), which is involved in cell cycle entry.

When it gets out of the nucleus, -catenin is recaptured by APC and, in the absence of a new WNT signal, reinserted into a destruction complex.

Canonical and noncanonical pathways
This pathway is called canonical pathway where wnt acts in through -catenin. There are noncanonical pathways which operate independently of -catenin.

Regulation
In order to ensure proper functioning, Wnt signaling is constantly regulated at several points along its signaling pathways. The protein porcupine mediates this palmitoylation process, which ensures Wnt ligand is secreted by determining when it is fully formed. Secretion of Wnt protein is further controlled with proteins such as 'wnt-less' and 'evenness interrupted' and complexes such as the retromer complex. Upon secretion, the ligand can also be prevented from reaching its receptor through the binding of certain proteins such as the stabilizers Dally and glypican, which inhibit its diffusion. At the FZD receptor, the binding of proteins other than Wnt can antagonize signaling. Specific antagonists include Dickkopf (Dkk), Wnt inhibitory factor 1 (WIF-1), secreted FZD-related proteins (SFRP).

Roles of Wnt signalling
Wnt signaling plays a critical role in the embryonic development

Wnt signaling can is implicated in the formation of the anteroposterior and dorsoventral axes. Wnt signaling is also involved in the axis formation of specific body parts and organ systems that are a part of later development, for example, dorsal-ventral formation of the central nervous system through its involvement in axon guidance, spinal cord and its anterior-posterior direction, etc.

Wnt signaling induces differentiation of pluripotent stem cells into mesoderm and endoderm progenitor cells. Wnt signaling can also induce blood formation from stem cells, neural differentiation, germ cell determination, gut tissue specification, hair follicle development, lung tissue development, trunk neural crest cell differentiation, nephron development, ovary development, and sex determination.

Increased levels of -catenin can initiate transcriptional activation of proteins such as cyclin D1 and c-myc, which control the G1 to S phase transition in the cell cycle. Entry into the S phase causes DNA replication and ultimately mitosis, which are responsible for cell proliferation and cell migration process.

Activity of the canonical Wnt pathway is involved in the development of cancers. Increased -catenin expression is strongly correlated with poor prognosis in breast cancer patients. This accumulation may be due to several factors such as mutations in -catenin, deficiencies in the -catenin destruction complex, overexpression of Wnt ligands, loss of inhibitors, and/or decreased activity of regulatory pathways.

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