Untitled Deck Flashcards
What is Wnt?
Wnt ligands are proteins secreted by nearly all cell types and play a critical role in proliferation and development. They are cysteine-rich glycoproteins that usually function as dimers. The name Wnt comes from wingless in Drosophila and its murine homolog, Int-1.
What is Wnt-1?
Wnt-1 is a proto-oncogene, and mutations in Wnt can promote tumor development. Disruption or uncontrolled Wnt signaling is a hallmark of cancer.
How are Wnt ligands processed and secreted?
Wnt ligands are modified with palmitate by Porcupine (PORCN) in the ER. This palmitoylation is critical for Wnt binding to the cargo-receptor protein Wntless (Wls), which shuttles Wnt between the Golgi and the plasma membrane. Wnts are secreted associated with a lipoprotein particle or an exocytic vesicle.
Describe the canonical Wnt signaling pathway.
Wnt binds to Frizzled and LRP 5/6 co-receptors. Dishevelled is recruited. A complex of proteins including GSK3, Axin, and APC is formed. This releases 𝛽-catenin, which enters the nucleus. 𝛽-catenin binds to TCF protein, displacing the inhibitory factor Gro.
Describe the non-canonical Wnt signaling pathway.
Wnt binds directly to Frizzled, which recruits Dishevelled (Dvl). Signals via Rho family GTPases to affect cytoskeletal remodeling and transcription. Dvl activates PLC, generating PIP2 and involving Wnt in Ca2+-dependent signaling events.
What is the role of 𝛽-catenin?
𝛽-catenin links cadherins to the cytoskeleton, mediating cell-cell interactions and stabilizing the epithelial monolayer.
How is 𝛽-catenin regulated?
Under basal conditions, non-junctional 𝛽-catenin is phosphorylated by CK1 and GSK3 and bound to a complex of proteins (axin, APC), targeting it for ubiquitination and degradation by the proteasome.
What is Notch signaling?
A juxtacrine signaling pathway, critical in development and a driver in cancer, where the ligand on a sending cell binds to the receptor on a receiving cell.
What are the ligands for Notch receptors?
The ligands for Notch receptors are Delta and Jagged.
How does Notch signaling initiate gene expression?
Ligand binding triggers the cleavage of the Notch receptor by ADAM metalloprotease and 𝛾-secretase, releasing the Notch intracellular domain (NICD). NICD translocates to the nucleus and interacts with CSL, displacing co-repressors and recruiting co-activators like MAML. This acts as a transcriptional switch, initiating gene expression.
What is the Hedgehog signaling pathway?
An ancient, highly conserved signaling pathway discovered in Drosophila that is critical for normal development, tissue homeostasis, and tissue repair.
What are the key components of the Hedgehog signaling pathway?
Ligand: Hedgehog (Hh) in Drosophila, Sonic (Shh), Indian (Ihh), and Desert (Dhh) in mammals. Receptor: Patched (Ptch). Signal Transducer: Smoothened (Smo). Transcription Factors: Cubitus interruptus (Ci) in Drosophila, Gli1, Gli2, Gli3 in mammals.
Describe Hedgehog ligand processing and secretion.
The Hh-C region acts as an intramolecular cholesterol transferase, cleaving full-length Hh and attaching cholesterol to the Hh-N terminus. The acyltransferase Skinny hedgehog (Ski) palmitoylates Hh, which is essential for its activity. Lipid modifications make Hh hydrophobic. Disp is required for the spread of Hh from producing cells.
Explain the role of Patched (Ptch) and Smoothened (Smo).
In the absence of Hh, Ptch inhibits Smo by preventing its accumulation on the cell surface. Hh binding to Ptch relieves this inhibition, allowing Smo to accumulate and activate the pathway.
What is the role of primary cilia in Hedgehog signaling?
Primary cilia are essential for Hh signal transduction. Hh binds to Ptch in the cilia membrane, inducing Ptch exit and Smo accumulation in the cilium. Cilia are crucial for the proteolytic processing and activation of Gli transcription factors.
How do Gli transcription factors regulate Hedgehog signaling?
Gli proteins exist in full-length (GliFL) and repressor (GliR) forms. Without Hh, GliFL is phosphorylated and degraded, while Gli3FL is processed into Gli3R, repressing the pathway. With Hh, Gli3FL processing is inhibited, and Gli2FL activates transcription of Hh target genes (e.g., Gli1 and Ptch).
How is the Hedgehog signaling pathway implicated in cancer?
Uncontrolled activation of the Hh pathway is a common cause of cancer. Mutations in pathway components, such as Ptch and Smo, can lead to constitutive activation and tumor development. Hh signaling can drive cancer progression by regulating cell proliferation, malignancy, metastasis, and cancer stem cell expansion.
What are the types of Hh pathway-related cancers?
Type I: Ligand-independent: Constitutively activated pathway due to mutations in SMO or PTCH1 (e.g., rhabdomyosarcoma). Type II: Ligand-dependent (autocrine/juxtacrine): Tumor cells produce Hh ligands that activate the pathway in an autocrine or juxtacrine manner (e.g., pancreatic, colon, breast cancers). Type III: Ligand-dependent (paracrine): Cancer cells release Hh ligands that activate the pathway in stromal cells, which in turn secrete growth factors that promote tumor growth (e.g., prostate, pancreas, colon cancers).
What are some examples of cancers caused by Hh pathway activation?
Basal cell carcinoma, medulloblastoma, rhabdomyosarcoma, and various other tumor types (e.g., colorectal, prostate, liver, breast, ovarian, gastric, melanoma, pancreatic).
What are some treatment strategies for Hedgehog-driven tumors?
Smo antagonists (e.g., vismodegib, sonidegib), Gli inhibitors, atypical protein kinase C (aPKC) inhibitors, phosphodiesterase inhibitors. Understanding the specific genetic defects driving Hh pathway activation in patients is crucial for effective treatment.
