Frizzed receptors in development and disease.pptx

Frizzed receptors in development and disease - Dr.M.Jothimuniyandi- PowerPoint presentation - WNt signaling pathway - structure - functions - mechanisms- canonical - non canonical - development - diseases

1. Frizzed receptors in development and disease By Dr.M.Jothimuniyandi Assistant Professor

2. Frizzed receptors Frizzled (FZD) receptors are a family of G protein-coupled receptors (GPCRs) that play a critical role in the Wnt signaling pathway, which is essential for numerous developmental processes and has significant implications in various diseases.

3. Structure and Function Frizzled receptors are integral membrane proteins characterized by a cysteine-rich domain (CRD) at the extracellular N-terminus, which binds to Wnt ligands. The C-terminal intracellular domain interacts with Dishevelled (DVL) proteins, mediating downstream signalling pathways.

4. Structure and Function These receptors function primarily in the canonical Wnt /β-catenin pathway, where Wnt binding to FZD leads to the stabilization of β-catenin and its translocation to the nucleus, initiating gene transcription. Frizzled receptors also participate in non-canonical Wnt pathways, influencing cell polarity and movement without involving β-catenin.

5. Structure and Function of Frizzled receptors Ref:

6. Mechanisms Frizzled (FZD) receptors are key components of the Wnt signaling pathways, which are involved in various cellular processes during development and in disease states. The mechanisms by which FZD receptors mediate these processes can be broadly categorized into canonical (β-catenin-dependent) and non-canonical (β-catenin-independent) Wnt signaling pathways.

7. Canonical Wnt / β- Catenin Signaling Pathway Wnt Ligand Binding: The canonical pathway is initiated when a Wnt ligand binds to a Frizzled receptor and its co-receptor, low-density lipoprotein receptor-related protein 5/6 (LRP5/6), on the cell surface . Dishevelled Activation: Upon Wnt binding, the intracellular domain of FZD recruits and activates Dishevelled (DVL) proteins, which are key intracellular signaling mediators.

8. Canonical Wnt / β- Catenin Signaling Pathway Inhibition of the β- Catenin Destruction Complex: Activated DVL inhibits the β- catenin destruction complex, which includes Axin , GSK3 β ( glycogen synthase kinase 3 β), APC (adenomatous polyposis coli), and CK1 (casein kinase 1). This inhibition prevents β- catenin from being phosphorylated and targeted for degradation . β- Catenin Stabilization and Nuclear Translocation: Stabilized β- catenin accumulates in the cytoplasm and eventually translocates into the nucleus. Once in the nucleus, β- catenin interacts with TCF/LEF (T-cell factor/lymphoid enhancer-binding factor) transcription factors to activate the transcription of Wnt target genes, which are involved in cell proliferation, differentiation, and survival.

9. Non-Canonical Wnt Signaling Pathways Non-canonical Wnt signaling pathways are β-catenin-independent and can be further divided into the planar cell polarity (PCP) pathway and the Wnt /Ca²⁺ pathway. Planar Cell Polarity (PCP) Pathway: Wnt Ligand Binding: In the PCP pathway, Wnt ligands bind to Frizzled receptors and co-receptors such as ROR2 or Ryk .

10. Non-Canonical Wnt Signaling Pathways Activation of DVL and JNK: This binding activates DVL, which in turn activates downstream effectors such as small GTPases ( RhoA , Rac ) and the c-Jun N-terminal kinase (JNK) pathway. Cytoskeletal Rearrangements: Activation of these pathways leads to changes in the cytoskeleton, influencing cell shape, polarity, and migration. This is critical in processes such as gastrulation, neural tube closure, and oriented cell division

11. Non-Canonical Wnt Signaling Pathways Wnt /Ca²⁺ Pathway: Wnt Ligand Binding: In this pathway, Wnt ligands activate Frizzled receptors and possibly co-receptors like ROR2, leading to the release of intracellular calcium. Calcium Signaling : The increase in intracellular calcium activates calcium-sensitive signaling molecules such as calcineurin , protein kinase C (PKC), and CaMKII (calcium/ calmodulin -dependent protein kinase II ).

12. Non-Canonical Wnt Signaling Pathways Regulation of Gene Expression and Cell Behavior : These calcium-dependent pathways can influence gene expression, cell adhesion, and migration. This pathway is particularly important in processes like cardiac development and the regulation of inflammation.

13. Role in Development Frizzled receptors are crucial for embryonic development, including cell fate determination, tissue polarity, and organogenesis. During early development, FZD-mediated Wnt signaling guides the patterning of the body axis, neural development, and organ formation. The precise regulation of Wnt /FZD signaling is vital for normal development, as any disruption can lead to congenital anomalies.

14. Frizzled Receptors in Disease Dysregulation of Frizzled receptors and Wnt signaling is implicated in various diseases: Cancer: Aberrant Wnt /FZD signaling is associated with numerous cancers, including colorectal, breast, and lung cancer. Overactivation of the pathway often results in uncontrolled cell proliferation and resistance to apoptosis, contributing to tumor growth and metastasis . Neurodegenerative Diseases: Wnt signaling , mediated by FZD receptors , is important for maintaining adult neural stem cells and promoting neurogenesis. Dysregulation is linked to neurodegenerative diseases like Alzheimer’s disease, where impaired Wnt signaling is associated with neuronal loss and cognitive decline.

15. Frizzled Receptors in Disease Bone Diseases: Frizzled receptors play a role in bone formation and homeostasis. Abnormal FZD signaling can lead to bone-related disorders such as osteoporosis, where decreased Wnt signaling results in reduced bone density . Cardiovascular Diseases: The role of Frizzled receptors in heart development and repair is critical. Dysregulation can contribute to congenital heart defects, cardiac hypertrophy, and heart failure.

16. Therapeutic Potential Targeting Frizzled receptors offers potential therapeutic strategies for various diseases. Inhibitors or activators of FZD receptors are being explored to modulate Wnt signaling in cancer, regenerative medicine, and other conditions. For example, FZD antagonists might inhibit Wnt signaling in cancers where the pathway is overactive, while FZD agonists could enhance Wnt signaling in neurodegenerative diseases.

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