regulation of smoothened signaling pathway

Definition

Target type: biologicalprocess

Any process that modulates the frequency, rate or extent of smoothened signaling. [GOC:go_curators]

The Smoothened (SMO) signaling pathway is a crucial component of the Hedgehog (Hh) signaling pathway, a highly conserved developmental pathway essential for proper embryonic development and tissue homeostasis in animals. The regulation of SMO signaling is a complex process involving multiple steps and key players. Here’s a detailed breakdown:

**1. Hh Ligand Binding and Receptor Activation:**

* **Hh Ligand Binding:** The pathway is initiated by the binding of Hh ligands (Sonic, Indian, and Desert Hedgehog) to the transmembrane receptor Patched (PTCH). In the absence of Hh ligands, PTCH acts as a repressor of SMO activity, preventing its activation.
* **PTCH Inhibition:** When Hh binds to PTCH, it inhibits the repressor activity of PTCH, allowing SMO to become active.

**2. SMO Activation and Translocation:**

* **SMO Activation:** The inhibition of PTCH releases SMO from its repressive state, leading to its activation. SMO, a G protein-coupled receptor (GPCR)-like protein, undergoes a conformational change upon activation, allowing it to interact with downstream signaling components.
* **SMO Translocation:** Activated SMO translocates from the primary cilium, where it is typically located, to the plasma membrane. This translocation is essential for SMO to interact with and activate its downstream signaling molecules.

**3. Activation of the Transcription Factor Gli:**

* **Gli Processing:** The downstream effector of SMO signaling is the Gli transcription factor. In the absence of Hh, Gli proteins are proteolytically processed, generating repressor forms that translocate to the nucleus and suppress Hh target gene transcription.
* **Gli Activation:** When SMO is activated, it blocks Gli processing and promotes the formation of full-length, activator forms of Gli. These activator forms translocate to the nucleus and bind to specific DNA sequences called Hedgehog Responsive Elements (HREs) in the promoters of target genes, activating their transcription.

**4. Regulation of SMO Activity:**

* **Negative Feedback Loop:** The Hh pathway is tightly regulated by negative feedback mechanisms to prevent excessive signaling. Gli proteins themselves can bind to HREs in the promoter regions of genes encoding negative regulators of the pathway, such as PTCH, suppressing their expression and further reducing Hh signaling.
* **Protein Degradation:** SMO activity is also regulated by protein degradation. Ubiquitin ligases, such as Smurf1 and Smurf2, can target SMO for degradation, reducing its levels and limiting signal transduction.

**5. Aberrant SMO Signaling and Disease:**

* **Cancer:** Deregulation of the Hh pathway, including persistent SMO activation, can contribute to various cancers, particularly those involving basal cell carcinoma and medulloblastoma.
* **Developmental Defects:** Aberrant Hh signaling during embryonic development can lead to various birth defects, such as holoprosencephaly (a severe malformation of the brain), polydactyly (extra fingers or toes), and cyclopia (fusion of the eyes).

In summary, the regulation of SMO signaling is a complex and tightly controlled process involving multiple players. It is crucial for proper embryonic development, tissue homeostasis, and the maintenance of normal cellular function. Dysregulation of this pathway can contribute to a range of developmental defects and diseases, highlighting the importance of understanding its mechanisms and identifying potential therapeutic targets.'
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Proteins (4)

Compounds (148)