negative regulation of receptor signaling pathway via JAK-STAT

Definition

Target type: biologicalprocess

Any process that stops, prevents, or reduces the frequency, rate or extent of a receptor signaling pathway via JAK-STAT. [GOC:bf]

Negative regulation of receptor signaling pathway via JAK-STAT is a crucial cellular process that dampens the intensity and duration of signaling triggered by receptor activation. This pathway is initiated by the binding of ligands, such as cytokines, growth factors, or hormones, to cell surface receptors. Ligand binding induces receptor dimerization and activation of associated Janus kinases (JAKs), a family of tyrosine kinases. Activated JAKs phosphorylate the receptor, creating docking sites for STAT proteins (Signal Transducers and Activators of Transcription). STAT proteins bind to the phosphorylated receptor and are themselves phosphorylated by JAKs. Phosphorylated STATs dimerize and translocate to the nucleus, where they bind to specific DNA sequences and regulate gene expression. Negative regulation of this pathway ensures that signaling is appropriately controlled and prevents excessive or prolonged activation. This regulation is accomplished through multiple mechanisms:

1. **Protein phosphatases:** These enzymes dephosphorylate JAKs and STATs, reversing their activation and leading to the termination of signaling.

2. **Suppressor of cytokine signaling (SOCS) proteins:** These proteins are induced by JAK-STAT signaling itself and act as negative feedback regulators. SOCS proteins bind to phosphorylated JAKs and inhibit their activity, blocking further phosphorylation of the receptor and STAT proteins. Some SOCS proteins can also target JAK-STAT components for proteasomal degradation.

3. **Protein inhibitors of activated STAT (PIAS) proteins:** These proteins bind to phosphorylated STATs and block their nuclear translocation and DNA binding, thereby inhibiting gene transcription.

4. **Ubiquitin ligases:** These enzymes attach ubiquitin tags to JAK-STAT components, marking them for degradation by proteasomes.

5. **MicroRNAs:** These small non-coding RNAs can target JAK-STAT mRNAs for degradation, reducing the levels of JAK-STAT proteins.

These regulatory mechanisms ensure that JAK-STAT signaling is tightly controlled and prevents uncontrolled cell growth, inflammation, and other pathologies. Dysregulation of JAK-STAT signaling is implicated in various diseases, including cancer, autoimmune disorders, and inflammatory diseases.'
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Proteins (3)

Compounds (34)