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Negative Regulators of the Jak/STAT Pathway

Signaling through the Jak/STAT pathway is tightly controlled by a number of distinct mechanisms as dysregulation of Jak/STAT signaling is thought to underlie several disorders including rheumatologic and autoimmune disorders, transplant rejection, and several cancers. Key negative regulators of this pathway include Suppressors of Cytokine Signaling (SOCS), Protein Inhibitors of Activated STATs (PIASs), and protein tyrosine phosphatases (PTPs). The SOCS proteins are the primary regulators of the Jak/STAT pathway. They act as pseudo Jak substrates to inhibit Jak/STAT signaling. They also block STAT activation and target multiple components of the Jak/STAT pathway for Ubiquitin-mediated proteasomal degradation. PIAS proteins interact with activated STAT dimers and inhibit STAT-mediated transcription. These regulatory proteins also modulate the DNA-binding properties of STATs by facilitating SUMOylation of the dimers. Jak/STAT signaling is also regulated by numerous constitutively expressed PTPs that dephosphorylate important tyrosine residues on multiple components of the pathway, thereby attenuating Jak/STAT signaling.