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. 2022 Jan 3;8:792546. doi: 10.3389/fmolb.2021.792546

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Copyright © 2022 La Manna, De Benedictis and Marasco.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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Endogenous activation of the JAK-STAT pathway and its regulation through natural inhibitors. PIASs act mainly by suppressing STAT-regulated gene expression and inhibiting STAT binding to DNA. Hyperactivation of the JAK-STAT pathway also activates its own negative feedback regulators: SOCS proteins. SOCS1 and SOCS3 inhibit signaling by different mechanisms: SOCS1 forms a binary complex with JAKs (phosphorylated or unphosphorylated) and inhibits their catalytic activity; SOCS3 inhibits JAK activity through the formation of a ternary complex, binding simultaneously to the cytokine receptor and JAKs. Cavin-1 and CUEDC2 inhibit the JAK-STAT pathway by interacting with SOCS1,3 via an SH2 domain PEST sequence.