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Cytokine signalling pathways

JAK/STAT signalling pathway is one of the major mechanisms by which cytokine receptors transduce intracellular signals.

Binding of cytokines to their receptor induces receptor dimerization and association with specific JAK family members. Activated JAKs cause tyrosine phosphorylation, dimerization and translocation of STATs to the nucleus.

Four mammalian Jaks have been indentified (Jak1, Jak2, Jak3 and Tyk2) and seven STAT factors have been characterized (Stat1, Stat2, Stat3, Stat4, Stat5a, Stat5b and Stat6) [1].

The JAK/STAT signalling pathway is relatively promiscuous since multiple cytokine receptors use common JAKs to phosphorylate specific STATs and multiple cytokines can signal via a common STAT.

Negative regulators of cytokine signalling pathways have been identified. A SH2-containing protein called SOCS JAB SSI has been identified. There are eight members of the SOCS family, SOCS1 through SOCS7 and CIS, which control signalling through cytokine receptors and through other receptor tyrosine kinases (for instance the IGF-1 pathway.

SOCS1 mRNA levels, very low in unstimulated bone marrow and liver cells, rapidly increased in response to stimulation with various cytokines including IL-6, IFNγ and LIF. SOCS proteins inhibit signalling through cytokine receptors by interacting directly with JAKs to interfere with their catalytic activity while CIS inhibits cytokine signalling by docking at the receptor to block STAT binding.

[1] Diehl, S. et al. (2000) Immunity 13, 805-815