The Janus protein tyrosine kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway is one of the major mechanisms by wich 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 identifited (Jak1, Jak2, Jak3 and Tyk2) and seven STAT factors have been charaterized (Stat1, Stat2, Stat3, Stat4, Stat5, Stat5b and Stat6b). This signaling system is relatively promiscuous since multiple cytokine receptors use common JAKs to phosphorylate specific STATs and multiple cytokine can signal via a common STAT.
Negative regulators of cytokine signaling pathway have been identifited. An SH2-containing protein called suppressor of cytokine signaling (SOCS)/Jak binding protein (JAB)/Stat induced Stat inhibitor (SSI) has been identified. There are eight members of the SOCS family, SOCS1 through SOCS7 and cytokine inducible SH2-containing protein (CIS), which control signaling through cytokine receptors and also through other receptors tyrosine kinase such as the insulin-like growth factor-1 (IGF-1) pathway. SOCS1 mRNA levels are very low in unstimulated bone marrow and liver cells but are rapidly increased in response to stimulation with various cytokines including IL-6, IFNγ and leukemia inhibitory factor (LIF).
|Activation of Jaks by cytokines|
|Cytokines whose receptors share γc
IL-2, IL-4, IL-7, IL-9, IL-15
Jak1, Jak2, Tyk2
|Cytokines whose receptors share βc
IL-3, IL-5, GM-CSF
|Cytokines whose receptors share gp130
IL-6, IL-11, OSM, CNTF, LIF, CT-1
|Jak1, Jak2, Tyk2
|Cytokines whose receptors are homodimers
Growth hormone, Prolactin, EPO, TIPO
Although constitutive expression of SOC1 occurs in thymus and spleen, the modulation of SOCS1 expression in T cells is unclear. SOCS proteins inhibit signaling through cytokine receptors by interacting directly with JAKs to interfere with their catalytic activity while CIS inhibit cytokine signaling by docking at the receptor to block STAT binding .
|||Imada, K. and Leonard, W. J. Molecul. Immunol. 37, 1-11 (2000).|
|||Diehl,S. et al. Immunity 13, 805-815 (2000).|