The Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway is a pathway used to transduce a multitude of signals for development and homeostasis in animals, from humans to flies, and in mammals it is the principal signaling mechanism for a wide array of cytokines and growth factors.
First discovered in ‘90s this kinases, along with other member of the tyrosine kinase family resulted in the usage of the acronym JAK (Just Another Kinase). Subsequent sequencing studies revealed that the JAK family of protein tyrosine kinases differs markedly from other classes for the presence of an additional kinase domain. To denote this unique structural feature, these kinases were renamed as “Janus kinases” (JAK) in reference to an ancient two-faced Roman God of gates and doorways.
Janus kinases are believed to be present in unstimulated cells in an inactive form, ligand-induced receptor oligomerization serves as a trigger to signal the recruitment of JAKs to close proximity of the receptors. A number of studies showed that the family of JAK kinases is involved in signaling by numerous interleukins as shown in the table below. In summary it appears that specific JAK kinases, either alone or in combination with other JAKs, may be preferentially activated depending on the type of the receptor that is being activated and subsequentially different STATs are going to be activated.
The JAK/STAT cascade provides a direct mechanism to translate an extracellular signal into a transcriptional response, it is known to stimulate
- cell proliferation,
- differentiation,
- cell migration,
- apoptosis
A road map for those who don’t know JAK-STAT, 2002
Signaling through the JAK/STAT pathway, recent advances and future challenges.
Cytokine signaling in 2002: new surprises in the Jak/Stat pathway.
Janus kinases: components of multiple signaling pathways.
The JAK/STAT signaling pathway.
IL-6 dependent pathway
1 (see image) – A variety of ligands and their receptors stimulate the
JAK/STAT pathway, its intracellular activation occurs when ligand binding induces the multimerization of receptor subunits, that can be bound as homodimers or heteromultimers. The activation of the
JAK family (for mammals:
JAK1, JAK2, JAK 3 and Tyk2) occurs upon ligand-mediated receptor multimerization, when two
JAKs are brought into close proximity and trans-phosphorylation is allowed. Once activated
JAKs can phosphorylate additional targets, including both the receptors and their major substrates, the
STATs.
2 – STATs (Signal Transducers and Activator of Transcription proteins) are latent transcription factors that until inactivated reside in the cytoplasm. The seven mammalian STATs bear a conserved tyrosine residue near the C-terminus that is phosphorylated by JAKs. This phosphotyrosine permits the dimerization of STATs through interaction with a conserved SH2 domain. Phosphorylated and dimerized STATs enter the nucleus where can bind specific regulatory sequences to activate or repress transcription of target genes.
2b – In addition to these principal components of the pathway, other effector proteins have been identified that contribute to at least a subset of JAK/STAT signaling events.
STAMs also known as signal-transducing adapter molecules (STAM1 and STAM2A) are adapter molecules with conserved VHS and SH3 domains that can be phosphorylated by JAK1-JAK3 and facilitate the transcriptional activation of specific target genes.
StIP (stat-interacting protein), a WD40 protein, can associate with both JAKs and unphosphorylated STATs, perhaps serving as a scaffold to facilitate the phosphorylation of STATs by JAKs.
SH2B/Lnk/APS family, these proteins contain both pleckstrin homology and SH2 domains and are also substrates for JAK phosphorylation.
3 – In addition to the effectors, there are three major classes of negative regulators:
Tyrosine phosphatases : the simplest way to reverse the activity of the JAKs. The best characterized of these is SHP-1, it contains two SH2 domains and can bind to either phosphorylated JAKs or phosphorylated receptors to facilitate dephosphorylation of these activated signaling molecules.
SOCS proteins are a family of at least eight members containing an SH2 domain and a SOCS box at the C-terminus. In addition, a small kinase inhibitory region located N-terminal to the SH2 domain has been identified for SOCS1 and SOCS3. The SOCS are responsible of a complete negative feedback loop in the JAK/STAT circuitry: activated STATs stimulate transcription of the SOCS genes and the resulting SOCS proteins bind phosphorylated JAKs and their receptors to turn off the pathway. The SOCS can affect their negative regulation by three means: by binding phosphotyrosines on the receptors (SOCS physically block the recruitment of signal transducers to the receptor), by bindind directly to JAKs or to the receptors to specifically inhibit JAK kinase activity, by the interaction with the elongin BC complex and cullin 2 (so facilitating the ubiquitination of JAKs and receptors, targeting them for proteasomal degradation).
PIAS proteins: PIAS1, PIAS3, PIASx and PIASy. These proteins have a Zn-binding RING-finger domain in the central portion, a well-conserved SAP (SAF-A/Acinus/PIAS) domain at the N-terminus, and a less-well-conserved carboxyl domain. The latter domains are involved in target protein binding. The PIAS proteins bind to activated STAT dimers and prevent them from binding DNA. The mechanism by which PIAS proteins act remains unclear. Although there is evidence that STATs can be modified by sumoylation, the function of that modification in negative regulation is not yet known.
4 – Infact, in addition to the activation of STATs, JAKs can mediate the recruitment of other molecules involved in signal transduction such as the src-family kinases, protein tyrosine phosphatises, MAP kinases, PI3K kinase etc. These molecules process downstream signals via the Ras-Raf-MAP kinase and PI3 kinase pathway which results in the activation of additional transcription factors. The combined action of STATs and the other transcription factors activated by these pathway dictate the phenotype produced by a given cytokine/interferon stimulation.
Furthermore, the functions of activated
STATs can be altered through association with other transcription factors and cofactors that are regulated by other signaling pathways. Thus the integration of input from many signaling pathways must be considered if we are to understand the biological consequences of cytokine stimulation.
Suppressors of cytokine signalling (SOCS) in the immune system.
Negative regulation of cytokine signaling.
