Page 101 - 85 cell signalling pathways

Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 101

Module 2: Figure JAK and STAT structure

0 200 400 600 800 1000 1200

JH7 JH6 JH5 JH4 JH3 JH2 JH1
JAKs Pseudokinase Kinase
domain domain
Receptor
binding region

STATs

2 & 6 SH3 SH2
Y

1,3,4 SH3 SH2 TAD
5A & 5B
STAT DNA Y S
dimerization binding
domain domain

Domain structure of the JAKs and STATs.
There are four mammalian Janus kinases (JAKs): JAK1, JAK2, JAK3 and Tyk2. They all have a similar domain structure, which has seven JAK
homology (JH) domains. JH1 is the kinase domain, whereas JH2 is a pseudokinase domain. Some of the other JH regions seem to contribute to
the binding of JAKs to various cell-surface receptors, where they function to activate the signal transducers and activators of transcription (STATs).
There are seven mammalian STAT genes. STATs 2 and 6 have 850 amino acids, whereas the others are somewhat shorter. The tyrosine residue
near residue 700 is phosphorylated during the activation domain and functions as a binding site for the Src homology 2 (SH2) sites on other STATs
during the dimerization process (Module 2: Figure JAK/STAT function). The DNA-binding domain is located between the SH3 (Src homology 3) and
SH2 domains. The C-terminus has a transcriptional activation domain (TAD), which, on the shorter-length STATs, contains a serine residue that can
modulate transcriptional activity when phosphorylated.

Signal transducer and activator of transcription 4. Once the STATs have docked, they are then phos-
(STAT) activation cascade phorylated by the JAKs on the tyrosine residue located
The signal transducers and activators of transcription in the C-terminal region (Module 2: Figure JAK and
(STATs) are a family of latent cytoplasmic receptors that STAT structure).
are activated by a phosphorylation cascade that can be 5. The phosphorylated STATs, which are dimerized
induced by many different receptors (e.g. cytokine recept- through an intermolecular SH2--phosphotyrosine in-
ors, tyrosine kinase-linked receptors, non-receptor tyr- teraction, leave the receptor.
osine kinases and G protein-linked receptors). The versat- 6. These dimers are imported into the nucleus using
ility of this signalling mechanism is greatly enhanced by importin-α (Imp-α) and attach to promoter regions
the way the Janus kinases (JAKs) and STATs can be mixed through their DNA-binding domains (Module 2: Fig-
and matched to generate an enormous number of com- ure STAT1/DNA complex).
binations as illustrated by the different cytokine receptors 7. STATs activate the transcription of a number of target
(Module 2: Figure JAK/STAT heterogeneity). genes. One group of these genes code for the suppressor
A typical activation cascade for cytokine receptors, of cytokine signalling proteins (SOCS), which thus
which illustrates the essential role of the JAKs in a se- function as part of a negative-feedback loop to limit
quence of tyrosine phosphorylations that culminates in the the action of the signalling pathway (Module 2: Figure
phosphorylation and activation of the STATs, is outlined JAK/STAT function).
in the following sequence (Module 2: Figure JAK/STAT 8. STAT activity is terminated by a nuclear protein tyr-
function): osine phosphatase (N-PTP) that removes the tyrosyl
phosphate groups. The inactive STAT is then exported
1. Agonists induce dimerization by binding to the extra-
cellular domains of the receptor subunits. from the nucleus by chromosome region maintenance
2. The JAKs, which are associated with the cytoplasmic 1 (CRM1), thus completing the cycle.
domain of these receptors, phosphorylate each other.
3. The activated JAKs then phosphorylate tyrosine For some of the other receptors, these tyrosine phos-
residues on the receptors to provide docking sites for phorylations are carried out by kinases other than the
the Src homology 2 (SH2) domains on the STATs. JAKs. After the STATs are phosphorylated, they leave

C 2012 Portland Press Limited www.cellsignallingbiology.org