Biomedical Engineering Reference
In-Depth Information
Janus kinases (JAKs) represent a recently discovered family of PTKs that seem to play a central
role in mediating signal transduction of many cytokines, and probably many non-cytokine regu-
latory molecules. These enzymes harbour two potential active sites and were thus named after
Janus, a Roman god with two faces. It is likely that only one of those 'active' sites is functional.
Four members of the JAK family have been best characterized to date: JAK1, JAK2, JAK3 and
TYK2. They all exhibit molecular masses in the region of 130 kDa and approximately 40 per
cent amino acid sequence homology. They appear to be associated with the cytoplasmic domain
of many cytokine receptors, but remain catalytically inactive until binding of the cytokine to the
receptor (Figure 8.2).
In most instances ligand binding appears to promote receptor dimerization, bringing their asso-
ciated JAKs into close proximity (Figure 8.2). The JAKs then phosphorylate (and hence activate)
each other (transphosphorylation). The activated kinases subsequently phosphorylate specifi c
tyrosine residues on the receptor itself. This promotes direct association between one or more
members of a family of cytoplasmic proteins (signal transducers and activators of transcription
(STATs)) and the receptor. Once docked at the receptor surface, the STATs are in turn phospho-
rylated (and hence activated) by the JAKs (Figure 8.2). As described below, activated STATs
then translocate to the nucleus, and directly regulate expression of interferon and other cytokine-
sensitive genes.
As the term STAT suggests, these proteins (a) form an integral part of cytoplasmic signal trans-
duction initiated by certain regulatory molecules and (b) activate transcription of specifi c genes in
the nucleus. Thus far, at least six distinct mammalian STATs (STAT1-STAT6) have been identifi ed
which range in size from 84 to 113 kDa. Some may be differentially spliced, increasing the number
of functional proteins in the family, e.g. STAT1 exists in two forms; STAT1
contains 750 amino
acid residues and exhibits a molecular mass of 91 kDa (it is sometimes called STAT91). STAT1β is
a splicing variant of the same gene product. It lacks the last 38 amino acid residues at the C-termi-
nal of the protein and exhibits a molecular mass of 84 kDa (hence, it is sometimes called STAT84).
Similar variants have been identifi ed for STAT3 and STAT5. STATs have also been located in
non-mammalian species such as the fruit fl y. All STATs exhibit signifi cant sequence homology
and are composed of a number of functional domains (Figure 8.3). The SH2 domain functions to
bind phosphotyrosine, thus docking the STAT at the activated receptor surface. As detailed below,
this domain is also required for STAT interaction with JAKs (which then phosphorylate the STAT)
and to promote subsequent dimerization of the STATs. An essential tyrosine is located towards the
STAT C-terminus (around residue 700), which in turn is then phosphorylated by PTK.
STATs are differentially distributed in various cells/tissues. STATs 1, 2 and 3 seem to be present
in most cell types, all be it at varying concentrations. Tissue distribution of STATs 4 and 5 is more
limited.
Not surprisingly different ligands activate different members of the STAT family (Table 8.6).
Some, such as STATs 1 and 3, are activated by many ligands, whereas others respond to far fewer
ligands, e.g. STAT2 appears to be activated only by type I interferons.
STAT phosphorylation ensures its binding to the receptor, with subsequent disengagement from
the receptor in dimeric form. STAT dimerization is believed to involve intermolecular associa-
tions between the SH2 domain of one STAT and phosphotyrosine of its partner. Dimerization ap-
pears to be an essential prerequisite for DNA binding. Dimers may consist of two identical STATs,
but STAT1-STAT2 and STAT1-STAT3 heterodimers are also frequently formed in response to
certain cytokines. The STAT dimers then translocate to the nucleus where they bind to specifi c
α
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