Biomedical Engineering Reference
In-Depth Information
Table 8.6 Ligands which, upon binding to their cell
surface receptors, are known to promote activation
of one or more STATs. (The STATs activated are also
shown.) This list, though representative, is not
exhaustive
Ligand
STAT activated
IFN-α
1, 2, 3
IFN-γ
1
IL-2
1, 3, 5
IL-3
5
IL-6
1, 3
GM-CSF
5
EGF
1, 3
GH
1, 3, 5
DNA sequences. (STAT2-dependent signalling represents a partial exception. This STAT forms
a complex with STAT1 and a non-STAT cytoplasmic protein (p48), and this complex translocates
to the nucleus. Binding of this complex to the DNA is believed not to involve STAT2 directly.)
STATs bind specifi c sequences of DNA that approach symmetry, or are palindromic (often TTCC
X GGAA, where X can be different bases). These sequences are normally present in upstream
regulatory regions of specifi c genes. Binding of the STAT complex enhances transcription of these
genes, and the gene products mediate the observed cellular response to cytokine binding.
A number of proteins that inhibit the JAK-STAT function have also been identifi ed. These in-
clude members of the so-called SOCS/Jab/Cis family and the PIAS family of regulatory proteins.
Several appear to function by inhibiting the activation of various STATs, although the mechanisms
by which this is achieved remain to be elucidated in detail. The JAK- STAT pathway likely does not
function in isolation within the cell. JAKs are believed to activate elements of additional signalling
pathways, and STATs are also likely activated by factors other than JAKs. As such, there may be
considerable crosstalk between various JAK- and/or STAT-dependent signalling pathways.
8.2.7 The interferon JAK-STAT pathway
Binding of type I interferons to the IFN-
(type I) receptor results in the phosphorylation and,
hence, activation of two members of the JAK family: Tyk2 and JAK1. These kinases then phos-
phorylate STAT1
α
/
β
(STAT84) and STAT2 (STAT113). The three
activated STATs disengage from the receptor and bind to the cytoplasmic protein p48. This entire
complex translocates to the nucleus, where it interacts directly with upstream regulatory regions of
interferon-sensitive genes. These nucleotide sequences are termed ISREs. This induces/augments
expression of specifi c genes, as discussed later.
The essential elements of the signal transduction pathway elicited by IFN-
α
(also called STAT91), STAT1
β
γ
are even more
straightforward. IFN-
binding to the type II receptor induces receptor dimerization with con-
sequent activation of JAK1 and JAK2. The JAKs phosphorylate the receptor and subsequently
the associated STAT1
γ
α
. STAT1
α
is then released and forms a homodimer that translocates to the
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