Here are some background JAKs/STATs abstracts:
Science 264: 1415-21 (1994)[94255764]
Jak-STAT pathways and transcriptional activation in
response to IFNs and other extracellular signaling
proteins.
J. E. Darnell, I. M. Kerr & G. R. Stark
Laboratory of Molecular Cell Biology, Rockefeller University,
New York, NY 10021.
Through the study of transcriptional activation in response to
interferon alpha (IFN-alpha) and
interferon gamma (IFN-gamma), a previously unrecognized direct
signal transduction pathway to the
nucleus has been uncovered: IFN-receptor interaction at the cell
surface leads to the activation of
kinases of the Jak family that then phosphorylate substrate
proteins called STATs (signal transducers
and activators of transcription). The phosphorylated STAT
proteins move to the nucleus, bind
specific DNA elements, and direct transcription. Recognition of
the molecules involved in the
IFN-alpha and IFN-gamma pathway has led to discoveries that a
number of STAT family members
exist and that other polypeptide ligands also use the Jak-STAT
molecules in signal transduction.
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Nature 377: 591-594 (1995)[96026298]
Cytokine receptor signalling.
J. N. Ihle
Department of Biochemistry, St. Jude Children's Research
Hospital, Memphis, Tennessee
38101-0318, USA.
Many cell functions are regulated by members of the cytokine
receptor superfamily. Signalling by
these receptors depends upon their association with Janus
kinases (JAKs), which couple ligand
binding to tyrosine phosphorylation of signalling proteins
recruited to the receptor complex. Among
these are the signal transducers and activators of transcription
(STATs), a family of transcription
factors that contribute to the diversity of cytokine responses.
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Nucleic Acids Res 23: 459-463 (1995)[95192056]
The genomic structure of the STAT genes: multiple exons
in coincident sites in Stat1 and Stat2.
R. Yan, S. Qureshi, Z. Zhong, Z. Wen & J. E. Darnell
Laboratory of Molecular Cell Biology, Rockefeller University,
New York, NY 10021.
The genomic structure of Stat2 has been determined and compared
with a large portion of the Stat1
gene. There are 24 exons in the Stat2 gene and a matching number
in very similar positions in the
Stat1 gene. Thus a very complicated genomic structure was
presumably duplicated and has been
closely maintained throughout evolution.
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STAT proteins have the dual function of signal transduction and
activation of transcription (Darnell et
al., 1994). These proteins are activated by phosphorylation on
tyrosine in response to different
ligands after which they form homodimers or heterodimers that
translocate to the cell nucleus where
they either directly bind to DNA or act together with other
DNA-binding proteins in multiprotein
transcription complexes to direct transcription. The first of
these proteins to be described, which
they termed STAT1 (for signal transduction and activator of
transcription-1), is activated by a
number of different ligands, including interferon-alpha
(147660), interferon-gamma (147570), EGF
(131530), PDGF (see 173430), and IL6 (147620). The same tyrosine
residue is activated at least
by IFN-alpha, IFN-gamma, and EGF. STAT2 (600556), in contrast,
is activated by IFN-alpha but
not by IFN-gamma or any of the other ligands mentioned above.
STAT3 is known to be activated
by IGF, IL6, LIF, and perhaps other ligands but is not activated
by IFN-gamma. STAT4 (600558)
is present in high concentration in the testis but has not been
found in a phosphorylated form in cells.
The STAT proteins differ in the DNA sites to which they bind.
STAT1 homodimer binds to a site
termed GAS, first defined as required for IFN-gamma induction.
Variations on this site are also used
in response to IL6, PDGF, and other ligands. The multiprotein
complex ISGF3 (147574), which is
composed of STAT1, STAT2, and p48, binds to a 15-bp element,
designated the ISRE
(interferon-stimulated response element), that is different from
the GAS element. Yan et al. (1995)
reported the complete genomic sequence and characterization of
the promoter region and exonic
structure of the human STAT2 gene. It contains 24 exons and has
an imperfect ISRE and no
demonstrably active GAS sites, consistent with its weak
transcriptional induction by IFN-alpha and
IFN-gamma. In comparison with the STAT1 protein, they found that
there is considerable
conservation throughout a 700-amino acid coding region and the
genomic structure has been largely
conserved.
Copeland et al. (1995) reported that 7 mouse Stat loci mapped in
3 clusters, with each cluster
located on a different mouse autosome, numbers 1, 10, and 11.
They interpreted the data as
indicating that the family had arisen via a tandem duplication
of the ancestral locus, followed by
dispersion of the linked loci to different mouse chromosomes.
Ihle (1995) reviewed the Janus kinases (JAKs; e.g., 147795)
which couple ligand binding to
tyrosine phosphorylation of signalling proteins recruited by
cytokine receptor complexes. The
STATs belong to this class of signal transduction proteins. Ihle
(1996) reviewed the STATs
specifically.
Meraz et al. (1996) reported the generation and characterization
of mice deficient in STAT1.
STAT1-deficient mice showed no overt development abnormalities
but displayed a complete lack of
responsiveness to either interferon-alpha or interferon-gamma
and were highly sensitive to infection
by microbial pathogens and viruses. In contrast, these mice
responded normally to several other
cytokines that activate STAT1 in vitro. These observations
documented that STAT1 plays an
obligate and dedicated role in mediating IFN-dependent biologic
responses and revealed an
unexpected level of physiologic specificity for STAT1 action.
Durbin et al. (1996) likewise found that although the STAT1
transcription factor is activated in
response to many cytokines and growth factors, disruption of the
Stat1 gene in embryonic stem (ES)
cells and in mice when homozygous resulted in unresponsiveness
to interferon but retained
responsiveness to leukemia inhibitory factor (159540) and
remained LIF-dependent for
undifferentiated growth. The homozygous animals were born at
normal frequencies and displayed no
gross developmental defects; however, these animals failed to
thrive and were extremely susceptible
to viral disease. Cells and tissues from the homozygous
deficient mice were unresponsive to IFN,
but remained responsive to all other cytokines tested.
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The Stat5 (Stat5a) was recently cloned from mouse mammary
tissue and hence is also known as
mamary gland factor (MGF). This protein shows a 96% homology to
the Stat5b (Liu et al, 1995)
Stat5a is comprised of 793 amino acids and is encoded by a
mRNA of 4.2 kb (Liu et al, 1995)
The expression of Stat5 is higher in breast carcinoma as
compared to normal breast tissue
(Watson et al, 1995)
Stat5 gets activated by:
IL-2 (Fujii et al, 1995, Johnston et al, 1995, Wakao et al,
1995)
IL-3 (Pallard et al, 1995)
IL-5 (Mui et al, 1995)
IL-15 (Johnston et al, 1995)
GM-CSF ( (Gouilleux et al, 1995, Mui et al, 1995)
Thrombopoientin (Bacon et al, 1995, Sattler et al, 1995,
Pallard et al, 1995a)
Erythropoietin (Pallard et al, 1995b, Wakao et al, 1995)
Prolactin (Gouilleux, 1994, Pallard et al, 1995b), growth
hormone (Gouilleux et al, 1995)
In T cells activated with HTLV-1 (Migone et al, 1995)
Stat5 gets tyrosine phosrphorylated by:
IL-2 (Johnston et al, 1995)
IL-15 (Johnston et al, 1995)
Thromobopoietin (Bacon et al, 1995)
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The protein-tyrosine kinases (PTKs) are a large family of
proteins, each of which bears a conserved
domain of 250 to 300 amino acids capable of phosphorylating
substrate proteins on tyrosine
residues. Wilks (1989) exploited the existence of 2 highly
conserved sequence elements within the
catalytic domain to generate PTK-specific degenerate
oligonucleotide primers. Wilks et al. (1991)
described the primary sequence of new PTKs identified by
application of PCR. One, called Janus
kinase 1 (JAK1), is a member of a new class of PTKs
characterized by the presence of a second
phosphotransferase-related domain immediately N-terminal to the
PTK domain--hence the name
Janus. The second phosphotransferase domain bore all the
hallmarks of a protein kinase, although its
structure differed significantly from that of the PTK and
threonine/serine kinase family members.
JAK1 is a large, widely expressed membrane-associated
phosphoprotein of approximately 130,000
Da. The PTK activity is located in the C-terminal PTK-like
domain; the role of the second
kinase-like domain was unknown. A second member of the family,
JAK2 (147796), was partially
characterized and exhibited a similar array of kinase-related
domains. By in situ hybridization and
Southern blot analysis of a panel of mouse/human hybrid cell
lines, Pritchard et al. (1992)
demonstrated that the JAK1 gene maps to 1p31.3. By in situ
hybridization, they mapped the JAK2
gene to 9p24. Howard et al. (1992) mapped JAK1 to chromosome 1
using somatic cell hybrids and
linkage studies based on the CEPH families. Modi et al. (1995)
used in situ hybridization to map
JAK1 to 1p32.3-p31.3; they referred to the gene as JAK1A.
By mutagenesis and selection for resistance to interferon,
Muller et al. (1993) produced a cell line
that lacks JAK1 and is completely defective in interferon
response. Complementation of this mutant
with JAK1 restored the response, establishing the requirement
for JAK1 in both the
interferon-alpha/beta and -gamma signal transduction pathways.
The reciprocal interdependence
between JAK1 and TYK2 (176941) activities in the
interferon-alpha pathway, and between JAK1
and JAK2 in the interferon-gamma pathway, may reflect a
requirement for these kinases in the
correct assembly of interferon receptor complexes.
Gough et al. (1995) mapped the murine homolog (Jak1) to mouse
chromosome 4 in a region of
homology of synteny to human 1p33-p31.
Ihle (1995) reviewed cytokine receptor signaling. Numerous
aspects of lymphoid and myeloid cell
function are controlled by a group of ligands termed cytokines,
all of which signal through a related
set of receptors. All such receptors are associated with one or
more members of the JAK family.
These kinases couple ligand binding to tyrosine phosphorylation
of various known signaling proteins
and of a unique family of transcription factors termed the
signal transducers and activators of
transcription, or STATs (e.g., 600555). The cytokine receptors
included those for IL-3 (308385;
138981) and IL-6 (147880).
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