Literature References | 1. IHLE, J.N.
Cytokine receptor signalling.
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2. LEONARD, W.J. AND O'SHEA, J.J.
JAKS AND STATS: Biological Implications.
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3. IMADA K. AND LEONARD, W.J.
The Jak-STAT pathway.
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4. HARPUR, A.G, ANDRES, A.C., ZIEMIECKI, A., ASTON, R.R. AND WILKS, A.F.
JAK2, a third member of the JAK family of protein tyrosine kinases.
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5. WILKS, A.F., HARPUR, A.G., KURBAN, R.R., RALPH, S.J., ZURCHER, G. AND
ZIEMIEKI, A.
Two novel protein-tyrosine kinases, each with a second phosphotransferase-
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D'ANDREA, A.D. AND DEAROLF, C.R.
Mutation in the Jak kinase JH2 domain hyperactivates Drosophila and
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Documentation | Janus kinases (JAKs) are tyrosine kinases that function in membrane-proximal
signalling events initiated by a variety of extracellular factors binding to
cell surface receptors. Many type I and II cytokine receptors lack a protein
tyrosine kinase domain and rely on JAKs to initiate the cytoplasmic signal
transduction cascade [1,2]. Ligand binding induces oligomerisation of the
receptors, which then activates the cytoplasmic receptor-associated JAKs.
These subsequently phosphorylate tyrosine residues along the receptor chains
with which they are associated. The phosphotyrosine residues are a target
for a variety of SH2 domain-containing transducer proteins. Amongst these
are the signal transducers and activators of transcription (STAT) proteins,
which, after binding to the receptor chains, are phosphorylated by the JAK
proteins. Phosphorylation enables the STAT proteins to dimerise and
translocate into the nucleus, where they alter the expression of cytokine-
regulated genes. This system is known as the JAK-STAT pathway [3]
Four mammalian JAK family members have been identified: JAK1, JAK2, JAK3,
and TYK2. They are relatively large kinases of approximately 1150 amino
acids, with molecular weights of ~120-130kDa. Their amino acid sequences
are characterised by the presence of 7 highly conserved domains, termed
JAK homology (JH) domains [4]. The C-terminal domain (JH1) is responsible
for the tyrosine kinase function. The next domain in the sequence (JH2) is
known as the tyrosine kinase-like domain, as its sequence shows high
similarity to functional kinases but does not possess any catalytic
activity [5]. Although the function of this domain is not well established,
there is some evidence for a regulatory role on the JH1 domain, thus
modulating catalytic activity [6]. The N-terminal portion of the JAKs
(spanning JH7 to JH3) is important for receptor association and
non-catalytic activity [7].
JAK1 was initially cloned using a PCR-based strategy utilising degenerate
primers corresponding to conserved motifs within the catalytic domain of
protein-tyrosine kinases [5]. In common with JAK2 and TYK2, and by contrast
with JAK3, JAK1 appears to be ubiquitously expressed [2].
JANUSKINASE1 is a 4-element fingerprint that provides a signature for the
janus kinase 1 (JAK1) proteins. The fingerprint was derived from an initial
alignment of 3 sequences: the motifs were drawn from conserved regions
spanning virtually the full alignment length, focusing on those sections
that characterise JAK1 but distinguish it from other family members - motif
1 lies in the JH6 domain; motif 2 resides between the JH4 and JH3 domains;
motif 3 lies partially between the JH4 and JH3 domains and partially within
the JH4 domain; and motif 4 resides within the JH2 tyrosine kinase-like
domain. Three iterations on SPTR40_20f were required to reach convergence,
at which point a true set comprising 7 sequences was identified.
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