| Literature References | 1. IHLE, J.N.
Cytokine receptor signalling.
NATURE 377 591-594 (1995).
2. LEONARD, W.J. AND O'SHEA, J.J.
JAKS AND STATS: Biological Implications.
ANNU.REV.IMMUNOL. 16 293-322 (1998).
3. IMADA K. AND LEONARD, W.J.
The Jak-STAT pathway.
MOL.IMMUNOL. 37 1-11 (2000).
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.
ONCOGENE 7 1347-1353 (1992).
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-
related catalytic domain, define a new class of protein kinase.
MOL.CELL BIOL. 11 2057-2065 (1991).
6. LUO, H., ROSE, P., BARBER, D., HANRATTY, W.P., LEE, S., ROBERTS, T.M.
D'ANDREA, A.D. AND DEAROLF, C.R.
Mutation in the Jak kinase JH2 domain hyperactivates Drosophila and
mammalian Jak-Stat pathways.
MOL.CELL BIOL. 17 1562-1571 (1997).
7. FRANK, S.J., GILLILAND, G., KRAFT, A.S. AND ARNOLD, C.S.
Interaction of the growth hormone receptor cytoplasmic domain with the JAK2
tyrosine kinase.
ENDOCRINOLOGY 135 2228-2239 (1994).
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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].
JANUSKINASE is a 3-element fingerprint that provides a signature for the
janus kinase family. The fingerprint was derived from an initial alignment
of 10 sequences: the motifs were drawn from conserved regions spanning the
C-terminal two thirds of the alignment - motif 1 lies in the JH4 domain;
motif 2 resides in the JH2 domain; and motif 3 lies in the JH1 domain. Two
iterations on SPTR40_20f were required to reach convergence, at which point
a true set comprising 27 sequences was identified. A single partial match
was also found, Q9TTJ0, a porcine kinase-defective JAK2 splice variant that
fails to match motif 3.
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