Kinase janus

Four mammalian Janus kinase (JAK family members have been identified JAK1, JAK2, JAK3 and Tyk2 with molecular weights ranging from 120 to 140 kDa. 

JAKs are composed of an amino-terminal region (N), catalytically inactive kinase-like (KL) domain and a tyrosine kinase (TK) domain. The family is distin- 

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Changelian PS, Flanagan ME, Ball DJ et al (2003) Prevention of organ allograft rejection by a specific Janus kinase 3 inhibitor. Science 302 875-878... 

Cytokine receptors that couple to the JAK-STAT Pathway decode the signaling though hematopoietic cytokines (erythropoietin, thrombopoietin, colony-stimulating factors), prolactin, growth hormone, the a-, (3- and y- interferons, and a number of immunomodulatory interleukins [3], They form homodimetic or heterodimeric receptor complexes, which after ligandbinding recruit and activate isotypes of Janus kinases (JAKs). Activated JAKs in turn... 

Figure 8.3 Schematic representation of the general domain structure of a STAT protein. A conserved ( C or con ) domain is located at the N-terminus, followed by the DNA-binding domain (D). Y represents a short se-guence that contains the tyrosine residue phosphorylated by the Janus kinase. The carboxy terminus domain (Tr) represents a transcriptional activation domain...

Uckun, F.M., Thoen, J., Chen, H., Sudbeck, E., Mao, C., Malaviya, R., Liu, X.-P. and Chen, C.-L. (2002) CYP1A-mediated metabolism of the janus kinase-3 inhibitor 4-(4 -hydroxyphenyl)-amino-6,7-dimethoxyquinazoline structural basis for inactivation by regioselective o-demethylation. Drug Metabolism and Disposition The Biological Fate of Chemicals, 30 (1), 74—85. 

Leptin signalling is via monomeric receptors in the brain. A short-form of the leptin receptor (Lep-R) is required to transport the hormone across the blood-brain barrier and a long-form Lep-R is located in the hypothalamus. The long-form is functionally linked with a particular type of receptor-associated tyrosine kinase called Janus kinase (JAK, see Section 4.7) whose function is to phosphorylate a STAT (signal transducer and activator of transcription) protein a similar mechanism to that often associated with signalling by inflammatory cytokines. 

These are indolent neoplasms characterised by uncontrolled expansion in the erythron where additional hazards are added by the thrombocytosis and, to a lesser extent, leucocytosis. There is a specific point mutation in the Janus Kinase 2 or JAK 2 gene that better defines these cases. 

Fig. 11.4. Model of signal transduction via the IL-2 receptor. Binding of IL-2 to the IL-2 receptor initiates activation of the Janus kinases Jakl and Jak3. These phosphorylate tyrosine residues in the P-chain of the IL-2 receptor and in the transcription factor StatS. SH2 domains or PTB domains of adaptor proteins can bind to the Tyr phosphate residues of the P-chain and, as shown in the figure for the Shc/Grb2/Sos complex, can transmit a signal in the direction of the Ras pathway. The phosphorylated transcription factor StatS is translocated into the nucleus and activates the transcription of corresponding gene sections. Another signaling pathway starting from the activated IL-2 receptor involves the Lck and Syk tyrosine kinases (see Chapter 8). The pathway leads to induction of genes for transcription factors such as c-Myc and c-Fos.

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