Janus kinase (JAK) is a family of intracellular, nonreceptor tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway. There are four mammalian genes encoding the non-receptor Janus kinase (Jak) family of proteins; Jak1, Jak2, Jak3 and Tyk2.

There are four mammalian genes encoding the non-receptor Janus kinase (Jak) family of proteins; Jak1, Jak2, Jak3 and Tyk2. They contain seven regions with significant sequence homology and collectively, these regions are referred to as the Jak homology domains (JH1-JH7). The JH1 domain contains the tyrosine kinase domain, and is located within the carboxyl terminus of the protein. This domain binds ATP and harbors the phospho-transferase activity of the protein. The JH2 domain shows close homology to the JH1 domain, but lacks tyrosine kinase activity. It is therefore termed the pseudokinase domain. Acting via a cis mechanism, the JH2 domain negatively regulates the kinase activity of the JH1 domain. The JH3 and half of the JH4 domain encode an SH2 like motif whose function is not well understood. Finally, the remaining half of the JH4 domain, along with the entirety of the JH5, JH6, and JH7 domains, collectively encode the FERM domain. The FERM domain directly mediates the interaction of the Jak kinases with other cellular proteins such as cytokine receptors.

The Jak kinases play a critical role in cytokine signaling. They transduce signals from the cell surface to the nucleus via the tyrosine phosphorylation of the

Studies have shown that Ang II binding to the AT1-R triggers activation of Jak2, leading to intracellular signaling cascades in VSMCs and cardiac myocytes. Ang II stimulates Jak2 co-association to the AT1-R in VSMCs leading to phosphorylation of Jak2 at Tyr 1007/Tyr 1008, phosphorylation of the STATs, and translocation of the STATs into the nucleus, resulting in cell growth/proliferative responses. Blockade of the RAAS by either angiotensinconverting enzyme (ACE) inhibitors or AT1-R specific antagonists prevents injury-induced neointima formation, and Ang II infusion exacerbates VSMC proliferation in arterial walls. In addition, the genes of the RAAS are up regulated in neointima formation following vascular injury. Interestingly, Jak2 has also been shown to play a role in other cardiovascular signaling processes. For example, in VSMC, Jak2 plays a critical role in reactive oxygen species (ROS) dependent VSMC proliferation. It is also involved in the pathogenesis of atherosclerosis via its interaction with cytokines such as interleukin 8. In addition, Jak2 activation has been linked to neointima formation and vascular occlusion in rat carotid arteries subjected to balloon injury, which is exacerbated by Ang II infusion. Although it is well established that Jak2 interacts with the AT1-R resulting in cell growth and hypertrophy, there is no in vitro or in vivo evidence suggesting that the AT1-R mediated growth effects are exclusively through Jak2 activation. Further studies need to be done to establish the relative involvement of Jak2 activation in comparison to other pathways such as the mitogenactivated protein (MAP) kinase or pp60c-src kinase in AT1-R mediated cardiovascular remodeling.

Jak2 not only mediates Ang II-dependent growth promoting effects, but is also involved in Ang II-induced contractile responses, increased vascular tone and hypertension. The established mechanism by which Ang II mediates vasoconstriction involves the heterotrimeric G protein-mediated pathway. In VSMCs, the binding of Ang II to the AT1-R results in the activation of Gq which leads to phospholipase C (PLC) activation. This releases inositol-1,4,5-triphosphate (IP3) and diacylglycerol (DAG) from plasma membrane derived phosphatidylinositol 4,5-bisphosphate.


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