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Am J Physiol Heart Circ Physiol 297: H1545-H1556, 2009. First published August 28, 2009; doi:10.1152/ajpheart.00032.2009
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REVIEW

JAK redux: a second look at the regulation and role of JAKs in the heart

¹Department of Chemistry and Biochemistry, Faculty of Sciences, Lebanese University, Rafic Hariri Educational Campus, Hadath, Lebanon; ²Department of Pharmacology and Toxicology, School of Medicine, University of Mississippi Medical Center, Jackson, Mississippi

Submitted January 12, 2009 ; accepted in final form August 24, 2009

ABSTRACT

A number of type 1 receptor cytokine family members protect the heart from acute and chronic oxidative stress. This protection involves activation of two intracellular signaling cascades: the reperfusion injury salvage kinase (RISK) pathway, which entails activation of phosphatidylinositol 3-kinase (PI3-kinase) and ERK1/2, and JAK-STAT signaling, which involves activation of transcription factor signal transducer and activator of transcription 3 (STAT3). Obligatory for activation of both RISK and STAT3 by nearly all of these cytokines are the kinases JAK1 and JAK2. Yet surprisingly little is known about how JAK1 and JAK2 are regulated in the heart or how they couple to PI3-kinase activation. Although the JAKs are linked to antioxidative stress programs in the heart, we recently reported that these kinases are inhibited by oxidative stress in cardiac myocytes. In contrast, others have reported that cardiac JAK2 is activated by acute oxidative stress by an undefined process. Here we summarize recent insights into the regulation of JAK1 and JAK2. Besides oxidative stress, inhibitory regulation involves phosphorylation, nitration, and intramolecular restraints. Stimulatory regulation involves phosphorylation and adaptor proteins. The net effect of stress on JAK activity in the heart likely represents the sum of both inhibitory and stimulatory processes, along with their dynamic interaction. Thus the regulation of JAKs in the heart, once touted as the paragon of simplicity, is proving rather complicated indeed, requiring a second look. It is our contention that a better understanding of the regulation of this kinase family that is implicated in cardiac protection could translate into effective therapeutic strategies for preventing myocardial damage or repairing the injured heart.

Janus kinase; oxidative stress; redox; cardiac remodeling; cytokine; cardiac myocyte