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

Abstract

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 A NUMBER OF TYPE 1 RECEPTOR cytokine family members, namely the interleukin (IL)-6-type cytokines [IL-6, IL-11, leukemia inhibitory factor (LIF), cardiotrophin-1 (CT-1), and oncostatin M (OSM)] (40, 78, 58, 85), growth hormone (GH; Ref. 91) erythropoietin (Epo; Refs. 20,134,138), and granulocyte colony-stimulating factor (G-CSF; Refs. 26,61,62,72,159,166), as well as insulin (3,23,54,64,99,164,186), have been shown to protect the heart from acute oxidative stress, viz., ischemia-reperfusion injury. LIF (121), GH (56), Epo (77), and insulin (141) have also been reported to protect cardiac myocytes from chronic oxidative stress. Notably, a number of clinical trials have been completed or are underway assessing the efficacy of Epo or G-CSF in treating myocardial infarction and heart failure (13,87,88,93).The protective action of the type 1 receptor cytokines (see Fig. 1 for IL-6 cytokine signaling) and insulin has been shown to involve activation of two intracellular signaling cascades: 1) the reperfusion injury salvage kinase (RISK) pathway (17,27,40,41,64,66,77,99,101,102,108,121,126,128,133,134,142,156,159,160,161,166) and 2) JAK-STAT signaling (20,40,61,85,16...

Hypoxia Induces Myocardial Regeneration in Zebrafish

“…Conversely, we also detected downregulation of a negative regulator of Jak-STAT signaling, cish (or socs), 54 which, although just below our level of stringency in the dnHIF1␣ sample (logFCϭϪ0.51), was dramatically reduced in the wild-type sample (logFCϭϪ2.18). Upstream of the Jak-STAT pathway, cxcr4b 55 was found to be upregulated in the wild-type sample but showed no change in the dnHIF1␣ sample (Table I in the online-only Data Supplement), although a putative downstream target of the Jak-STAT pathway, pim1, 56 is upregulated in the wild-type sample (logFCϭ1.44) but does not change in the dnHIF1␣ sample (logFCϭ0.32; Table I in the online-only Data Supplement).…”

Upregulation of Peptide Transporters PEPT1 and PEPT2 by Janus Kinase JAK2

“…Moreover, JAK2 is activated by oxidative stress [7], ischemia [7] and hypertonicity [8,9]. Excessive JAK2 activity may lead to development of malignancy and the gain of function mutation V617F JAK2 presumably predisposes to the development of myeloproliferative disease [10,11,12,13].…”

Impaired JAK2-induced activation of STAT3 in failing human myocytes

“…STAT3 activation is mediated by Janus-activated kinase (JAK)2 through phosphorylation of receptor tyrosine residues. 5,6 In addition to tyrosine phosphorylation STAT3 was also reported to require extracellular signal-regulated kinase (ERK)1/2 induced serine phosphorylation to exert full transcriptional activity.…”