Janus Kinase 2 (Jak2) Must Be Catalytically Active to Associate with the AT1Receptor in Response to Angiotensin II

Ms, Ali; Pp, Sayeski; Safavi, Afshin; Lyles, Michelle M.; Bernstein, Kenneth E.

doi:10.1006/bbrc.1998.9054

Cited by 16 publications

(12 citation statements)

References 8 publications

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“…However, this motif is not conserved in any of the other GPCRs known to associate with Jaks, raising questions about the significance of this observation. Available evidence indicates that Jak2 must be catalytically active to associate with the Ang II AT 1 receptor and to recruit STATs to the receptor (2,4). A kinase-inactive form of Jak2 with a mutation in subdomain VIII fails to associate with the receptor and to activate STAT1 following Ang II stimulation (2).…”

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confidence: 99%

Rho Family GTPases Are Required for Activation of Jak/STAT Signaling by G Protein-Coupled Receptors

Pelletier

Duhamel

Coulombe

et al. 2003

Molecular and Cellular Biology

144

118

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As do cytokine receptors and receptor tyrosine kinases, G protein-coupled receptors (GPCRs) signal to Janus kinases (Jaks) and signal transducers and activators of transcription (STATs). However, the early biochemical events linking GPCRs to this signaling pathway have been unclear. Here we show that GPCRstimulated Rac activity and the subsequent generation of reactive oxygen species are necessary for activating tyrosine phosphorylation of Jaks and STAT-dependent transcription. The requirement for Rac activity can be overcome by addition of hydrogen peroxide. Expression of activated mutants of Rac1 is sufficient to activate Jak2 and STAT-dependent transcription, and the activation of Jak2 correlates with the ability of Rac1 to bind to NADPH oxidase subunit p67 phox . We further show that GPCR agonists stimulate tyrosine phosphorylation of STAT1 and STAT3 proteins in a Rac-dependent manner. The tyrosine phosphorylation of STAT3 is biphasic; the first peak of phosphorylation is weak and correlates with rapid activation of Jaks by GPCRs, whereas the second peak is stronger and requires the synthesis of an autocrine factor. Rho also plays an essential role in the induction of STAT transcriptional activity. Our results highlight a novel role for Rho GTPases in mediating the regulatory effects of GPCRs on STAT-dependent gene expression.

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confidence: 99%

Rho Family GTPases Are Required for Activation of Jak/STAT Signaling by G Protein-Coupled Receptors

Pelletier

Duhamel

Coulombe

et al. 2003

Molecular and Cellular Biology

144

118

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“…Although JAK2 seems to physically associate with the AT 1 receptor, 4 its binding does not directly lead to JAK2 activation. 6 In this regard, Simon et al 7 reported that JAK2 activation in vitro depends on the presence of reactive oxygen species (ROS). Because Ang II activates the generation of O 2 Ϫ anions, 8 we hypothesized that a ROSgenerating system is involved in Ang II-induced activation of the JAK/STAT cascade and, subsequently, in interleukin-6 (IL-6) synthesis.…”

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confidence: 99%

Role of NAD(P)H Oxidase in Angiotensin II–Induced JAK/STAT Signaling and Cytokine Induction

Schieffer

Luchtefeld

Braun

et al. 2000

Circulation Research

256

185

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Abstract-Inflammatory processes involve both synthesis of inflammatory cytokines, such as interleukin-6 (IL-6), and the activation of their distinct signaling pathways, eg, the janus kinases (JAKs) and signal transducers and activators of transcription (STAT). Superoxide (O 2 Ϫ ) anions activate this signaling cascade, and the vasoconstrictor angiotensin II (Ang II) enhances the formation of O 2 Ϫ anions via the NAD(P)H oxidase system in rat aortic smooth muscle cells. Ang II activates the JAK/STAT cascade via its type 1 (AT 1 ) receptor and induces synthesis and release of IL-6. Therefore, we investigated the role of O 2 Ϫ anions generated by the NAD(P)H oxidase system on the Ang II activation of the JAK/STAT cascade and its impact on IL-6 synthesis. Ang II stimulation of rat aortic smooth muscle cells induced a rapid increase in O 2 Ϫ anions determined by laser fluoroscopy, which can be abolished by DPI, a flavoprotein inhibitor. Ang II-induced phosphorylation of JAK2, STAT1␣/␤, STAT3, and IL-6-synthesis can be abolished by DPI, as determined by immunoprecipitations and Northern blot analysis. Electroporation of neutralizing antisera targeted against p47 phox , a NAD(P)H oxidase subunit, abolished Ang II-induced JAK/STAT activation and IL-6 synthesis. Inhibition of JAK2 by its inhibitor AG490 (10 mol/L) blocked not only JAK2 activation but also IL-6 synthesis. These results suggest that stimulation of the JAK/STAT cascade by Ang II requires O 2 Ϫ anions generated by the NAD(P)H oxidase system, and O 2 Ϫ anion-dependent activation of the JAK/STAT cascade seems to be additionally involved in Ang II-induced IL-6 synthesis. Thus, Ang II-induced inflammatory effects seem to require O 2 Ϫ anions generated by the NAD(P)H oxidase system.

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“…To determine this, quiescent VSMC were either pretreated with Me 2 SO (control), pretreated with the Jak2 kinase inhibitor AG-490 (25), or pretreated with the Src family kinase inhibitor PP1 (26). For this study, we used 100 M of the Jak inhibitor AG-490, the lowest dose that in our hands fully inhibits Jak2 in cultured cells (27). After inhibitor treatment, cells were then left untreated or stimulated with 10 Ϫ7 M angiotensin II for either 5 min ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…We have previously used this system to delineate other Jak2 tyrosine phosphorylation-dependent cellular events (27). Using this system, COS-7 cells were transfected to express empty vector, Jak2 WT, or Jak2 DN.…”

Section: Resultsmentioning

confidence: 99%

A Catalytically Active Jak2 Is Required for the Angiotensin II-dependent Activation of Fyn

Safavi

et al. 1999

Journal of Biological Chemistry

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Recent work with interleukins has shown a convergence of tyrosine phosphorylation signal transduction cascades at the level of the Janus and Src families of tyrosine kinases. Here we demonstrate that activation of the seven-transmembrane AT 1 receptor by angiotensin II induces a physical association between Jak2 and Fyn, in vivo. This association requires the catalytic activity of Jak2 but not Fyn. Deletion studies indicate that the region of Jak2 that binds Fyn is located between amino acids 1 and 240. Studies of the Fyn SH2 and SH3 domains demonstrate that the SH2 domain plays the primary role in Jak2/Fyn association. Not surprisingly, this domain shows a marked preference for tyrosinephosphorylated Jak2. Surface plasmon resonance estimated the dissociation equilibrium constant (K d ) of this association to be 2.36 nM. Last, in vivo studies in vascular smooth muscle cells show that, in response to angiotensin II, Jak2 activation is required for Fyn activation and induction of the c-fos gene. The significance of these data is that Jak2, in addition to serving as a critical angiotensin II activated signal transduction kinase, also functions as a docking protein and participates in the activation of Fyn by providing phosphotyrosine residues that bind the SH2 domain of Fyn.The Jak family of nonreceptor tyrosine kinases includes Jak1, Jak2, Jak3, and Tyk2. Each protein is approximately 130 kDa and contains seven conserved Jak homology domains (JH1 to JH7) (1, 2). The Jak kinases induce gene regulation through the signal transducers and activators of transcription. Unlike almost all other protein-tyrosine kinases, members of the Jak family bear no SH2 1 or SH3 domains. In contrast to the Jaks, members of the Src family of protein-tyrosine kinases are approximately 55-62 kDa in mass and do possess SH2 and SH3 domains. There are nine known members of the Src kinase family. While the expression of most members is restricted to hematopoietic cells, Fyn and Src are widely expressed by many cell types. There appears to be some functional redundancy of these two proteins, since knockout mice lacking either gene are born alive, while disruption of both the fyn and src alleles results in embryonic lethality (3-5). This redundancy is also seen in the activation of similar signaling pathways by Fyn and Src (6).Recent studies have demonstrated various levels of crosstalk between Jak2 and other signaling pathways. For example, activation of gp130 by the hematopoietic cytokine, interleukin-11, induces protein complex formation between the Jak and Src family tyrosine kinases. Specifically, treatment of 3T3-L1 cells with interleukin-11 leads to a transient complex of Grb2, Jak2, and Fyn (7). Subsequent studies by Yang et al. demonstrated an interleukin-11-dependent association of Jak2 with other signaling molecules including protein phosphatase 2A, phosphatidylinositol-3-kinase, and the Src family kinase Yes (8). To date, the regions that mediate these interactions, as well as the hierarchy of the signal transduction cascades, hav...

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Janus Kinase 2 (Jak2) Must Be Catalytically Active to Associate with the AT1Receptor in Response to Angiotensin II

Cited by 16 publications

References 8 publications

Rho Family GTPases Are Required for Activation of Jak/STAT Signaling by G Protein-Coupled Receptors

Rho Family GTPases Are Required for Activation of Jak/STAT Signaling by G Protein-Coupled Receptors

Role of NAD(P)H Oxidase in Angiotensin II–Induced JAK/STAT Signaling and Cytokine Induction

A Catalytically Active Jak2 Is Required for the Angiotensin II-dependent Activation of Fyn

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