Angiotensin II Initiates Tyrosine Kinase Pyk2-dependent Signalings Leading to Activation of Rac1-mediated c-Jun NH2-terminal Kinase

Murasawa, Satoshi; Matsubara, Hiroaki; Mori, Yoshihide; Masaki, Hiroya; Tsutsumi, Yoshio; Shibasaki, Yasunobu; Kitabayashi, Issay; Tanaka, Yasuaki; Fujiyama, Sohichiro; Koyama, Yohko; Fujiyama, Atsuko; Iba, Satoshi; Iwasaka, Toshiji

doi:10.1016/s0021-9258(19)61453-5

Cited by 48 publications

(3 citation statements)

References 45 publications

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“…Pyk2 has been shown to interact with and activate Rac-1 and Cdc42 in some membrane receptor-mediated pathways (13)(14)(15)(16). To determine whether Rac-1 lies down-stream of Pyk2 in the reoxygenation-JNK pathway we measured the activity of Rac-1 using a PAK-1-linked binding assay as described in Materials and Methods.…”

Section: Activation Of Rac-1 and Selective Inhibition Of Jnk By Dnrac-1mentioning

confidence: 99%

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Mitochondrial signals initiate the activation of c‐Jun N‐terminal kinase (JNK) by hypoxia‐reoxygenation

Dougherty¹,

Kubasiak²,

Frazier³

et al. 2004

The FASEB Journal

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C-Jun N-terminal kinase (JNK) is part of the mitogen-activated protein kinase (MAPK) family of signaling pathways that are induced in response to extracellular stimuli. JNK is primarily a stress-response pathway and can be activated by proinflammatory cytokines and growth factors coupled to membrane receptors or through non-receptor pathways by stimuli such as heat shock, UV irradiation, protein synthesis inhibitors, and conditions that elevate the levels of reactive oxygen intermediates (ROI). The molecular initiators of MAPKs by non-receptor stimuli have not been described. Ischemia followed by reperfusion or hypoxia with reoxygenation represents a condition of high oxidative stress where JNK activation is associated with elevated ROI. We show here that the activation of JNK by this condition is initiated in the mitochondria and requires coupled electron transport, ROI generation, and calcium flux. These signals cause the selective, sequential activation of the calcium-dependent, proline-rich kinase Pyk2 and the small GTP binding factors Rac-1 and Cdc42. Interruption of these interactions with inactivated dominant negative mutant proteins, blocking calcium flux, or inhibiting electron transport through mitochondrial complexes II, III, or IV prevents JNK activation and results in a proapoptotic phenotype that is characteristic of JNK inhibition in this model of ischemia-reperfusion. The signaling pathway is unique for the reoxygenation stimulus and provides a framework for other non-receptor-mediated pathways of MAPK activation.

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Section: Activation Of Rac-1 and Selective Inhibition Of Jnk By Dnrac-1mentioning

confidence: 99%

“…Activated c-Raf initiates the sequential phosphorylation of MEKs in the ERK module. A parallel pathway has been described for the activation of JNK by heterotrimeric G-protein-coupled receptors and angiotensin II (Ang II) (13)(14)(15)(16)(17).…”

mentioning

confidence: 99%

Mitochondrial signals initiate the activation of c‐Jun N‐terminal kinase (JNK) by hypoxia‐reoxygenation

Dougherty¹,

Kubasiak²,

Frazier³

et al. 2004

The FASEB Journal

View full text Add to dashboard Cite

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“…A pioneering study indicates the involvement of Pyk2 in Ang II-induced activation of JNK and c-Jun in cardiac broblasts and the relevancy of Ang II on cardiac brosis and hypertrophy. 61 Other than the above, morin, piperine, veratric acid, syringic acid and vanillic acid target components of VEGF signaling pathway. Recent report have demonstrated that angiogenesis is an important factor in the progression of atherosclerosis and VEGF, a potent angiogenic growth factor, increases the rate of atherosclerosis in animal models and also suggested that the anti-atherosclerosis action of polyphenols might be through inhibition of VEGF signaling.…”

Section: Discussionmentioning

confidence: 99%

Systems pharmacology and molecular docking strategies prioritize natural molecules as cardioprotective agents

et al. 2015

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Pyk2 is essential for astrocytes mobility following brain lesion

Giralt

Coura

Girault

2015

Glia

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Proline-rich tyrosine kinase 2 (Pyk2) is a calcium-dependent, non-receptor protein-tyrosine kinase of the focal adhesion kinase (FAK) family. Pyk2 is enriched in the brain, especially the forebrain. Pyk2 is highly expressed in neurons but is also present in astrocytes, where its role is not known. We used Pyk2 knockout mice (Pyk2(-/-) ) developed in our laboratory to investigate the function of Pyk2 in astrocytes. Morphology and basic properties of astrocytes in vivo and in culture were not altered in the absence of Pyk2. However, following stab lesions in the motor cortex, astrocytes-mediated wound filling was slower in Pyk2(-/-) than in wild-type littermates. In an in vitro wound healing model, Pyk2(-/-) astrocytes migrated slower than Pyk2(+/+) astrocytes. The role of Pyk2 in actin dynamics was investigated by treating astrocytic cultures with the actin-depolymerizing drug latrunculin B. Actin filaments re-polymerization after latrunculin B treatment was delayed in Pyk2(-/-) astrocytes as compared with wild-type astrocytes. We mimicked wound-induced activation by treating astrocytes in culture with tumor-necrosis factor alpha (TNFα), which increased Pyk2 phosphorylation at Tyr402. TNFα increased PKC activity, and Rac1 phosphorylation at Ser71 similarly in wild-type and Pyk2-deficient astrocytes. Conversely, we found that gelsolin, an actin-capping protein known to interact with Pyk2 in other cell types, was less enriched at the leading edge of migrating Pyk2(-/-) astrocytes, suggesting that its lack of recruitment mediated in part the effects of the mutation. This work shows the critical role of Pyk2 in astrocytes migration during wound healing.

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Angiotensin II Initiates Tyrosine Kinase Pyk2-dependent Signalings Leading to Activation of Rac1-mediated c-Jun NH2-terminal Kinase

Cited by 48 publications

References 45 publications

Mitochondrial signals initiate the activation of c‐Jun N‐terminal kinase (JNK) by hypoxia‐reoxygenation

Mitochondrial signals initiate the activation of c‐Jun N‐terminal kinase (JNK) by hypoxia‐reoxygenation

Systems pharmacology and molecular docking strategies prioritize natural molecules as cardioprotective agents

Pyk2 is essential for astrocytes mobility following brain lesion

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