Proline-Rich Tyrosine Kinase 2 and Rac Activation by Chemokine and Integrin Receptors Controls NK Cell Transendothelial Migration

Gismondi, Angela; Jacobelli, Jordan; Strippoli, Raffaele; Mainiero, Fabrizio; Soriani, Alessandra; Cifaldi, Loredana; Piccoli, Mario; Frati, Luigi; Santoni, Angela

doi:10.4049/jimmunol.170.6.3065

Cited by 56 publications

(54 citation statements)

References 53 publications

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“…This suggests either that Syk no longer has access to the Vav1 substrate or raises the possibility of the activation by adhesion of one or more tyrosine phosphatase(s) capable of dephosphorylating Vav1 at Tyr174. The kinase Pyk2 has also been reported to bind and regulate Vav1 activation in certain leukocytes (43). We observed that Pyk2 activation was rapid in adherent neutrophils and that its activity did not correlate with the onset of Vav1 activity (data not shown).…”

Section: Discussionmentioning

confidence: 50%

The molecular basis for adhesion-mediated suppression of reactive oxygen species generation by human neutrophils

Zhao¹,

Benard²,

Bohl³

et al. 2003

J. Clin. Invest.

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Human neutrophil adherence to ECMs induces an initial inhibition of stimulated reactive oxygen species (ROS) formation, followed by an enhanced phase of oxidant production. The initial integrin-mediated suppression of ROS constitutes a mechanism to prevent inappropriate tissue damage as leukocytes migrate to inflammatory sites. The Rac2 guanosine 5′-triphosphatase (GTPase) is a critical regulatory component of the phagocyte NADPH oxidase. We show that activation of Rac2 is inhibited in adherent neutrophils, correlating with inhibition of ROS formation. Conversely, NADPH oxidase components p47 and p67 assemble normally, suggesting a specific action of adhesion on the Rac2 molecular switch. Reconstitution with activated Rac2 restored rapid NADPH oxidase activation kinetics to adherent neutrophils, establishing that inhibition was due to defective Rac2 activity. We provide evidence that integrins inhibit Rac2 activation via a membrane-associated guanine nucleotide exchange factor, likely to be Vav1. Activation of Vav1, but not its upstream activator, Syk, is suppressed by cell adhesion. Vav1 activity is inhibited due to dephosphorylation of the regulatory Tyr174 via enhanced tyrosine phosphatase activity in adherent cells. These studies identify an integrin-mediated pathway in which Vav1 is as a strong candidate for the critical regulatory point in suppression of Rac2 activation and ROS generation during inflammatory responses

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Section: Discussionmentioning

confidence: 50%

The molecular basis for adhesion-mediated suppression of reactive oxygen species generation by human neutrophils

Zhao¹,

Benard²,

Bohl³

et al. 2003

J. Clin. Invest.

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show abstract

“…For example, in cardiac fibroblasts, angiotensin II induces Pyk2 activation, which leads to Rac1 activation and MEKK1-dependent c-Jun NH 2 -terminal kinase (JNK) activation (46). In addition, Pyk2 is involved in the control of chemokine-and integrin-mediated Rac activation and associates with the Rac exchange factor, Vav1 (47). In another study, EGF potently activated MEKK1 and resulted in the association of Rac1 with MEKK1 (48).…”

Section: Egf Stimulation Results In the Recruitment Of C-src Pyk2mentioning

confidence: 99%

Pyk2 Amplifies Epidermal Growth Factor and c-Src-induced Stat3 Activation

Shi

Kehrl

2004

Journal of Biological Chemistry

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“…Thus, pyk2 activity is able to overcome the inhibition of Vav1 activation and the subsequent generation of Rac2 induced by cell adhesion. Interestingly, pyk2 has been reported to control NK cell transendothelial migration by conveying signals to Rac, also possibly via Vav1 (53).…”

Section: Discussionmentioning

confidence: 99%

Critical Role of Proline-Rich Tyrosine Kinase 2 in Reversion of the Adhesion-Mediated Suppression of Reactive Oxygen Species Generation by Human Neutrophils

Zhao

Bokoch

2005

The Journal of Immunology

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Neutrophils act as the first line of innate immune defense against invading microorganisms during infection and inflammation. The tightly regulated production of reactive oxygen species (ROS) through activation of NADPH oxidase is a major weapon used by neutrophils and other phagocytic leukocytes to combat such pathogens. Cellular adhesion signals play important physiological roles in regulating the activation of NADPH oxidase and subsequent ROS formation. We previously showed that the initial suppression of the oxidase response of chemoattractant-stimulated adherent neutrophils is mediated via inhibition of Vav1-induced activation of the NADPH oxidase regulatory GTPase Rac2 by adhesion signals. In this study we show that prior exposure of neutrophils to a number of cytokines and inflammatory mediators, including TNF-α, GM-CSF, and platelet-activating factor, overcomes the adhesion-mediated suppression of ROS formation. Proline-rich tyrosine kinase 2 (pyk2) activity is enhanced under these conditions, correlating with the restoration of Vav1 and Rac2 activities. Both dominant negative pyk2 and a pyk2-selective inhibitor prevented restoration of ROS production induced by TNF-α, GM-CSF, and platelet-activating factor, and this loss of pyk2 activity resulted in decreased Vav1 tyrosine phosphorylation and subsequent Rac2 activation. Our studies identify pyk2 as a critical regulatory component and a molecular switch to overcome the suppression of leukocyte oxidant generation by cell adhesion. This activity constitutes a mechanism by which cytokines might lead to rapid elimination of invading pathogens by adherent neutrophils under normal conditions or enhance tissue damage in pathological states.

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Proline-Rich Tyrosine Kinase 2 and Rac Activation by Chemokine and Integrin Receptors Controls NK Cell Transendothelial Migration

Cited by 56 publications

References 53 publications

The molecular basis for adhesion-mediated suppression of reactive oxygen species generation by human neutrophils

The molecular basis for adhesion-mediated suppression of reactive oxygen species generation by human neutrophils

Pyk2 Amplifies Epidermal Growth Factor and c-Src-induced Stat3 Activation

Critical Role of Proline-Rich Tyrosine Kinase 2 in Reversion of the Adhesion-Mediated Suppression of Reactive Oxygen Species Generation by Human Neutrophils

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