Arachidonic acid induces ERK activation via Src SH2 domain association with the epidermal growth factor receptor

Alexander, Larry D.; Ding, Yaxian; Alagarsamy, Suganthi; Cui, Xiaolan; Douglas, Janice G.

doi:10.1038/sj.ki.5000363

Cited by 27 publications

(25 citation statements)

References 35 publications

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“…Indeed, the c-Src inhibitor PP1, inhibited the AVP-induced phosphorylation EGFR at residue 845, whereas the metalloprotease inhibitor GM6001 did not affect the phosphorylation of EGFR at that residue (unpublished results). Similar mechanisms of EGFR transactivation have been previously reported with other GPCR systems [27,[45][46][47][48][49]. On the basis of our coimmunoprecipitation studies we argue that V 1a mediated EGFR transactivation involves the formation of V1a/EGFR complex assembled with β-arrestin 2 and intracellular proteins of the trafficking mechanisms [50].…”

Section: Discussionsupporting

confidence: 52%

Vasopressin up-regulates the expression of growth-related immediate-early genes via two distinct EGF receptor transactivation pathways

Fuentes

Reyes

Sarmiento

et al. 2008

Cellular Signalling

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Activation of V 1a receptor triggers the expression of growth-related immediate-early genes (IEGs), including c-Fos and Egr-1. Here we found that pre-treatment of rat vascular smooth muscle A-10 cell line with the EGF receptor inhibitor AG1478 or the over-expression of an EGFR dominant negative mutant (HEBCD533) blocked the vasopressin-induced expression of IEGs, suggesting that activation of these early genes mediated by V 1a receptor is via transactivation of the EGF receptor. Importantly, the inhibition of the metalloproteinases, which catalyzed the shedding of the EGF receptor agonist HB-EGF, selectively blocked the vasopressin-induced expression c-Fos. On the other hand, the inhibition of c-Src selectively blocked the vasopressin-induced expression of Egr-1. Interestingly, in contrast to the expression of c-Fos, the expression of Egr-1 was mediated via the Ras/MEK/MAPK-dependent signalling pathway. Vasopressin-triggered expression of both genes required the release of intracellular calcium, activation of PKC and β-arrestin 2. These findings demonstrated that vasopressin up-regulated the expression of c-Fos and Erg-1 via transactivation of two distinct EGF receptor-dependent signalling pathways.

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Section: Discussionsupporting

confidence: 52%

Vasopressin up-regulates the expression of growth-related immediate-early genes via two distinct EGF receptor transactivation pathways

Fuentes

Reyes

Sarmiento

et al. 2008

Cellular Signalling

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“…In some cell lines, Src is responsible for direct activation of the EGFR through phosphorylating essential tyrosine residues on EGFR [37,38]. In renal epithelium, Src tyrosine kinase activation and transactivation of EGFR were found to activate the ERK1/2 pathway in responding to Ang II or arachidonic acid stimulation [11,14]. A physical association of Src and EGFR was observed in these cells under basal conditions.…”

Section: Discussionmentioning

confidence: 99%

“…We have previously demonstrated that arachidonic acid mimics Ang II in activation of Src tyrosine kinase, induction of Src and EGFR association via SH2 domain, transactivation of the EGFR tyrosine kinase, activation of small GTPase ras, and activation of downstream ERK1/2 [11,12,14,22]. Experiments were designed to test whether Src and EGFR tyrosine kinases are responsible for mediating H 2 O 2 -induced signaling in these epithelial cells.…”

Section: Resultsmentioning

confidence: 99%

“…Transactivation of the EGFR tyrosine kinase is an upstream element of shc/grb2/sos-mediated ras activation in our system [11,12]. Recently, we have demonstrated that arachidonic acid and/or its metabolites mediate all downstream effects of Ang II in activation of members of the MAPK, i.e., the ERK1/2, p46/p54 SAPK , and p38 SAPK [13,14]. Arachidonic acid also induces ROS production in these proximal tubular epithelial cells [15], which provides mechanism for endogenous ROS generation [16].…”

Section: Introductionmentioning

confidence: 99%

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Oxidative signaling in renal epithelium: Critical role of cytosolic phospholipase A2 and p38SAPK

Cui

Ding

Alexander

et al. 2006

Free Radical Biology and Medicine

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Previous studies from this laboratory have demonstrated a critical role of cytosolic phospholipase A 2 (cPLA 2 ) and arachidonic acid in angiotensin II (Ang II) AT2 receptor-mediated signal transduction in renal epithelium. In primary proximal tubular epithelial cells exposed to hydrogen peroxide (H 2 O 2 ), both the selective cPLA 2 inhibitors and the cPLA 2 antisense oligonucleotides significantly attenuated H 2 O 2 -induced arachidonic acid liberation and activation of p38 SAPK , ERK1/2, and Akt1. This H 2 O 2 -induced kinase activation was significantly attenuated by a Src kinase inhibitor PP2, or by transient transfection of carboxyl-terminal Src kinase (CSK) that maintained Src in the dormant form. Under basal conditions, Src coimmunoprecipitated with epidermal growth factor receptor (EGFR), while H 2 O 2 increased EGFR phosphorylation in the complex. We observed that inhibition of EGFR kinase activity with AG1478 significantly attenuated H 2 O 2 -induced p38 SAPK and ERK1/2 activation, but did not inhibit Akt1 activation. Furthermore, it seems that p38 SAPK is upstream of ERK1/2 and Akt1, since a p38 SAPK inhibitor SB203580 significantly blocked H 2 O 2 -induced activation of ERK1/2 and Akt1. Interestingly, overexpression of the dominant-negative p38 SAPK isoform α inhibited ERK1/2 but not Akt1 activation. Our observations demonstrate that in these nontransformed cells, activation of cPLA 2 is a converging point for oxidative stress and Ang II, which share common downstream signaling mechanisms including Src and EGFR. In addition, p38 SAPK provides a positive input to both growth and antiapoptotic signaling pathways induced by acute oxidative stress.

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“…Arachidonic acid, in turn, either through cytochrome P450 metabolites or directly, stimulates the ERK pathway. [11][12][13][14][15][16] In sharp contrast to their proposal, however, several studies suggested that Ang II type 1 receptor (AT 1 ) mediates both stimulatory and inhibitory effects of Ang II. 10,17 Our own data obtained from AT 1A -deficient mice also led us to conclude that AT 1 mediates the biphasic regulation in intact mouse proximal tubules.…”

mentioning

confidence: 99%

Roles of ERK and cPLA2 in the Angiotensin II-Mediated Biphasic Regulation of Na+-HCO3 − Transport

Li¹,

Yamada²,

Kita

et al. 2008

Journal of the American Society of Nephrology

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Regulation of renal proximal transport by angiotensin II (Ang II) is biphasic: low concentrations (picomolar to nanomolar) stimulate reabsorption, but higher concentrations (nanomolar to micromolar) inhibit reabsorption. Traditionally, the stimulatory effect has been attributed to activation of protein kinase C and/or a decrease in intracellular cAMP, whereas the inhibitory action has been attributed to the activation of phospholipase A 2 (PLA 2 ) and the subsequent release of arachidonic acid. The Ang II receptor subtype responsible for these effects and the intracellular signaling pathways involved are not completely understood. We isolated proximal tubules from wild-type, Ang II type 1A receptor (AT 1A )-deficient, and group IVA cytosolic phospholipase A 2 (cPLA 2 ␣)-deficient mice, and compared their responses to Ang II. In wild-type mice, we found that the stimulatory and inhibitory effects of Ang II on Na ϩ -HCO 3 Ϫ cotransporter activity are both AT 1 -mediated but that ERK activation only plays a role in the former. The stimulatory effect of Ang II was also observed in AT 1A -deficient mice, suggesting that this occurs through AT 1B . In contrast, the inhibitory effects of Ang II appeared to be mediated by cPLA 2 ␣ activation because high-concentration Ang II stimulated Na ϩ -HCO 3 Ϫ cotransporter activity when cPLA 2 ␣ activity was abrogated by pharmacological means or genetic knockout. Consistent with this observation, we found that activation of the cPLA 2 ␣/P450 pathway suppressed ERK activation. We conclude that Ang II activates ERK and cPLA 2 ␣ in a concentration-dependent manner via AT 1 , and that the balance between ERK and cPLA 2 ␣ activities determines the ultimate response to Ang II in intact proximal tubules.

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Arachidonic acid induces ERK activation via Src SH2 domain association with the epidermal growth factor receptor

Cited by 27 publications

References 35 publications

Vasopressin up-regulates the expression of growth-related immediate-early genes via two distinct EGF receptor transactivation pathways

Vasopressin up-regulates the expression of growth-related immediate-early genes via two distinct EGF receptor transactivation pathways

Oxidative signaling in renal epithelium: Critical role of cytosolic phospholipase A2 and p38SAPK

Roles of ERK and cPLA2 in the Angiotensin II-Mediated Biphasic Regulation of Na+-HCO3 − Transport

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