Arachidonate-Induced Tyrosine Phosphorylation of Epidermal Growth Factor Receptor and Shc-Grb2-Sos Association

Dulin, Nickolai O.; Sorokin, Andrey; Douglas, Janice G.

doi:10.1161/01.hyp.32.6.1089

Cited by 34 publications

(29 citation statements)

References 29 publications

(32 reference statements)

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“…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].…”

Section: Introductionmentioning

confidence: 72%

“…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%

“…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%

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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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Section: Introductionmentioning

confidence: 72%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

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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“…However, the mechanism linking altered metabolic to mitogenic pathways is not completely understood (37). It may involve activation of EGFR by fatty acids, independently of EGF (38)(39)(40)(41)(42).…”

Section: Introductionmentioning

confidence: 99%

CEACAM1 modulates epidermal growth factor receptor–mediated cell proliferation

Abou-Rjaily¹,

Lee²,

May³

et al. 2004

J. Clin. Invest.

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Phosphorylation of the cell adhesion protein CEACAM1 increases insulin sensitivity and decreases insulindependent mitogenesis in vivo. Here we show that CEACAM1 is a substrate of the EGFR and that upon being phosphorylated, CEACAM1 reduces EGFR-mediated growth of transfected Cos-7 and MCF-7 cells in response to EGF. Using transgenic mice overexpressing a phosphorylation-defective CEACAM1 mutant in liver (L-SACC1), we show that the effect of CEACAM1 on EGF-dependent cell proliferation is mediated by its ability to bind to and sequester Shc, thus uncoupling EGFR signaling from the ras/MAPK pathway. In L-SACC1 mice, we also show that impaired CEACAM1 phosphorylation leads to ligand-independent increase of EGFR-mediated cell proliferation. This appears to be secondary to visceral obesity and the metabolic syndrome, with increased levels of output of free fatty acids and heparin-binding EGF-like growth factor from the adipose tissue of the mice. Thus, L-SACC1 mice provide a model for the mechanistic link between increased cell proliferation in states of impaired metabolism and visceral obesity.

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“…Moreover, in rat-1 fibroblast and Cos 7 cells, dominant negative mutants of the EGFR were used to demonstrate that the EGFR is important for linking GPCR activation with the activation of MAPK/p44/42 MAPK (ERK1/2) (11,29). In fact, in many cells, the EGFR kinase inhibitor AG1478 inhibited GPCR-mediated ERK1/2 activation (6,13,14,29). It is now well documented that G␤␥ subunits are also able to transmit signals to the effector molecules in renal epithelial cells (19,30).…”

mentioning

confidence: 99%

Angiotensin II stimulates fibronectin protein synthesis via a Gβγ/arachidonic acid-dependent pathway

Alexander

Ding

Alagarsamy

et al. 2014

American Journal of Physiology-Renal Physiology

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Alexander LD, Ding Y, Alagarsamy S, Cui X. Angiotensin II stimulates fibronectin protein synthesis via a G␤␥/arachidonic aciddependent pathway. Am J Physiol Renal Physiol 307: F287-F302, 2014. First published June 11, 2014 doi:10.1152/ajprenal.00094.2014.-In rabbit proximal tubular cells, ANG II type 2-receptor (AT 2 )-induced arachidonic acid release is PLA 2 coupled and dependent of G protein ␤␥ (G␤␥) subunits. Moreover, ANG II activates ERK1/2 and transactivates EGFR via a c-Src-dependent mechanism. Arachidonic acid has been shown to mimic this effect, at least in part, by an undetermined mechanism. In this study, we determined the effects of ANG II on fibronectin expression in cultured rabbit proximal tubule cells and elucidated the signaling pathways associated with such expression. We found that ANG II and transfection of G␤␥ subunits directly increased fibronectin protein expression, and this increase was inhibited by overexpression of ␤-adrenergic receptor kinase (␤ARK)-ct or DN-Src. Moreover, ANG II-induced fibronectin protein expression was significantly abrogated by the AT2 receptor antagonist PD123319. In addition, inhibition of cystolic PLA 2 diminished ANG II-induced fibronectin expression. Endogenous arachidonic acid mimicked ANG II-induced fibronectin expression. We also found that overexpression of G␤␥ subunits induced c-Src, ERK1/2, and EGFR tyrosine phosphorylation, which can be inhibited by overexpression of ␤ARK-ct or DN-Src. G␤␥ also induced c-Src SH2 domain association with the EGFR. Supporting these findings, in rabbit proximal tubular epithelium, immunoblot analysis indicated that ␤␥ expression was significant. Interestingly, arachidonic acid-and eicosatetraenoic acid-induced responses were preserved in the presence of ␤ARK-ct. This is the first report demonstrating the regulation of EGFR, ERK1/2, c-Src, and fibronectin by G␤␥ subunits in renal epithelial cells. Moreover, this work demonstrates a role for G␤␥ heterotrimeric proteins in ANG II, but not arachidonic acid, signaling in renal epithelial cells. arachidonic acid; angiotensin II; c-Src, epidermal growth factor receptor transactivation; carboxyl terminus of ␤-adrenergic receptor kinase-1; mitogen-activated protein kinase; G␤␥

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Arachidonate-Induced Tyrosine Phosphorylation of Epidermal Growth Factor Receptor and Shc-Grb2-Sos Association

Cited by 34 publications

References 29 publications

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

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

CEACAM1 modulates epidermal growth factor receptor–mediated cell proliferation

Angiotensin II stimulates fibronectin protein synthesis via a Gβγ/arachidonic acid-dependent pathway

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