Agonist-Induced Interactions between Angiotensin AT₁and Epidermal Growth Factor Receptors

Abstract

In rat hepatic C9 cells, angiotensin II (Ang II)-induced activation of angiotensin type 1 (AT 1 ) receptors (AT 1 -Rs) stimulates extracellular signal-regulated kinase (ERK) 1/2 phosphorylation via transactivation of the endogenous epidermal growth factor (EGF) receptor (EGF-R) by a protein kinase C (PKC) ␦/Src/Pyk2-dependent pathway. This leads to phosphorylation of the EGF-R as well as its subsequent internalization. On the other hand, EGF-induced activation of the EGF-R in C9 cells was found to cause phosphorylation of the AT 1 -R. This was prevented by selective inhibition of the intrinsic tyrosine kinase activity of the EGF-R by AG1478 [4-(3Ј-chloroanilino)-6,7-dimethoxy-quinazoline] and was reduced by inhibition of PKC and phosphoinositide 3-kinase. EGF-induced AT 1 -R phosphorylation was associated with a decrease in membrane-associated AT 1 -Rs and a reduced inositol phosphate response to Ang II. Agonist activation of endogenous AT 1 -Rs and EGF-Rs induced the formation of a multireceptor complex containing both the AT 1 -R and the transactivated EGF-R. The dependence of these responses on caveolin was indicated by the finding that cholesterol depletion of C9 cells abolished Ang II-induced inositol phosphate production, activation of Akt/PKB and ERK1/2, and AT 1 -R internalization. Confocal microscopy demonstrated that caveolin-1 was endogenously phosphorylated and was distributed on the plasma membrane in patches that undergo redistribution during Ang II stimulation. Agonist-induced phosphorylation and association of caveolin 1 with the AT 1 -R was observed, consistent with a scaffolding role of caveolin during transactivation of the EGF-R by Ang II. The EGF-induced AT 1 -R/caveolin association was abolished by AG1478, suggesting that activation of the EGF-R promotes the association of caveolin and the AT 1 -R.

Involvement of βPIX in angiotensin II-induced migration of vascular smooth muscle cells

“…The AT1 receptor in turn transactivates EGF receptor, which leads to activation of multiple downstream effectors such as Ras-ERK and PI3-K. In this regard, caveolin-1 appears to serve a scaffold forming a large signalplex, which includes AT1 receptor, EGF receptor and other signaling molecules such as Rac1 and NAD(P)H oxidase (Olivares-Reyes et al, 2005).…”

Caveolin-Dependent Angiotensin II Type 1 Receptor Signaling in Vascular Smooth Muscle

“…10 In a recent commentary, 37 the large signaling complex in hepatocyte C9 cells that was Ang II stimulated and Cav1 dependent and that contained not only Cav1 but also AT 1 R and EGF-R was referred to as a "signalplex." 38 Moreover, intactness of the microtubule and of the actin cytoskeleton systems and the presence of the actin-binding, nonreceptor tyrosine kinase cAbl, which is a substrate of cSrc and binds to Cav1, are essential for proper AT 1 R targeting into Cav1-enriched lipid rafts in VSMCs. 7,10,39 Mundy et al 40 reported that microtubules and the actin cytoskeleton are involved in trafficking, bidirectionally, of Cav1 containing vesicles ("cavicles") between the cell membrane and intracellular compartments, called caveosomes (Figure 1d).…”

A Single Initiating Cause of Hypertension; Potential for Primary Prevention

“…Angiotensin receptors tend to form physical complexes with EGFR [57]. AT1r forms complexes with the C-terminal part of EGFR [58].…”

“…Increased EGFR expression has profound effects on signalling pathways. High receptor density promotes its dimerization, which controls receptor endocytosis [134], which is further regulated by GPCR's [135] prominently via a mutual interaction with AT1r [57].…”