An Angiotensin II Type 1 Receptor Mutant Lacking Epidermal Growth Factor Receptor Transactivation Does Not Induce Angiotensin II–Mediated Cardiac Hypertrophy

Abstract

Abstract-We have shown previously that tyrosine 319 in a conserved YIPP motif in the C terminus of angiotensin II (Ang II) type 1 receptors (AT 1 Rs) is essential for transactivation of epidermal growth factor receptor (EGFR) in vitro. We hypothesized that the signaling mechanism mediated through the specific amino acid sequence in the G protein-coupled receptor plays an important role in mediating cardiac hypertrophy in vivo. Transgenic mice with cardiac-specific overexpression of wild-type AT 1 R (Tg-WT) and an AT 1 R with a mutation in the YIPP motif (Tg-Y319F) were studied. Tg-Y319F mice developed no significant cardiac hypertrophy, in contrast to the significant development of hypertrophy in Tg-WT mice. Expression of fetal-type genes, such as atrial natriuretic factor, was also significantly lower in Tg-Y319F than in Tg-WT mice. Infusion of Ang II caused an enhancement of hypertrophy in Tg-WT mice but failed to induce hypertrophy in Tg-Y319F mice. Left ventricular myocardium in Tg-Y319F mice developed significantly less apoptosis and fibrosis than that in Tg-WT mice. EGFR phosphorylation was significantly inhibited in Tg-Y319F mice, confirming that EGFR was not activated in Tg-Y319F mouse hearts. In contrast, activation/phosphorylation of protein kinase C, STAT3, extracellular signal-regulated kinase, and Akt and translocation of G␣q/11 to the cytosolic fraction were maintained in Tg-Y319F hearts. Furthermore, a genetic cross between Tg-WT and transgenic mice with cardiac-specific overexpression of dominant negative EGFR mimicked the phenotype of Tg-Y319F mice.

Determination of the Exact Molecular Requirements for Type 1 Angiotensin Receptor Epidermal Growth Factor Receptor Transactivation and Cardiomyocyte Hypertrophy

“…Although we found no evidence for Y319 phosphorylation, a recent study found Y319 mutation to suppress cardiac hypertrophy in vivo, 9 despite the indication that Y319 was not required for EGFR transactivation in COS-7 or vascular smooth muscle cells. 11,32 Thus, we next investigated whether Y319 mutation disrupted EGFR transactivation or NRVM hypertrophy independent of tyrosine phosphorylation.…”

Autotaxin–lysophosphatidic acid– LPA 3 signaling at the embryo‐epithelial boundary controls decidualization pathways

“…In our results, activation of LPA 3 in the epithelial layer leads to enhanced production of HB‐EGF and COX‐2, which then induces stromal cell growth in an EGFR‐Bmp2/Wnt4‐dependent manner. GPCRs such as β1, AT1, and LPA 6 were previously found to be co‐expressed with EGFR in epithelial cells and to activate (actually transactivate) EGFR by stimulating the ectodomain‐shedding of membrane bound EGF precursors (Zhai et al , 2006; Noma et al , 2007; Inoue et al , 2011). Interestingly, activation of LPA 3 also induced ectodomain‐shedding of HB‐EGF in vitro (Appendix Fig S5), which indicates that the LPA 3 signaling leads to the activation of EGF signaling not only by up‐regulating the expression of HB‐EGF but also by ectodomain‐shedding of HB‐EGF and the following transactivation of EGFR.…”

EGFR Activation Increases Parathyroid Hyperplasia and Calcitriol Resistance in Kidney Disease

“…28 In CKD, increases in parathyroid or renal expression of EGFR ligands and/or G protein-coupled receptor (GPCR) ligands, known to transactivate the EGFR, could further aggravate the severity of EGFR-driven growth and VDR reduction induced by TGF-␣. 14,29 Indeed, EGFR transactivation upon binding to their cognate G protein-coupled receptor mediates the mitogenic properties of molecules that circulate at high levels in patients with CKD, including endothelin I, 30 -32 prostaglandin E2, 33 and AngII, 34,35 in the vasculature and in the hypertrophic growth of cardiac myocytes 30,33,34,36 ; therefore, in CKD, progressive decreases in VDR levels induced by increased EGFR activation/transactivation, at multiple sites in addition to the PTG, could partially account for the resistance to calcitriol antiproliferative and anti-inflammatory actions that accelerate the progression of SH and renal and cardiovascular disorders. BASIC RESEARCH www.jasn.org TGF-␣/EGFR induction of LIP synthesis contributes to the link between severe EGFR-driven growth and VDR reduction.…”