Calcium-dependent Epidermal Growth Factor Receptor Transactivation Mediates the Angiotensin II-induced Mitogen-activated Protein Kinase Activation in Vascular Smooth Muscle Cells

Abstract

We have recently reported that angiotensin II (Ang II)-induced mitogen-activated protein kinase (MAPK) activation is mainly mediated by Ca 2؉ -dependent activation of a protein tyrosine kinase through G q -coupled Ang II type 1 receptor in cultured rat vascular smooth muscle cells (VSMC). In the present study, we found Ang II rapidly induced the tyrosine phosphorylation of the epidermal growth factor (EGF) receptor and its association with Shc and Grb2. These reactions were inhibited by the EGF receptor kinase inhibitor, AG1478. The Ang II-induced phosphorylation of the EGF receptor was mimicked by a Ca 2؉ ionophore and completely inhibited by an intracellular Ca 2؉ chelator. Thus, AG1478 abolished the MAPK activation induced by Ang II, a Ca 2؉ ionophore as well as EGF but not by a phorbol ester or platelet-derived growth factor-BB in the VSMC. Moreover, Ang II induced association of EGF receptor with catalytically active c-Src. This reaction was not affected by AG1478. These data indicate that Ang II induces Ca 2؉ -dependent transactivation of the EGF receptor which serves as a scaffold for pre-activated c-Src and for downstream adaptors, leading to MAPK activation in VSMC.

The galanin receptor type 2 initiates multiple signaling pathways in small cell lung cancer cells by coupling to Gq, Gi and G12 proteins

“…In vascular smooth muscle cells and in neuroendocrine PC12 cells, a rise in [Ca 2+ ] i appears to be su cient to engage the ERK cascade via growth factor-independent tyrosine phosphorylation of receptor tyrosine kinases (Eguchi et al, 1998;Zwick et al, 1997). In these cellular settings Pyk2, a focal adhesion kinase related tyrosine kinase independently activated by Ca 2+ and phorbol esters (Lev et al, 1995), has recently been placed upstream of receptor tyrosine kinases in the signaling pathway from G q/11 -coupled receptors to ERKs (Eguchi et al, 1999;Solto , 1998).…”

Neferine inhibits angiotensin II-stimulated proliferation in vascular smooth muscle cells through heme oxygenase-1

“…Early in 2001, EI Mabrouk et al demonstrated that ERK1/2 phosphorylation is dose dependently increased by Ang II in VSMCs from spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats, and the ERK1/2 inhibitor PD-98059 can block Ang IIinduced VSMC growth [21] . In VSMCs, Ang II type I receptorinduced ERK1/2 activation occurs via Ca 2+ and Src-dependent transactivation of the EGFR [33,34] . Ang II can activate ERK1/2 by the Ras/PKCzeta/MEK pathway in VSMC [35] .…”

The angiotensin II type 1 receptor and receptor-associated proteins

“…The effects of Gq-protein-mediated activation of the AT1 receptor varies in different tissues, including vasoconstriction, aldosterone release, renal sodium reabsorption, adrenergic facilitation, VSMC hypertrophy and cardiac myocyte hyperplasia. In VSMC, Ang II activates numerous tyrosine phosphorylated proteins, which share similarity with that the response to growth factors and cytokines, including the JAK kinase family, JAK2 and Tyk2 [38], [39], the Src kinase family, Fyn and c-Src [40], [41], the growth factor receptor family, platelet-derived growth factor receptor (PDGFR), epidermal growth factor receptor (EGFR) and insulin growth factor receptor (IGFR) [42][43][44][45][46], the STAT transcriptional factor family [47], [48], and the cell adhesion proteins, Paxillin and focal adhesion kinase (FAK) [49], [50]. In addition, the adaptor protein SHC, tyrosine phosphatase SHP2, PLC-γ1, p130CAS and insulin receptor substance 1 (IRS1) are also tyrosinephosphorylated in response to Ang II [42], [51][52][53].…”

“…The pathway was also found by using EGFR, which provides a scaffold for the activation of MAP kinase cascades [44][45][46]. EGFR was tyrosine-phosphorylated by unknown tyrosine kinases, but it was clearly demonstrated that EGFR activity was not activated by Ang II stimulation.…”