Convergence of Angiotensin II and Platelet-derived Growth Factor Receptor Signaling Cascades in Vascular Smooth Muscle Cells

Abstract

Signaling cascades elicited by angiotensin II resemble those characteristic of growth factor stimulation. In this report, we demonstrate that angiotensin II converges with platelet-derived growth factor (PDGF) beta-receptor signaling cascades, independent of PDGF. Stimulation of smooth muscle cells with angiotensin II resulted in tyrosine phosphorylation on Shc proteins and subsequent complex formation between Shc and growth factor receptor binding protein-2 (GRB2). A 180-kDa protein co-precipitating with Shc.GRB2 complexes also demonstrated increased phosphorylation in response to angiotensin II. Immunoblot analyses and proteolytic digests failed to distinguish this 180-kDa protein from authentic PDGF beta-receptors. Corresponding with Shc and PDGF receptor phosphorylation induced by angiotensin II was the recruitment and phosphorylation of c-Src. Autocrine release of platelet-derived growth factor failed to account for Shc complex formation at the PDGF receptor following angiotensin II treatment, and a specific angiotensin II type I receptor antagonist, losartan, abolished the response. These results support a novel model for cross-talk between the G-protein-linked angiotensin II receptor and the PDGF receptor tyrosine kinase in vascular smooth muscle cells. Communication with the PDGF receptor may account for the ability of angiotensin II to elicit responses typical of growth factor signal transduction.

PTHrP on MCF-7 breast cancer cells: a growth factor or an antimitogenic peptide?

“…Probably, Hoey is dealing with the so-called transactivation of growth factors tyrosine kinase (TK) receptors by PTHrP G-protein-coupled receptor (GPCR) (Linseman et al, 1995;Lowes et al, 2002). We observed a similar phenomenon in 2002 while culturing skin fibroblasts in the presence of serum (then of growth factors) .…”

“…Hoey describes an effect of PTHrP on cell sensitivity to growth factors, but this is not a novel phenomenon, as it was already described by Linseman et al (1995). Probably, Hoey is dealing with the so-called transactivation of growth factors tyrosine kinase (TK) receptors by PTHrP G-protein-coupled receptor (GPCR) (Linseman et al, 1995;Lowes et al, 2002).…”

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].…”

Cell growth control by G protein-coupled receptors: from signal transduction to signal integration

“…Receptors of the tyrosine kinase class have been also shown to play a role in GPCR signaling. For example, PDGF and EGF receptors were found to become tyrosine-phosphorylated upon GPCR stimulation (Daub et al, 1996;Linseman et al, 1995), and to participate in MAPK activation by GPCRs. We can conclude that a number of receptor and non-receptor tyrosine kinases might link GPCRs to the Ras-MAPK pathway.…”