Caveolin-1 negatively regulates a metalloprotease-dependent epidermal growth factor receptor transactivation by angiotensin II

Abstract

A metalloprotease, ADAM17, mediates the generation of mature ligands for the epidermal growth factor receptor (EGFR). This is the key signaling step by which angiotensin II (AngII) induces EGFR transactivation leading to hypertrophy and migration of vascular smooth muscle cells (VSMCs). However, the regulatory mechanism of ADAM17 activity remains largely unclear.Here we hypothesized that caveolin-1 (Cav1), the major structural protein of a caveolae, a membrane microdomain, is involved in the regulation of ADAM17. In cultured VSMCs, infection of adenovirus encoding Cav1 markedly inhibited AngII-induced EGFR ligand shedding, EGFR transactivation, ERK activation, hypertrophy and migration, but not intracellular Ca 2+ elevation. Methyl-β-cyclodextrin and filipin, reagents that disrupt raft structure, both stimulated an EGFR ligand shedding and EGFR transactivation in VSMCs. In addition, non-detergent sucrose gradient membrane fractionations revealed that ADAM17 cofractionated with Cav1 in lipid rafts. These results suggest that lipid rafts and perhaps caveolae provide a negative regulatory environment for EGFR transactivation linked to vascular remodeling induced by AngII. These novel findings may provide important information to target cardiovascular diseases under the enhanced renin angiotensin system.

Expression and Function of the Epidermal Growth Factor Receptor in Physiology and Disease

“…Of these signaling molecules, ADAM17 is compartmentalized within caveolae (399). Overexpression of caveolin-1 (Cav1), the major structural protein of caveolae, prevents ANG II-induced hypertrophy and migration of VSMCs through suppression of HB-EGF shedding, EGFR transactivation, and ERK activation (534). However, Cav1 silencing is also protective against EGFR transactivation, suggesting a tight regulatory component via Cav1/caveolae may be critical for EGFR transactivation (535).…”

Transactivation of the epidermal growth factor receptor in responses to myocardial stress and cardioprotection

“…Thus, the EGFR, relevant GPCRs (AT1, endothelin, β-adrenergic, muscarinic, opioid, adenosine), G proteins (α and βγ), Src family kinases, and ADAM17 have been reported to be, at least in part, localised to caveolae in non-cardiac cells (Smart et al, 1995;Mineo et al, 1996;Ushio-Fukai and Alexander, 2006;Takaguri et al, 2011).…”

“…Infection of vascular smooth muscle with adenovirus encoding caveolin-1 inhibits Ang II-induced HB-EGF shedding, EGFR transactivation, ERK activation, hypertrophy and migration (Takaguri et al, 2011).…”

Overexpression of sigma-1 receptor inhibits ADAM10 and ADAM17 mediated shedding in vitro

“…As cholesterol depletion with MβCD can increase the amount of sigma-1 receptor in lipid raft fractions in breast cancer cell lines (Palmer et al, 2007), it is very likely that cholesterol depletion also increased the amount of sigma-1 receptor in lipid raft fraction in our experiments and such translocation might cause relocation of ADAM10 and in turn inhibit its function. On the other hand, ADAM17 has been reported to locate at both lipid raft region (Thiel and Carpenter, 2006;Takaguri et al, 2011) and nonraft region (Parr-Sturgess et al, 2010). Therefore, it is likely ADAM17 could shed HB-EGF in both microenvironments and therefore cholesterol depletion had no effect on ADAM17-dependent HB-EGF shedding (Fig.…”

“…It has been reported that ADAM10 is located in the nonraft region of the membrane of neuroblastoma SH-SY5Y cells when functioning as α-secretase of APP (Harris et al, 2009) and it cannot cleave APP in a cholesterolrich environment (Kojro et al, 2010). Overexpressing caveolin-1 can markedly inhibit angiotensin II-induced ADAM17-dependent EGFR ligand shedding (Takaguri et al, 2011). Therefore, both metalloproteases' function can be modified by lipid raft.…”