Caveolin-1 differentially regulates the transforming growth factor-β and epidermal growth factor signaling pathways in MDCK cells

• Published in: Biochimica et biophysica acta. General subjects Vol. 1868; no. 9; p. 130660
• Main Authors: Hsiao, Shih-Chuan, Liao, Wei-Hsiang, Chang, Heng-Ai, Lai, Yi-Shyun, Chan, Ta-Wei, Chen, Ying-Chi, Chiu, Wen-Tai
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.09.2024
• Subjects: Animals; Caveolin 1 - genetics; Caveolin 1 - metabolism; Caveolin-1; Caveolin-1 scaffolding domain; Dogs; domain; Epidermal growth factor; Epidermal Growth Factor - metabolism; Epidermal Growth Factor - pharmacology; epidermal growth factor receptors; ErbB Receptors - metabolism; fibrosis; Humans; kidneys; Madin Darby Canine Kidney Cells; Non-canonical pathway; peptides; Phosphorylation; Receptors, Transforming Growth Factor beta - metabolism; Signal Transduction; Transactivation; transcriptional activation; Transforming Growth Factor beta - metabolism; Transforming Growth Factor beta1 - metabolism; Transforming growth factor-β; tyrosine; Caveolin-1; N/C; Cav-1-Y14F-RFP; Non-canonical pathway; EGFR; p-Smad3; TGFβR; Epidermal growth factor; ERK2; CSD; shRNA; MβCD; MDCK; Caveolin-1 scaffolding domain; F.I; EGF; shCav-1; ROI; TGFβR-I; TGFβR-II; p-ERK1/2; Transforming growth factor-β; TGF-β1; Cav-1-WT-RFP; Transactivation; Y14; ERK; shNC
• ISSN: 0304-4165; 1872-8006; 1872-8006
• DOI: 10.1016/j.bbagen.2024.130660

Caveolin-1 is critical for interacting with the TGF-β receptor (TGFβR) and EGF receptor (EGFR) signaling, often observed in advanced cancers and tissue fibrosis. However, the mechanism underlying caveolin-1-mediated transactivation of TGFβR and EGFR signaling remains unclear. Therefore, we sought to determine whether caveolin-1 is involved in canonical and non-canonical TGFβR and EGFR signaling transactivation in this study. Methyl-β-cyclodextrin (MβCD) was used to disrupt the cholesterol-containing membranes domains, and the caveolin-1 scaffolding domain (CSD) peptide was used to mimic the CSD of caveolin-1. Additionally, we transfected the Madin-Darby canine kidney cells with wild-type or phosphorylation-defective caveolin-1. We discovered that tyrosine 14 of caveolin-1 was critical for the negative regulation of TGFβR and EGFR canonical signaling. On the contrary, caveolin-1 inhibited TGF-β1-induced ERK2 activation independent of tyrosine 14 phosphorylation. Although EGF failed to induce Smad3 phosphorylation in caveolin-1 knockdown cells, it activated Smad3 upon MβCD co-treatment, indicating that caveolin-1 indirectly regulated the non-canonical pathway of EGF. In conclusion, caveolin-1 differentially modulates TGFβR and EGFR signaling. Thus, targeting caveolin-1 is a potential strategy for treating diseases involving TGF-β1 and EGF signaling. [Display omitted] •Caveolin-1 is critical for interacting with the TGF-β receptor and EGF receptor signaling in fibrosis and cancers.•Tyrosine 14 of caveolin-1 is critical for the negative regulation of both TGFβR and EGFR canonical signaling.•Caveolin-1 inhibits TGF-β1-induced ERK2 transactivation is independent of caveolin-1 tyrosine 14 phosphorylation.•Caveolin-1 indirectly facilitates EGF-induced Smad3 transactivation.