Year: 2003
Type: article
Abstract: Antagonists of alphavbeta3 and alphavbeta5 disrupt angiogenesis in response to bFGF and VEGF, respectively. Here, we show that these alphav integrins differentially contribute to sustained Ras-extracellular signal-related kinase (Ras-ERK) signaling in blood vessels, a requirement for endothelial cell survival and angiogenesis. Inhibition of FAK or alphavbeta5 disrupted VEGF-mediated Ras and c-Raf activity on the chick chorioallantoic membrane, whereas blockade of FAK or integrin alphavbeta3 had no effect on bFGF-mediated Ras activity, but did suppress c-Raf activation. Furthermore, retroviral delivery of active Ras or c-Raf promoted ERK activity and angiogenesis, which anti-alphavbeta5 blocked upstream of Ras, whereas anti-alphavbeta3 blocked downstream of Ras, but upstream of c-Raf. The activation of c-Raf by bFGF/alphavbeta3 not only depended on FAK, but also required p21-activated kinase-dependent phosphorylation of serine 338 on c-Raf, whereas VEGF-mediated c-Raf phosphorylation/activation depended on Src, but not Pak. Thus, integrins alphavbeta3 and alphavbeta5 differentially regulate the Ras-ERK pathway, accounting for distinct vascular responses during two pathways of angiogenesis.
Source: The Journal of Cell Biology
Institution: Scripps Research Institute
Language: English
Subfield: Immunology and Allergy
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Awards: G1648785187, G2003983467, G2123497792, Integrin alpha v beta 3 promotes resistance to EGF receptor inhibitors, CRAF-mediated vascular resistance to cancer therapies, VEGF and PDGF in angiogenesis and tumor progression, Combinatorial Chemistry and Cancer Target, G6782846866, G7663115156, Regulation of cell invasion by apoptotic mechanisms, Fragments of TrpRS to Treat Neovascular Eye Diseases
OpenAlex ID: W2088037057