Background: Osteopontin (OPN) promotes the migration and adhesion of vascular smooth muscle cells (VSMCs) through cell surface receptor, integrin beta3. In order to elucidate the signaling pathway by which OPN is involved in neointimal formation, we focused on integrin beta3-focal adhesion kinase (FAK) upon VSMC migration.
Methods: The integrin beta3 and FAK expression in VSMC and in neointima was detected by Western blot and immunohistochemistry staining. FAK phosphorylation induced by OPN was verified using a linear OPN 13 peptide containing RGD motif and anti-OPN antibody. The role of integrin beta3-FAK pathway in VSMC adhesion and migration induced with OPN was tested by the overexpression of FAK-related nonkinase and integrin beta3 cytoplasmic domain.
Results: The results showed that OPN increased integrin beta3 expression and induced rapid and transient FAK phosphorylation. Inhibition of the phosphorylation of FAK significantly suppressed VSMC migration induced by OPN. Similarly, blockade of the interaction of integrin beta3 with OPN inhibited VSMC adhesion induced by OPN. The experiment, in vivo, demonstrated that OPN expression level was consistent with neointimal thickening. Administration of anti-OPN antibody for blocking OPN function suppressed integrin beta3 and FAK expression induced by balloon injury, and neointimal thickening was inhibited.
Conclusions: These data indicate that integrin beta3-FAK signaling modulates OPN-induced VSMC migration during neointimal formation.
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| http://dx.doi.org/10.1016/j.carpath.2007.04.002 | DOI Listing |
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Gastric cancer (GC) remains a significant global health burden due to its high aggressiveness, early metastasis, and poor prognosis. Despite advances in chemotherapy and targeted therapies, drug resistance remains a major obstacle to improving patient outcomes. Integrins, a family of transmembrane receptors, play a pivotal role in mediating tumor growth, invasion, and drug resistance by interacting with the tumor microenvironment (TME) and regulating signaling pathways such as Wnt/β-catenin, FAK, and MAPK.
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Mechanobiology Institute, National University of Singapore, Singapore 117411, Singapore.
Transmembrane signaling receptors, such as integrins, organize as nanoclusters that provide several advantages, including increasing avidity, sensitivity (increasing the signal-to-noise ratio), and robustness (signaling threshold) of the signal in contrast to signaling by single receptors. Furthermore, compared to large micron-sized clusters, nanoclusters offer the advantage of rapid turnover for the disassembly of the signal. However, whether nanoclusters function as signaling hubs remains poorly understood.
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