Abstract Fibrosarcoma is a tumor of mesenchymal origin, originating from fibroblasts. IGF-I is an anabolic growth factor which exhibits significant involvement in cancer progression. In this study, we investigated the possible participation of syndecan-2 (SDC-2), a cell membrane heparan sulfate (HS) proteoglycan on IGF-I dependent fibrosarcoma cell motility. Our results demonstrate that SDC-2-deficient HT1080 cells exhibit attenuated IGF-I-dependent chemotactic migration (p < 0.001). SDC-2 was found to co-localize to IGF-I receptor (IGF-IR) in a manner dependent on IGF-I activity (P ≤ 0.01). In parallel, the downregulation of SDC-2 significantly inhibited both basal and due to IGF-I action ERK1/2 activation, (p < 0.001). The phosphorylation levels of ezrin (Thr567), which is suggested to act as a signaling bridge between the cellular membrane receptors and actin cytoskeleton, were strongly enhanced by IGF-I at both 1h and 24h (p < 0.05; p < 0.01). The formation of an immunoprecipitative complex revealed an association between SDC2 and ezrin which was enhanced through IGF-I action (p < 0.05). Immunoflourescence demonstrated a co-localization of IGF-IR, SDC2 and ezrin upregulated by IGF-I action. IGF-I enhanced actin polymerization and ezrin/actin specific localization to cell membranes. Finally, treatment with IGF-I strongly increased SDC2 expression at both the mRNA and protein level (p < 0.001). Therefore, we propose a novel SDC2-dependent mechanism, where SDC2 is co-localized with IGF-IR and enhances its’ IGFI-dependent downstream signaling. SDC2 mediates directly IGFI-induced ERK1/2 activation, it recruits ezrin, contributes to actin polymerization and ezrin/actin specific localization to cell membranes, ultimately facilitating the progression of IGFI-dependent fibrosarcoma cell migration. Highlights IGF-I exhibits significant involvement in cancer progression. Syndecan-2 (SDC-2), has a discrete role in mesenchymal tumors progression. SDC2 facilitates IGF-I-dependent HT1080 fibrosarcoma cell chemotactic migration. SDC2 / IGF-IR / ezrin co-localization is demonstrated. Mediator co-localization enhances actin polymerization and membrane linking.
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