hSef potentiates EGF-mediated MAPK signaling through affecting EGFR trafficking and degradation

Abstract

Sef (similar expression to fgf genes) was identified as an effective antagonist of fibroblast growth factor (FGF) in vertebrates. Previous reports have demonstrated that Sef interacts with FGF receptors (FGFRs) and inhibits FGF signaling, however, its role in regulating epidermal growth factor receptor (EGFR) signaling remains unclear. In this report, we found that hSef localizes to the plasma membrane (PM) and is subjected to rapid internalization and well localizes in early/ recycling endosomes while poorly in late endosomes/lysosomes. We observed that hSef interacts and functionally colocalizes with EGFR in early endosomes in response to EGF stimulation. Importantly, we demonstrated that overexpression of hSef attenuates EGFR degradation and potentiates EGF-mediated mitogen-activated protein kinase (MAPK) signaling by interfering EGFR trafficking. Finally, our data showed that, with overexpression of hSef, elevated levels of Erk phosphorylation and differentiation of rat pheochromocytoma (PC12) cells occur in response to EGF stimulation. Taken together, these data suggest that hSef plays a positive role in the EGFRmediated MAPK signaling pathway. This report, for the first time, reveals opposite roles for Sef in EGF and FGF signalings.

IL-17RD (Sef or IL-17RLM) interacts with IL-17 receptor and mediates IL-17 signaling

“…IL-17RD has recently been shown to inhibit FGF signaling [28][29][30][31][32][33] and to facilitate EGF signaling [43]. In this report, we provide data showing that IL-17RD functions in IL-17 signaling, suggesting that IL-17RD has two distinct types of functions.…”

miR-193a-3p is a Key Tumor Suppressor in Ulcerative Colitis–Associated Colon Cancer and Promotes Carcinogenesis through Upregulation of IL17RD

“…In previous studies, IL17RD prevented degradation of EGFR and potentiated EGF signaling in HEK293T human embryonic kidney cells (27). As such, we explored the effect of IL17RD over-expression on proliferation of colon cancer cells with or without EGF treatment.…”

“…Interestingly, IL17RD has been described to inhibit tumorigenesis in vitro through antagonistic effects on fibroblast growth factor (FGF) signaling and inhibition of MAP kinase (MAPK) signaling (22,26,44). In contrast to this tumor suppressing mechanism, Ren et al demonstrated a dual role of IL17RD whereby IL17RD potentiates epidermal growth factor (EGF)-mediated MAPK signaling in the presence of EGF, whereas it exerts opposing effects in the presence of FGF (27). Our findings support this mechanism as basal cell proliferation was inhibited by IL17RD in the absence of EGF treatment, but IL17RD transfection increased cell proliferation in the presence of EGF.…”

A Monoclonal Antibody Against RAGE Alters Gene Expression and is Protective in Experimental Models of Sepsis and Pneumococcal Pneumonia

“…Tnfaip3 is an inhibitor of NF-.B activation, and studies suggest that it is a negative regulator of inflammation (30). In a study of influenza, infection in murine lungs induced Tnfaip3, and overexpression attenuated NF-.B promoter activity in bronchial epithelial cells after infection (31). In a model of airway inflammation, the overexpression of Tnfaip3 decreased inflammation (30).…”