Abstract
The Eph receptor tyrosine kinases and their ephrin ligands form a unique cell-cell contact-mediated bidirectional signaling mechanism for regulating cell localization and organization. High expression of Eph receptors in a wide variety of human tumors indicates some roles in tumor progression, which makes these proteins potential targets for anticancer therapy. For this purpose, we did gene expression profiling for 47 surgical specimens of brain tumors including 32 high-grade glioma using a microarray technique. The analysis, focused on the receptor tyrosine kinases, showed that EphA4 mRNA in the tumors was 4-fold higher than in normal brain tissue. To investigate the biological significance of EphA4 overexpression in these tumors, we analyzed EphA4-induced phenotypic changes and the signaling mechanisms using human glioma U251 cells. EphA4 promoted fibroblast growth factor 2-mediated cell proliferation and migration accompanied with enhancement of fibroblast growth factor 2-triggered mitogen-activated protein kinase and Akt phosphorylation. In addition, active forms of Rac1 and Cdc42 increased in the EphA4-overexpressing cells. Furthermore, we found that EphA4 formed a heteroreceptor complex with fibroblast growth factor receptor 1 (FGFR1) in the cells and that the EphA4-FGFR1 complex potentiated FGFR-mediated downstream signaling. Thus, our results indicate that EphA4 plays an important role in malignant phenotypes of glioblastoma by enhancing cell proliferation and migration through accelerating a canonical FGFR signaling pathway.
Highlights
The Eph receptors represent the largest family of receptor protein tyrosine kinases and interact with their ligands, ephrins
High Expression of EphA4 mRNA in Malignant Glioma We analyzed the expression of 13,156 clones from Incyte’s human cDNA library genes using Agilent human cDNA microarrays (Agilent Technologies) for 32 malignant gliomas consisting of 10 anaplastic astrocytomas and 22 glioblastomas
EphA4 was weakly phosphorylated by exogenous addition of FGF2 (Supplementary Fig. S3).6. These results showed that EphA4 enhanced FGF2-triggered activation of fibroblast growth factor receptor 1 (FGFR1) through a EphA4-FGFR1 heteroreceptor complex, which possibly explained the reason that EphA4 promoted downstream signaling of fibroblast growth factor receptor (FGFR) and contributed to glioma cell proliferation and migration
Summary
The Eph receptors represent the largest family of receptor protein tyrosine kinases and interact with their ligands, ephrins. The Eph receptors and ephrins are divided into two subclasses, A and B, based on their homologies, structures, and binding affinities [1]. Fourteen Eph receptors and eight ephrin ligands have been identified far in mammals (2 – 4). The Eph-ephrin system relays a direct cell-cell contact-mediated bidirectional signaling pathway [5, 6]. This bidirectional signaling is fundamentally involved in developmental processes (7 – 9) or in the remodeling of blood vessels [10, 11]. It is speculated that Eph signaling could play some roles in tumorigenesis as one of their possible consequences
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