EphA4 promotes cell proliferation and migration through a novel EphA4-FGFR1 signaling pathway in the human glioma U251 cell line

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. [Mol Cancer Ther 2008;7(9):2768 -78]

The tetraspanin CD9 regulates migration, adhesion, and homing of human cord blood CD34+ hematopoietic stem and progenitor cells

“…7 Other SDF-1-modulated genes identified in our profiling experiments only displayed modest overlapping with those reported by Rossi et al 19 This discrepancy could be due to the difference in the source of CD34 ϩ cells (cord blood vs granulocyte-colony stimulating factormobilized peripheral blood) 45 and the duration of SDF-1 treatment (4 hours vs 24 hours). Although some of the SDF-1-regulated genes in cord blood CD34 ϩ cells have known homing functions (eg, MMP-9 7 and integrins 5 ), we discovered many others (eg, CD9, 22 CKLF, 46 and EPHA4 47 ) that have not been characterized in hematopoietic progenitors but were involved in regulating homingrelated functions in other cell types. Our microarray data have thus provided a useful platform for the identification of novel intrinsic regulators of HSC homing.…”

Direct interaction of receptor tyrosine kinases, EphA4 and PDGFRβ, plays an important role in the proliferation of neural stem cells

“…Cell-cell contact-dependent signaling pathway from ephrins to Ephs (forward signaling) or from Ephs to ephrins (reverse signaling) regulates many physiological and developmental processes. Bidirectional signaling possesses many functions, including neural stem cell maintenance and plasticity regulation in the proliferation zone of adult brain, 6,7 neuron migration, 8 axon guidance, 9 angiogenesis, 10 bone homeostasis, 11 embryonic patterning, 12 tumorgenesis, [13][14][15][16][17][18] insulin secretion, 19 and so on. EphA4 expression is very high in the brain, and recently, EphA4 has been proposed to be implicated in Alzheimer's disease (AD), 20,21 Parkinson's disease (PD), 22,23 amyotrophic lateral sclerosis (ALS), 24 and other neurodegenerative diseases.…”

Fibroblast Growth Factors and their Emerging Cancer-Related Aspects

“…This path indicates the role of Ras that is can be activated by two separate proteins, in the activation of MAPK. FRS2 [106] and Shc-src homology 2 containing protein [107]. Proliferating cells express both of these proteins.…”