EphA Receptors Regulate Growth Cone Dynamics through the Novel Guanine Nucleotide Exchange Factor Ephexin

Shamah, Steven M.; Lin, Michael Z.; Goldberg, Jeffrey L.; Estrach, Soline; Şahin, Mustafa; Hu, Linda; Bazalakova, Mihaela H.; Neve, Rachel L.; Corfas, Gabriel; Debant, Anne; Greenberg, Michael E.

doi:10.1016/s0092-8674(01)00314-2

Cited by 492 publications

(486 citation statements)

References 34 publications

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“…The reason might be that the U251 glioma cells expressed little ephexin, a guanine nucleotide exchanging factor for Rho, which was identified as a direct signaling molecule relayed from EphA4 (data not shown; ref. 47). On the contrary, Rac1 and Cdc42 were both activated by FGF2 or ephrin-A1 stimulation and EphA4 further enhanced these activities.…”

Section: Discussionmentioning

confidence: 99%

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

Fukai

Yokote²,

Yamanaka³

et al. 2008

Molecular Cancer Therapeutics

127

112

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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]

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Section: Discussionmentioning

confidence: 99%

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

Fukai

Yokote²,

Yamanaka³

et al. 2008

Molecular Cancer Therapeutics

127

112

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“…Ephrin-stimulated growth cone collapse occurs through activation of rho and ROCK (Wahl et al 2000). A novel rhoGEF, ephexin, has been identified downstream of the Ephrin receptor and is required for Ephrin-stimulated retraction (Shamah et al 2001). GEF64C, a Dbl family member in Drosophila, causes too many neurons to cross the midline when overexpressed.…”

Section: Rho Gtpases: Organizers Of Actin Structuresmentioning

confidence: 99%

Signaling mechanisms that regulate actin‐based motility processes in the nervous system

Meyer

Feldman

2002

Journal of Neurochemistry

172

108

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Actin-based motility is critical for nervous system development. Both the migration of neurons and the extension of neurites require organized actin polymerization to push the cell membrane forward. Numerous extracellular stimulants of motility and axon guidance cues regulate actin-based motility through the rho GTPases (rho, rac, and cdc42). The rho GTPases reorganize the actin cytoskeleton, leading to stress fiber, filopodium, or lamellipodium formation. The activity of the rho GTPases is regulated by a variety of proteins that either stimulate GTP uptake (activation) or hydrolysis (inactivation). These proteins potentially link extracellular signals to the activation state of rho GTPases. Effectors downstream of the rho GTPases that directly influence actin polymerization have been identified and are involved in neurite development.The Arp2/3 complex nucleates the formation of new actin branches that extend the membrane forward. Ena/VASP proteins can cause the formation of longer actin filaments, characteristic of growth cone actin morphology, by preventing the capping of barbed ends. Actin-depolymerizing factor (ADF)/cofilin depolymerizes and severs actin branches in older parts of the actin meshwork, freeing monomers to be re-incorporated into actively growing filaments. The signaling mechanisms by which extracellular cues that guide axons to their targets lead to direct effects on actin filament dynamics are becoming better understood. Keywords: actin-depolymerizing factor (ADF)/cofilin, actinrelated protein Arp2/3, ena/VASP, LIM kinase, rho GTPase.

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“…The mouse ortholog of Ngef, ephexin, is expressed in the central nervous system during development and was originally cloned on the basis of its ability to interact with the EphA4 receptor tyrosine kinase. Ephexin was shown to activate RhoA, Rac1, and Cdc42 in cell-based assays and mediate ephrinA-induced growth cone collapse (14). In addition, ephexin was shown to be phosphorylated by Src-family kinases downstream of EphA4 receptor activation (13).…”

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confidence: 98%

Role of the C-Terminal SH3 Domain and N-Terminal Tyrosine Phosphorylation in Regulation of Tim and Related Dbl-Family Proteins

2008

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Dbl-related oncoproteins are guanine nucleotide exchange factors (GEFs) specific for Rho-family GTPases and typically possess tandem Dbl (DH) and pleckstrin homology (PH) domains that act in concert to catalyze exchange. Although the exchange potential of many Dbl-family proteins is constitutively activated by truncation, the precise mechanisms of regulation for many Dbl-family proteins are unknown. Tim and Vav are distantly related Dbl-family proteins that are similarly regulated; their Dbl homology (DH) domains interact with N-terminal helices to exclude and prevent activation of Rho GTPases. Phosphorylation, substitution, or deletion of the blocking helices relieves this autoinhibition. Here we show that two other Dbl-family proteins, Ngef and Wgef, which like Tim contain a C-terminal SH3 domain, are also activated by tyrosine phosphorylation of a blocking helix. Consequently, basal autoinhibition of DH domains by direct steric exclusion using short Nterminal helices likely represents a conserved mechanism of regulation for the large family of Dblrelated proteins. N-Terminal truncation or phosphorylation of many other Dbl-family GEFs leads to their activation; similar autoinhibition mechanisms could explain some of these events. In addition, we show that the C-terminal SH3 domain binding to a polyproline region N-terminal to the DH domain of the Tim subgroup of Dbl-family proteins provides a unique mechanism of regulated autoinhibition of exchange activity that is functionally linked to the interactions between the autoinhibitory helix and the DH domain.The activation cycle of Rho GTPases 1 is tightly controlled by three families of proteins: GTPase-activating proteins (GAPs), guanine nucleotide dissociation inhibitors (GDIs), and guanine nucleotide exchange factors (GEFs). The Dbl family of proteins constitutes the largest group of GEFs specific for Rho GTPases. Dbl-family proteins are characterized by a Dbl homology (DH) domain, which contacts the Rho GTPase to catalyze nucleotide exchange by promoting and stabilizing an intermediate, nucleotide-free GTPase state, and an associated pleckstrin homology (PH) domain, which fine-tunes the exchange process. The 69 human Dbl-

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EphA Receptors Regulate Growth Cone Dynamics through the Novel Guanine Nucleotide Exchange Factor Ephexin

Cited by 492 publications

References 34 publications

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

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

Signaling mechanisms that regulate actin‐based motility processes in the nervous system

Role of the C-Terminal SH3 Domain and N-Terminal Tyrosine Phosphorylation in Regulation of Tim and Related Dbl-Family Proteins

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