Connecting EphrinA to the Cytoskeleton

Science's STKE  24 Apr 2001:
Vol. 2001, Issue 79, pp. tw6
DOI: 10.1126/stke.2001.79.tw6

Ephrins are repulsive signals for neuron migration. A yeast two-hybrid screen with the ephrinA4 receptor (EphA4) identified a novel member of the Dbl family of guanine exchange factors (GEFs), Shamah et al. have named ephexin. The interaction was confirmed through coprecipitation experiments with transfected cells. An expression pattern in rat brain that is spatially and temporally similar to the expression of EphA4 supports a role for ephexin in Eph receptor signaling. Ephexin strongly stimulated RhoA and Cdc42 guanosine triphosphatases (GTPases) and weakly stimulated the GTPase Rac1 in vitro and in embryonic cortical neurons that overexpress ephexin. Activation of EphA receptors in wild-type and ephexin-overexpressing cortical neurons produced an inhibition of activation of the kinase Pak, suggesting that Eph receptors inhibit ephexin activity toward Rac1 and Cdc42. In cultured retinal ganglion cells, overexpression of ephexin enhanced growth-cone collapse caused by activation of EphA receptors, and expression of a GEF inactive mutant of ephexin blocked growth-cone collapse. Finally, analysis of the effect of ephexin on the actin cytoskeleton in transfected fibroblasts suggests that activation of the EphA4 receptor in cells also expressing ephexin leads to inhibition of ephexin-mediated formation of lamellapodia and filopodia and stimulation of ephexin-mediated formation of stress fibers, suggesting that EphA receptors enhance ephexin activity toward RhoA and inhibit ephexin activity toward Rac1 and Cdc42.

S. M. Shamah, M. Z. Lin, J. L. Goldberg, S. Estrach, M. Sahin, L. Hu, M. Bazalakova, R. L. Neve, G. Corfas, A. Debant, M .E. Greenberg, EphA receptors regulate growth cone dynamics through the novel guanine exchange factor ephexin. Cell 105, 233-244 (2001). [Online Journal]