Reelin Dab-bles in the Brain

The secreted protein Reelin controls neuron positioning during embryonic brain development. The intracellular response to Reelin includes phosphorylation of the cytoplasmic protein Dab1 by Src-family tyrosine kinases. To further characterize the Reelin-Dab1 signaling pathway that controls neuronal migration, Ballif et al. identified proteins associated with phosphorylated Dab1 in the mouse brain during cortical development. Dab1-associated proteins were identified by mass spectrometry and included Crk-family proteins. Cultured cortical neurons treated with Reelin stimulated association of endogenous Crk proteins with phosphorylated Dab1. The interaction required phosphorylation of two of four potential tyrosine-phosphorylation sites in Dab1, and the authors speculate that Crk protein dimers may associate with the phosphorylated residues through an SH2 domain present on each monomer. The authors further determined that in response to Reelin, Crk proteins associate with phosphorylated C3G, an exchange protein that acts on the small GTP-binding protein Rap1. An increase in activated, GTP-bound Rap1 was also observed. Rap1 regulates cytoskeletal dynamics and migration and may thus may be a critical downstream effector of a Reelin-Dab1-Crk-C3G signaling pathway that controls neuron placement in the brain. B. A. Ballif, L. Arnaud, W. T. Arthur, D. Guris, A. Imamoto, J. A. Cooper, Activation of a Dab1/CrkL/C3G/Rap1 pathway in Reelin-stimulated neurons. Curr. Biol. 14 , 606-610 (2004). [Online Journal]