Tiam1 mediates neurite outgrowth induced by ephrin-B1 and EphA2

EMBO J. 2004 Mar 10;23(5):1075-88. doi: 10.1038/sj.emboj.7600128. Epub 2004 Feb 26.


Bidirectional signals mediated by Eph receptor tyrosine kinases and their membrane-bound ligands, ephrins, play pivotal roles in the formation of neural networks by induction of both collapse and elongation of neurites. However, the downstream molecular modules to deliver these cues are largely unknown. We report here that the interaction of a Rac1-specific guanine nucleotide-exchanging factor, Tiam1, with ephrin-B1 and EphA2 mediates neurite outgrowth. In cells coexpressing Tiam1 and ephrin-B1, Rac1 is activated by the extracellular stimulation of clustered soluble EphB2 receptors. Similarly, soluble ephrin-A1 activates Rac1 in cells coexpressing Tiam1 and EphA2. Cortical neurons from the E14 mouse embryos and neuroblastoma cells significantly extend neurites when placed on surfaces coated with the extracellular domain of EphB2 or ephrin-A1, which were abolished by the forced expression of the dominant-negative mutant of ephrin-B1 or EphA2. Furthermore, the introduction of a dominant-negative form of Tiam1 also inhibits neurite outgrowth induced by the ephrin-B1 and EphA2 signals. These results indicate that Tiam1 is required for neurite outgrowth induced by both ephrin-B1-mediated reverse signaling and EphA2-mediated forward signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Size
  • Cells, Cultured
  • Chlorocebus aethiops
  • Cytoplasm / metabolism
  • Ephrin-A2 / genetics
  • Ephrin-A2 / metabolism*
  • Ephrin-B1 / genetics
  • Ephrin-B1 / metabolism*
  • Guanine Nucleotide Exchange Factors
  • Humans
  • Mice
  • Neurites / metabolism*
  • Protein Binding
  • Protein Structure, Tertiary
  • Proteins / genetics
  • Proteins / metabolism*
  • Signal Transduction
  • T-Lymphoma Invasion and Metastasis-inducing Protein 1
  • rac1 GTP-Binding Protein / metabolism


  • Ephrin-A2
  • Ephrin-B1
  • Guanine Nucleotide Exchange Factors
  • Proteins
  • T-Lymphoma Invasion and Metastasis-inducing Protein 1
  • TIAM1 protein, human
  • Tiam1 protein, mouse
  • rac1 GTP-Binding Protein