Article
- The EMBO Journal (2004) 23, 1075 - 1088
- doi:10.1038/sj.emboj.7600128
Published online: 26 February 2004
Subject Categories:
Tiam1 mediates neurite outgrowth induced by ephrin-B1 and EphA2
Masamitsu Tanaka1,2, Riuko Ohashi1,a, Ritsuko Nakamura1, Kazuya Shinmura1, Takaharu Kamo1, Ryuichi Sakai2 and Haruhiko Sugimura1
- First Department of Pathology, Hamamatsu University School of Medicine, Handayama, Hamamatsu, Japan
- Growth Factor Division, National Cancer Center Research Institute, Tsukiji, Chuo-ku, Tokyo, Japan
Correspondence to:
Haruhiko Sugimura, First Department of Pathology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu 431-3192, Japan. Tel.: +81 53 435 2220; Fax: +81 53 435 2225; E-mail: hsugimur@hama-med.ac.jp
aPresent address: Division of Cellular and Molecular Pathology, Department of Cellular Function, Niigata University Graduate School of Medical and Dental Sciences, Asahimachi-dori 1, Niigata 951-8510, Japan
Received 9 April 2003; Accepted 19 January 2004
Abstract
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.
Keywords:
- cortical neuron,
- Eph,
- ephrin,
- neurite outgrowth,
- Tiam1
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