PAR-6-PAR-3 mediates Cdc42-induced Rac activation through the Rac GEFs STEF/Tiam1

Takashi Nishimura, Tomoya Yamaguchi, Katsuhiro Kato, Masato Yoshizawa, Yo Ichi Nabeshima, Shigeo Ohno, Mikio Hoshino, Kozo Kaibuchi

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Abstract

A polarity complex of PAR-3, PAR-6 and atypical protein kinase C (aPKC) functions in various cell-polarization events, including neuron specification. The small GTPase Cdc42 binds to PAR-6 and regulates cell polarity. However, little is known about the downstream signals of the Cdc42-PAR protein complex. Here, we found that PAR-3 directly interacted with STEF/Tiam1, which are Rac-specific guanine nucleotide-exchange factors, and that STEF formed a complex with PAR-3-aPKC-PAR-6-Cdc42-GTP. Cdc42 induces lamellipodia in a Rac-dependent manner in N1E-115 neuroblastoma cells. Disruption of Cdc42-PAR-6 or PAR-3-STEF binding inhibited Cdc42-induced lamellipodia but not filopodia. The isolated STEF-binding PAR-3 fragment was sufficient to induce lamellipodia independently of Cdc42 and PAR-6. PAR-3 is required for Cdc42-induced Rac activation, but is not essential for lamellipodia formation itself. In cultured hippocampal neurons, STEF accumulated at the tip of the growing axon and colocalized with PAR-3. The spatio-temporal activation and signalling of Cdc42-PAR-6-PAR-3-STEF/Tiam1-Rac seem to be involved in neurite growth and axon specification. We propose that the PAR-6-PAR-3 complex mediates Cdc42-induced Rac activation by means of STEF/Tiam1, and that this process seems to be required for the establishment of neuronal polarity.

Original languageEnglish
Pages (from-to)270-277
Number of pages8
JournalNature Cell Biology
Volume7
Issue number3
DOIs
Publication statusPublished - 03-2005

All Science Journal Classification (ASJC) codes

  • Cell Biology

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    Nishimura, T., Yamaguchi, T., Kato, K., Yoshizawa, M., Nabeshima, Y. I., Ohno, S., Hoshino, M., & Kaibuchi, K. (2005). PAR-6-PAR-3 mediates Cdc42-induced Rac activation through the Rac GEFs STEF/Tiam1. Nature Cell Biology, 7(3), 270-277. https://doi.org/10.1038/ncb1227