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

Nature Cell Biology volume 7, pages 270–277 (2005)Cite this article

Abstract

A polarity complex of PAR-3, PAR-6 and atypical protein kinase C (aPKC) functions in various cell-polarization events, including neuron specification1,2,3,4. 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.

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Figure 1: Interaction of PAR-3 with STEF in vivo and in vitro.
Figure 2: Interaction of STEF with Cdc42 via the PAR-6–aPKC–PAR-3 complex.
Figure 3: Effects of the PAR complex and STEF fragments on cell morphology in N1E-115 cells.
Figure 4: PAR-3 is required for Cdc42-induced lamellipodia formation in N1E-115 cells.
Figure 5: Effects of the PAR complex and STEF fragments on neurite growth and neuronal polarity in cultured hippocampal neurons.

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Acknowledgements

We thank members of the Kaibuchi lab for useful discussions and for preparing some materials; N. Ui and M. Yoshizaki for technical assistance; and T. Ishii for secretarial assistance. This research was supported, in part, by Grant-in-Aid for Scientific Research; Grant-in-Aid for Creative Scientific Research; The 21st Century Center of Excellence Program from the Ministry of Education, Culture, Sports, Science and Technology of Japan; The Research Grant for Nervous and Mental Disorders from the Ministry of Health, Labour and Welfare; and The Pharmaceuticals and Medical Devices Agency. T.N. is a Research Fellow of the Japan Society for the Promotion of Science.

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Authors and Affiliations

  1. Department of Cell Pharmacology, Graduate School of Medicine, Nagoya University, 65 Tsurumai, Showa, Nagoya, 466-8550, Aichi, Japan

    Takashi Nishimura, Tomoya Yamaguchi, Katsuhiro Kato & Kozo Kaibuchi

  2. Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan

    Masato Yoshizawa, Yo-ichi Nabeshima & Mikio Hoshino

  3. Department of Molecular Biology, Yokohama City University School of Medicine, Fuku-ura 3-9, Kanazawa-ku, Yokohama, 236-0004, Japan

    Shigeo Ohno

  4. PRESTO, JST, 4-1-8 Honcho Kawaguchi, Saitama, 332-0012, Japan

    Mikio Hoshino

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Correspondence to Kozo Kaibuchi.

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Nishimura, T., Yamaguchi, T., Kato, K. et al. PAR-6–PAR-3 mediates Cdc42-induced Rac activation through the Rac GEFs STEF/Tiam1. Nat Cell Biol 7, 270–277 (2005). https://doi.org/10.1038/ncb1227

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