title: PAR-6-PAR-3 mediates Cdc42-induced Rac activation through the Rac GEFs STEF/Tiam1.
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.
authors.affiliation: Department of Cell Pharmacology, Graduate School of Medicine, Nagoya University, 65 Tsurumai, Showa, Nagoya, Aichi 466-8550, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nishimura
authors.forename: Tomoya
authors.initials: T
authors.lastname: Yamaguchi
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Kato
authors.forename: Masato
authors.initials: M
authors.lastname: Yoshizawa
authors.forename: Yo-ichi
authors.initials: Y
authors.lastname: Nabeshima
authors.forename: Shigeo
authors.initials: S
authors.lastname: Ohno
authors.forename: Mikio
authors.initials: M
authors.lastname: Hoshino
authors.forename: Kozo
authors.initials: K
authors.lastname: Kaibuchi
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism; D019556:COS Cells; D002352:Carrier Proteins / Q000378:metabolism / Q000502:physiology*; D045744:Cell Line, Tumor; D018076:DNA, Complementary / Q000378:metabolism; D004789:Enzyme Activation; D005982:Glutathione Transferase / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D047468:Immunoprecipitation; D008856:Microscopy, Fluorescence; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000378:metabolism / Q000502:physiology*; D034741:RNA, Small Interfering / Q000378:metabolism; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism*; D020744:rac GTP-Binding Proteins / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D018076:DNA, Complementary; D020662:Guanine Nucleotide Exchange Factors; D009419:Nerve Tissue Proteins; C472451:Pard3 protein, rat; D011506:Proteins; D034741:RNA, Small Interfering; D049452:Green Fluorescent Proteins; D005982:Glutathione Transferase; D020764:cdc42 GTP-Binding Protein; D020744:rac GTP-Binding Proteins