title: PAR3-aPKC regulates Tiam1 by modulating suppressive internal interactions.
abstract: Tiam1 is one of the most extensively analyzed activators of the small GTPase Rac. However, fundamental aspects of its regulation are poorly understood. Here we demonstrate that Tiam1 is functionally suppressed by internal interactions and that the PAR complex participates in its full activation. The N-terminal region of Tiam1 binds to the protein-binding and catalytic domains to inhibit its localization and activation. Atypical PKCs phosphorylate Tiam1 to relieve its intramolecular interactions, and the subsequent stabilization of its interaction with PAR3 allows it to exert localized activity. By analyzing Tiam1 regulation by PAR3-aPKC within the context of PDGF signaling, we also show that PAR3 directly binds PDGF receptor β. Thus we provide the first evidence for the negative regulation of Tiam1 by internal interactions, elucidate the nature of Tiam1 regulation by the PAR complex, and reveal a novel role for the PAR complex in PDGF signaling.
authors.affiliation: Department of Cell Pharmacology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Matsuzawa
authors.affiliation: Department of Cell Pharmacology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Akita
authors.affiliation: Department of Cell Pharmacology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: Department of Cell Pharmacology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Mai
authors.initials: M
authors.lastname: Kakeno
authors.affiliation: Department of Cell Pharmacology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Toshinori
authors.initials: T
authors.lastname: Matsui
authors.affiliation: Department of Neural Regeneration and Cell Communication, Graduate School of Medicine, Mie University, Tsu 514-8507, Japan.
authors.forename: Shujie
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Cell Pharmacology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan kaibuchi@med.nagoya-u.ac.jp.
authors.forename: Kozo
authors.initials: K
authors.lastname: Kaibuchi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D018929:Cell Culture Techniques; D018797:Cell Cycle Proteins; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D006801:Humans; D051379:Mice; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D011485:Protein Binding; D000072417:Protein Domains; D051571:Protein Kinase C-alpha / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D051381:Rats; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D015398:Signal Transduction; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; D020744:rac GTP-Binding Proteins / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015815:Cell Adhesion Molecules; D018797:Cell Cycle Proteins; D020662:Guanine Nucleotide Exchange Factors; C115084:Pard3 protein, mouse; D010982:Platelet-Derived Growth Factor; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; C513260:Tiam1 protein, mouse; D017479:Receptors, Platelet-Derived Growth Factor; D051571:Protein Kinase C-alpha; D020744:rac GTP-Binding Proteins