title: The cell polarity protein mInsc regulates neutrophil chemotaxis via a noncanonical G protein signaling pathway.
abstract: Successful chemotaxis requires not only increased motility but also sustained directionality. Here, we show that, during neutrophil chemotaxis via receptors coupled with the Gi family of heterotrimeric G proteins, directional movement is regulated by mInsc, a mammalian protein distantly related to the Drosophila polarity-organizer Inscuteable. The GDP-bound, Gβγ-free Gαi subunit accumulates at the front of chemotaxing neutrophils to recruit mInsc-complexed with the Par3-aPKC evolutionarily conserved polarity complex-via LGN/AGS3 that simultaneously binds to Gαi-GDP and mInsc. Both mInsc-deficient and aPKC-blocked neutrophils exhibit a normal motile activity but migrate in an undirected manner. mInsc deficiency prevents neutrophils from efficiently stabilizing pseudopods at the leading edge; the stability is restored by wild-type mInsc, but not by a mutant protein defective in binding to LGN/AGS3. Thus, mInsc controls directional migration via noncanonical G protein signaling, in which Gβγ-free Gαi-GDP, a product from Gαi-GTP released after receptor activation, plays a central role.
authors.affiliation: Department of Biochemistry, Kyushu University Graduate School of Medical Sciences, Fukuoka 812-8582, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Kamakura
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Nomura
authors.forename: Junya
authors.initials: J
authors.lastname: Hayase
authors.forename: Yuko
authors.initials: Y
authors.lastname: Iwakiri
authors.forename: Akihiko
authors.initials: A
authors.lastname: Nishikimi
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Takayanagi
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Fukui
authors.forename: Hideki
authors.initials: H
authors.lastname: Sumimoto
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism*; D016764:Cell Polarity / Q000502:physiology*; D002630:Chemotactic Factors / Q000502:physiology*; D019143:Evolution, Molecular; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000235:genetics / Q000378:metabolism*; D020730:Guanine Nucleotide Dissociation Inhibitors; D006153:Guanosine Diphosphate / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009504:Neutrophils / Q000166:cytology* / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D011554:Pseudopodia / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D059008:Time-Lapse Imaging
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D015815:Cell Adhesion Molecules; D018797:Cell Cycle Proteins; D002630:Chemotactic Factors; C498915:Gpsm1 protein, mouse; D020730:Guanine Nucleotide Dissociation Inhibitors; C518597:Par6 protein, mouse; C115084:Pard3 protein, mouse; C561632:inscuteable protein, mouse; D006153:Guanosine Diphosphate; D006160:Guanosine Triphosphate; D011493:Protein Kinase C; D019206:GTP-Binding Protein alpha Subunits, Gi-Go