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10.1074/jbc.M114.576827

http://scihub22266oqcxt.onion/10.1074/jbc.M114.576827
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C4067212!4067212 !24808183
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suck abstract from ncbi


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pmid24808183
      J+Biol+Chem 2014 ; 289 (25 ): 17791-801
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  • A chemical biology approach demonstrates G protein ?? subunits are sufficient to mediate directional neutrophil chemotaxis #MMPMID24808183
  • Surve CR ; Lehmann D ; Smrcka AV
  • J Biol Chem 2014[Jun]; 289 (25 ): 17791-801 PMID24808183 show ga
  • Our laboratory has identified a number of small molecules that bind to G protein ?? subunits (G??) by competing for peptide binding to the G?? "hot spot." M119/Gallein were identified as inhibitors of G?? subunit signaling. Here we examine the activity of another molecule identified in this screen, 12155, which we show that in contrast to M119/Gallein had no effect on G??-mediated phospholipase C or phosphoinositide 3-kinase (PI3K) ? activation in vitro. Also in direct contrast to M119/Gallein, 12155 caused receptor-independent Ca(2+) release, and activated other downstream targets of G?? including extracellular signal regulated kinase (ERK), protein kinase B (Akt) in HL60 cells differentiated to neutrophils. We show that 12155 releases G?? in vitro from G?i1?1?2 heterotrimers by causing its dissociation from G?GDP without inducing nucleotide exchange in the G? subunit. We used this novel probe to examine the hypothesis that G?? release is sufficient to direct chemotaxis of neutrophils in the absence of receptor or G protein ? subunit activation. 12155 directed chemotaxis of HL60 cells and primary neutrophils in a transwell migration assay with responses similar to those seen for the natural chemotactic peptide n-formyl-Met-Leu-Phe. These data indicate that release of free G?? is sufficient to drive directional chemotaxis in a G protein-coupled receptor signaling-independent manner.
  • |Animals [MESH]
  • |Calcium/metabolism [MESH]
  • |Chemotaxis/drug effects/*physiology [MESH]
  • |Cyclohexanes/chemistry/pharmacology [MESH]
  • |Extracellular Signal-Regulated MAP Kinases/genetics/metabolism [MESH]
  • |GTP-Binding Protein alpha Subunits, Gi-Go/genetics/metabolism [MESH]
  • |GTP-Binding Protein beta Subunits/antagonists & inhibitors/genetics/*metabolism [MESH]
  • |GTP-Binding Protein gamma Subunits/antagonists & inhibitors/genetics/*metabolism [MESH]
  • |HL-60 Cells [MESH]
  • |Humans [MESH]
  • |Mice [MESH]
  • |N-Formylmethionine Leucyl-Phenylalanine/pharmacology [MESH]
  • |Neutrophils/cytology/*metabolism [MESH]
  • |Proto-Oncogene Proteins c-akt/genetics/metabolism [MESH]
  • |Signal Transduction/drug effects/*physiology [MESH]


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