July 1, 2007 Journal article Closed Access

André Nantel; André Nantel; Colin L. Stewart; Maria Huber; Matthew G. Annis; John P. Hagan; Josée Ash; Malcolm Whiteway; Malcolm Whiteway; Sem Kebache; Jennifer Hassard

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  "doi": "10.1074/jbc.m611066200", 
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        "name": "Andr\u00e9 Nantel"
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      {
        "name": "Andr\u00e9 Nantel"
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      {
        "name": "Colin L. Stewart"
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      {
        "name": "Maria Huber"
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      {
        "name": "Matthew G. Annis"
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      {
        "name": "John P. Hagan"
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      {
        "name": "Jos\u00e9e Ash"
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      {
        "name": "Malcolm Whiteway"
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      {
        "name": "Malcolm Whiteway"
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      {
        "name": "Sem Kebache"
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      {
        "name": "Jennifer Hassard"
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    "description": "The proapoptotic protein Bad is a key player in cell survival decisions, and is regulated post-translationally by several signaling networks. We expressed Bad in mouse embryonic fibroblasts to sensitize them to apoptosis, and tested cell lines derived from knock-out mice to establish the significance of the interaction between the adaptor protein Grb10 and the Raf-1 protein kinase in anti-apoptotic signaling pathways targeting Bad. When compared with wild-type cells, both Grb10 and Raf-1-deficient cells exhibit greatly enhanced sensitivity to apoptosis in response to Bad expression. Structure-function analysis demonstrates that, in this cellular model, the SH2, proline-rich, and pleckstrin homology domains of Grb10, as well as its Akt phosphorylation site and consequent binding by 14-3-3, are all necessary for its anti-apoptotic functions. As for Raf-1, its kinase activity, its ability to be phosphorylated by Src on Tyr-340/341 and the binding of its Ras-associated domain to the Grb10 SH2 domain are all necessary to promote cell survival. Silencing the expression of either Grb10 or Raf-1 by small interfering RNAs as well as mutagenesis of specific serine residues on Bad, coupled with signaling inhibitor studies, all indicate that Raf-1 and Grb10 are required for the ability of both the phosphatidylinositol 3-kinase/Akt and MAP kinase pathways to modulate the phosphorylation and inactivation of Bad. Because total Raf-1, ERK, and Akt kinase activities are not impaired in the absence of Grb10, we propose that this adapter protein creates a subpopulation of Raf-1 with specific anti-apoptotic activity.", 
    "doi": "10.1074/jbc.m611066200", 
    "keywords": [
      "Cell Biology", 
      "Molecular Biology", 
      "Biochemistry"
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    "language": "eng", 
    "license": {
      "id": "CC-BY-4.0"
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    "notes": "", 
    "publication_date": "2007-07-01", 
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    "title": "Grb10 and Active Raf-1 Kinase Promote Bad-dependent Cell Survival"
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