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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<oai_dc:dc xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:oai_dc="http://www.openarchives.org/OAI/2.0/oai_dc/" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xsi:schemaLocation="http://www.openarchives.org/OAI/2.0/oai_dc/ http://www.openarchives.org/OAI/2.0/oai_dc.xsd">
  <dc:creator>André Nantel</dc:creator>
  <dc:creator>André Nantel</dc:creator>
  <dc:creator>Colin L. Stewart</dc:creator>
  <dc:creator>Maria Huber</dc:creator>
  <dc:creator>Matthew G. Annis</dc:creator>
  <dc:creator>John P. Hagan</dc:creator>
  <dc:creator>Josée Ash</dc:creator>
  <dc:creator>Malcolm Whiteway</dc:creator>
  <dc:creator>Malcolm Whiteway</dc:creator>
  <dc:creator>Sem Kebache</dc:creator>
  <dc:creator>Jennifer Hassard</dc:creator>
  <dc:date>2007-07-01</dc:date>
  <dc: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.</dc:description>
  <dc:identifier>https://www.openaccessrepository.it/record/95821</dc:identifier>
  <dc:identifier>10.1074/jbc.m611066200</dc:identifier>
  <dc:language>eng</dc:language>
  <dc:relation>url:https://www.openaccessrepository.it/communities/itmirror</dc:relation>
  <dc:rights>info:eu-repo/semantics/closedAccess</dc:rights>
  <dc:rights>https://creativecommons.org/licenses/by/4.0/</dc:rights>
  <dc:subject>Cell Biology</dc:subject>
  <dc:subject>Molecular Biology</dc:subject>
  <dc:subject>Biochemistry</dc:subject>
  <dc:title>Grb10 and Active Raf-1 Kinase Promote Bad-dependent Cell Survival</dc:title>
  <dc:type>info:eu-repo/semantics/article</dc:type>
  <dc:type>publication-article</dc:type>
</oai_dc:dc>