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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  <identifier identifierType="URL">https://www.openaccessrepository.it/record/95821</identifier>
  <creators>
    <creator>
      <creatorName>André Nantel</creatorName>
    </creator>
    <creator>
      <creatorName>André Nantel</creatorName>
    </creator>
    <creator>
      <creatorName>Colin L. Stewart</creatorName>
    </creator>
    <creator>
      <creatorName>Maria Huber</creatorName>
    </creator>
    <creator>
      <creatorName>Matthew G. Annis</creatorName>
    </creator>
    <creator>
      <creatorName>John P. Hagan</creatorName>
    </creator>
    <creator>
      <creatorName>Josée Ash</creatorName>
    </creator>
    <creator>
      <creatorName>Malcolm Whiteway</creatorName>
    </creator>
    <creator>
      <creatorName>Malcolm Whiteway</creatorName>
    </creator>
    <creator>
      <creatorName>Sem Kebache</creatorName>
    </creator>
    <creator>
      <creatorName>Jennifer Hassard</creatorName>
    </creator>
  </creators>
  <titles>
    <title>Grb10 and Active Raf-1 Kinase Promote Bad-dependent Cell Survival</title>
  </titles>
  <publisher>INFN Open Access Repository</publisher>
  <publicationYear>2007</publicationYear>
  <subjects>
    <subject>Cell Biology</subject>
    <subject>Molecular Biology</subject>
    <subject>Biochemistry</subject>
  </subjects>
  <dates>
    <date dateType="Issued">2007-07-01</date>
  </dates>
  <language>en</language>
  <resourceType resourceTypeGeneral="Text">Journal article</resourceType>
  <alternateIdentifiers>
    <alternateIdentifier alternateIdentifierType="url">https://www.openaccessrepository.it/record/95821</alternateIdentifier>
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  <relatedIdentifiers>
    <relatedIdentifier relatedIdentifierType="DOI" relationType="IsIdenticalTo">10.1074/jbc.m611066200</relatedIdentifier>
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  <rightsList>
    <rights rightsURI="https://creativecommons.org/licenses/by/4.0/">Creative Commons Attribution 4.0</rights>
    <rights rightsURI="info:eu-repo/semantics/closedAccess">Closed Access</rights>
  </rightsList>
  <descriptions>
    <description descriptionType="Abstract">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.</description>
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