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Inhibition of Apoptosis Signaling Interactive Pathway

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Pathway Description:

Cell survival requires the active inhibition of apoptosis, which is accomplished by inhibiting the expression of pro-apoptotic factors as well as promoting the expression of anti-apoptotic factors. The PI3K pathway, activated by many survival factors, leads to the activation of Akt, an important player in survival signaling. PTEN negatively regulates the PI3K/Akt pathway. Activated Akt phosphorylates and inhibits the pro-apoptotic Bcl-2 family members Bad, Bax, caspase-9, GSK-3, and FoxO1. Many growth factors and cytokines induce anti-apoptotic Bcl-2 family members. The Jaks and Src phosphorylate and activate Stat3, which in turn induces the expression of Bcl-xL and Bcl-2. Erk1/2 and PKC activate p90RSK, which activates CREB and induces the expression of Bcl-xL and Bcl-2. These Bcl-2 family members protect the integrity of mitochondria, preventing cytochrome c release and the subsequent activation of caspase-9. TNF-α may activate both pro-apoptotic and anti-apoptotic pathways; TNF-α can induce apoptosis by activating caspase-8 and -10, but can also inhibit apoptosis via NF-κB, which induces the expression of anti-apoptotic genes such as Bcl-2. cIAP1/2 inhibit TNF-α signaling by binding to TRAF2. FLIP inhibits the activation of caspase-8.

Selected Reviews:

We would like to thank Prof. Junying Yuan, Harvard Medical School, Boston, MA, for reviewing this diagram.

created September 2008

revised November 2012

  • KinaseKinase
  • PosphatasePosphatase
  • Transcription FactorTranscription Factor
  • CaspaseCaspase
  • ReceptorReceptor
  • EnzymeEnzyme
  • pro-apoptoticpro-apoptotic
  • pro-survivalpro-survival
  • GAP/GEFGAP/GEF
  • GTPaseGTPase
  • G-proteinG-protein
  • AcetylaseAcetylase
  • DeacetylaseDeacetylase
  • Ribosomal subunitRibosomal subunit
  • Direct Stimulatory ModificationDirect Stimulatory Modification
  • Direct Inhibitory ModificationDirect Inhibitory Modification
  • Multistep Stimulatory ModificationMultistep Stimulatory Modification
  • Multistep Inhibitory ModificationMultistep Inhibitory Modification
  • Tentative Stimulatory ModificationTentative Stimulatory Modification
  • Tentative Inhibitory ModificationTentative Inhibitory Modification
  • Separation of Subunits or Cleavage ProductsSeparation of Subunits or Cleavage Products
  • Joining of SubunitsJoining of Subunits
  • TranslocationTranslocation
  • Transcriptional Stimulatory ModificationTranscriptional Stimulatory Modification
  • Transcriptional Inhibitory ModificationTranscriptional Inhibitory Modification