Border Color Location
  Extracellular
  Cell membrane
  Cytoplasm
  Organelle
  Bacterial membrane or virus envelope
  Other
Backgound Color Node Shape Object Type
  Box Protein or gene
  Box Protein of gene complex
  Ellipse Pathway or action
  Box Eukaryotic cell or cell component
  Box Microorganism or its component
  Box Microbe-host cell complex

Phinet Name: Bacillus anthracis-induced PCD

Phinet Information
Pathogen Name: Bacillus anthracis
Pathogen NIAID Category: NIAID Category A
Bio-objects
Bio-object 1: ?1
  • Type: Other
  • Location: Other
  • Function: Unknown
  • Description:
Bio-object 2: Bfl-1/A1
  • GI Number: 118130280
  • DB Links: B-cell leukemia/lymphoma 2 related protein A1a
    MGI:102687
  • Type: Protein or gene
  • Location: Organelle -- Nucleus
  • Function: Other
  • Description: Major anti-apoptotic gene which was proposed to inhibit cell death along with Bfl-1/A1 (<a href="#reference8663">Park et al., 2005</a>).
Bio-object 3: cAMP
  • DB Links: http://pubchem.ncbi.nlm.nih.gov/summary.cgi?cid=6076
  • Type: Other -- ion
  • Location: Intracellular
  • Function: Other
Bio-object 4: Cebpb-T217
  • GI Number: 145301630
  • DB Links: CCAAT/enhancer binding protein (C/EBP), beta
  • Type: Protein or gene
  • Location: Intracellular
  • Function: Transcription regulation
  • Description:
Bio-object 5: Cell death
  • Type: Other
  • Location: Other
  • Function: Other
Bio-object 6: CREB
  • GI Number: 82546873
  • DB Links: Creb1 cAMP responsive element binding protein 1
    Variant B: (NCBI-GI:82546875)
  • Type: Protein or gene
  • Location: Cytoplasm
  • Function: Transcription regulation
  • Description: Two transcript variants known for mRNA (variants A and B).
Bio-object 7: ET
  • Type: Enzyme
  • Location: Intracellular
  • Function: Toxicity
  • Description: B. anthracis endotoxin. Includes EF subunit which catalyzes PKA production (<a href="#reference8663">Park et al., 2005</a>).
Bio-object 8: IκB
  • GI Number: 24111253
  • Accession Number:
  • DB Links: MGI:104752
    Nfkbia:NCBI-GI:6754840
    Nfkbie:NCBI-GI:31543321
  • Type: Protein or gene complex
  • Location: Cytoplasm
  • Function: Enzyme inhibitor
  • Description: Nf-κB inhibitors which include Nfkbia, Nfkbib, Nfkbie.
Bio-object 9: IKK
  • GI Number: 33469101
  • Accession Number:
  • DB Links: http://www.genome.jp/dbget-bin/www_bget?mmu+16150
  • Type: Protein or gene complex
  • Location: Cytoplasm
  • Function: Signal transducer
  • Description: Ikbkb (inhibitor of kappaB kinase beta). Other genes related to Ikbkb via IKK complex: Ikbkg, Chuk.
Bio-object 10: LT
  • DB Links: B. anthracis lethal toxin
  • Type: Enzyme
  • Location: Other
  • Function: Toxicity
  • Description: Catalytic subunit (LF) of anthrax lethal toxin (<a href="#reference8663">Park et al., 2005</a>).
Bio-object 11: Mapk1
  • GI Number: 84579909
  • DB Links: ERK2
    http://www.genome.jp/dbget-bin/www_bget?mmu+26413
  • Type: Protein or gene
  • Location: Cytoplasm
  • Function: Signal transducer
  • Description: mitogen-activated protein kinase 1
Bio-object 12: Mapk3
  • GI Number: 1346859
  • DB Links: ERK1
    http://www.genome.jp/dbget-bin/www_bget?mmu+26417
  • Type: Protein or gene
  • Location: Cytoplasm
  • Function: Signal transducer
  • Description: Mitogen-activated protein kinase 3
Bio-object 13: MEKK
  • DB Links: MAP2K1/2
  • Type: Protein or gene complex
  • Location: Cytoplasm
  • Function: Signal transducer
  • Description: Mitogen-activated protein kinase kinase
Bio-object 14: MKK6
  • GI Number: 33859654
  • DB Links: Map2k6
    www.genome.jp/dbget-bin/www_bget?mmu+26399
  • Type: Protein or gene
  • Location: Cytoplasm
  • Function: Enzyme
  • Description: Mitogen-activated protein kinase kinase 6.
Bio-object 15: MSK1
  • GI Number: 118130094
  • DB Links: ribosomal protein S6 kinase, polypeptide 5 (Rps6ka5)
    www.genome.jp/dbget-bin/www_bget?mmu+73086
  • Type: Protein or gene
  • Location: Organelle -- Ribosome
  • Function: Enzyme activator
  • Description: Ribosomal protein S6 kinase, polypeptide 5
Bio-object 16: MSK2
  • GI Number: 9910453
  • DB Links: Rps6ka4
    www.genome.jp/dbget-bin/www_bget?mmu+56613
  • Type: Protein or gene
  • Location: Organelle -- Ribosome
  • Function: Enzyme
  • Description: ribosomal protein S6 kinase, polypeptide 4
Bio-object 17: Nf-κB
  • GI Number: 117606364
  • Accession Number:
  • DB Links: http://www.genome.jp/dbget-bin/www_bget?mmu+18033+18034
  • Type: Protein or gene complex
  • Location: Cytoplasm
  • Function: Transcription regulation
  • Description: Nfkb monomers dissociate and translocate to nucleus to induce transcriptional activation following activation of IκB subunits.
Bio-object 18: p38
  • GI Number: 142367641
  • DB Links: Mapk14
    (Mapk11; Mapk12; Mapk13)
    http://www.genome.jp/dbget-bin/www_bget?mmu+19094+26415+26416+29857
  • Type: Enzyme
  • Location: Cytoplasm
  • Function: Signal transducer
  • Description: mitogen-activated protein kinase 14
Bio-object 19: PAI-2
  • GI Number: 51468082
  • Accession Number:
  • DB Links: Serpinb2
    www.genome.jp/dbget-bin/www_bget?mmu:18788
  • Type: Protein or gene
  • Location: Organelle -- Nucleus
  • Function: Chaperone
  • Description: Serpinb2 serine (or cysteine) peptidase inhibitor, clade B, member 2. Pai-2 identified to have Nf-κB and CREB binding sites within its control region via ChIP analysis. Inhibits apoptosis in TLR4-activated macrophages. (<a href="#reference8663">Park et al., 2005</a>)
Bio-object 20: PKA
  • GI Number: 24475738
  • Accession Number:
  • DB Links: Prkaca
    http://www.genome.jp/dbget-bin/www_bget?mmu:18747
  • Type: Enzyme
  • Location: Cytoplasm
  • Function: Enzyme activator
  • Description: protein kinase, cAMP dependent, catalytic, alpha
Bio-object 21: RSK
  • GI Number: 158636006*
  • Accession Number:
  • DB Links: Rps6ka1
    http://www.genome.jp/dbget-bin/www_bget?mmu+20111
  • Type: Protein or gene
  • Location: Organelle -- Ribosome
  • Function: Signal transducer
  • Description: ribosomal protein S6 kinase polypeptide 1
Bio-object 22: TLR4
  • GI Number: 10946594
  • Accession Number:
  • DB Links: NCBI-GeneID: 21898
    http://www.genome.jp/dbget-bin/www_bget?mmu+21898
  • Type: Protein or gene
  • Location: Cell membrane
  • Function: Signal transducer
  • Description: Toll-like receptors recognize pathogen-associated molecular patterns (PAMPs) and transduce such signals to IκB and MAP kinases, which can control downstream transcription factor activities, localization, etc. (<a href="#reference8663">Park et al., 2005</a>)
Interactions
Interaction 1: IKK Activation By TLR4
  • Type: Activation
  • Input Objects: TLR4
  • Output Objects: IKK
  • GO Evidence Code: Traceable Author Statement
  • Description: (<a href="#reference8663">Park et al., 2005</a>)
Interaction 2: IκB inhibition
  • Type: Inhibition
  • Input Objects: IKK
  • Output Objects: IκB
  • GO Evidence Code: Traceable Author Statement
  • Description: IκB subunit phosphorylated by IKK units prior to cleavage of Nf-κB dimer into monomers.(<a href="#reference8663">Park et al., 2005</a>)
Interaction 3: Nf-κB Inhibition by IκB
  • Type: Inhibition
  • Input Objects: IκB
  • Output Objects: Nf-κB
  • GO Evidence Code: Inferred by Curator
  • Description: Nf-κB is sequestered in the cytoplasm by IκB initially. Phosphorylation of IκB by IKK allows inactivation of IκB, followed by dissociation of Nf-κB monomers and translocation to nucleus.
Interaction 4: Anti-apoptotic response
  • Type: Inhibition
  • Input Objects: Bfl-1/A1, PAI-2
  • Output Objects: Cell death
  • GO Evidence Code: Inferred from Expression Pattern
  • Description: A microarray experiment measuring resting vs. LPS-stimulated J774A.1 macrophage cells identified ~1.5% of 8,000 genes as LPS-inducible. Fourteen genes, including Bbl-1/A1, identified in the microarray analysis were selected according to p38-dependent LPS induction. Microarray results were confirmed via quantitative PCR analysis (<a href="#reference8663">Park et al., 2005</a>).

    Either Pai-2 or Bfl-1/Al are required for survival of RAW264.7 macrophages transfected with various apoptotic genes (<a href="#reference8663">Park et al., 2005</a>).
Interaction 5: CREB activation by PKA
  • Type: Activation
  • Input Objects: PKA
  • Output Objects: CREB
  • GO Evidence Code: Traceable Author Statement
  • Description: CREB activated through PKA or other protein kinases via S133 residue phosphorylation (<a href="#reference8668">Mayr and Montminy, 2001</a>).
Interaction 6: CREB activation by Msk1/2
  • Type: Activation
  • Input Objects: MSK1, MSK2
  • Output Objects: CREB
  • GO Evidence Code: Inferred by Curator
  • Description: Authors identified CREB, c-Jun, and ATF-2 as activated targets downstream of LPS treatment in RAW264.7 macrophages using targeted antibody strategy. CREB was selected for its p38 dependent behavior which was observed previously in J774A.1 macrophages, and further confirmed by loss of LPS-controlled CREB activation in presence of LT. Double knockout mice for MSK1/2 exhibited strongly reduced CREB phosphorylation (<a href="#reference8663">Park et al., 2005</a>).
Interaction 7: Msk1/2 activation by p38
  • Type: Activation
  • Input Objects: p38
  • Output Objects: MSK1, MSK2
  • GO Evidence Code: Inferred by Curator
Interaction 8: p38 Target Regulation
  • Type: Unknown
  • Input Objects: p38
  • Output Objects: ?1
  • GO Evidence Code: Traceable Author Statement
  • Description: Regulation of downstream Pai-2 and Bfl-1/Al was shown to depend upon p38 activity. However, the mechanism by which p38 regulates downstream Bfl-1/Al activity is not known. (<a href="#reference8663">Park et al., 2005</a>)
Interaction 9: Unknown target regulates Bfl-1/Al activity
  • Type: Regulation
  • Input Objects: ?1
  • Output Objects: Bfl-1/A1
  • GO Evidence Code: Traceable Author Statement
  • Description: Regulation of downstream Pai-2 and Bfl-1/Al was shown to depend upon p38 activity. However, the mechanism by which p38 regulates downstream Bfl-1/Al activity is not known. (<a href="#reference8663">Park et al., 2005</a>)
Interaction 10: Activation of PKA
  • Type: Activation
  • Cofactors: cAMP
  • Input Objects: ET
  • Output Objects: PKA
  • GO Evidence Code: Inferred by Curator
  • Description: The anthrax ET toxin has a catalytic subunit, edema factor (EF), which provides adenylyl cyclase (AC) for generating intracellular cAMP (<a href="#reference8666">Collier and Young, 2003</a>). The cAMP is then expected to activate PKA, permitting an ET-mediated activation strategy of PKA (<a href="#reference8663">Park et al., 2005</a>).
Interaction 11: MKK6 cleavage by LF subunit of B. anthracis lethal toxin (LT)
  • Type: Inhibition
  • Input Objects: LT
  • Output Objects: MKK6
  • GO Evidence Code: Inferred by Curator
  • Description: Park et al. generated MKK3 and MKK6 mutants to show that MKK6 was targeted downstream by LF. MKK6CR mutants exhibited strong resistance to LF-induced apoptosis (<a href="#reference8667">Park et al., 2002</a>).
Interaction 12: TLR4 activates MK6
  • Type: Activation
  • Input Objects: TLR4
  • Output Objects: MKK6
  • GO Evidence Code: Non-traceable Author Statement
Interaction 13: p38 activation by MKK6
  • Type: Activation
  • Input Objects: MKK6
  • Output Objects: p38
  • GO Evidence Code: Traceable Author Statement
  • Description: Activation of p38 by MKK6 is disrupted via LT-mediated cleavage of MKK6 (<a href="#reference8663">Park et al., 2005</a>).
Interaction 14: Pai-2 activation by CREB, NFKB
  • Type: Activation
  • Input Objects: CREB, Nf-κB
  • Output Objects: PAI-2
  • GO Evidence Code: Inferred from Direct Assay
  • Description: Pai-2−/− bone marrow-derived macrophages (BMDMs) exhibited a stronger apoptotic response to LPS versus wild-type BMDMs. ChIP experiments demonstrated that Pai-2 is a transcriptional target of NfkB and CREB (<a href="#reference8663">Park et al., 2005</a>).
Interaction 15: Bfl-1/A1 activation
  • Type: Activation
  • Input Objects: Nf-κB
  • Output Objects: Bfl-1/A1
  • GO Evidence Code: Inferred from Expression Pattern
  • Description: Downstream targets of NfKB activation determined via microarray analysis of LPS- or SB202190 (SB)- treated mutant BMDMs followed by promoter analysis of selected genes (<a href="#reference8663">Park et al., 2005</a>).
Interaction 16: ERK1/2 inhbition by LT
  • Type: Inhibition
  • Input Objects: LT
  • Output Objects: MEKK
  • GO Evidence Code: Traceable Author Statement
  • Description: Multiple MAPK kinases can be cleaved by the zinc-dependent LF protease in LT (<a href="#reference8669">Buck and Chojkier, 2007</a>).
Interaction 17: RSK activation by ERK1/2
  • Type: Activation
  • Input Objects: Mapk1, Mapk3
  • Output Objects: RSK
  • GO Evidence Code: Traceable Author Statement
  • Description: Authors et al. showed that RSK is activated directly by ERK phosphorylation (<a href="#reference8669">Buck and Chojkier, 2007</a>).
Interaction 18: C/EBPbetaT217 activation by RSK
  • Type: Activation
  • Input Objects: RSK
  • Output Objects: Cebpb-T217
  • GO Evidence Code: Traceable Author Statement
  • Description: C/EBPbetaT217 activation by RSK via phosphorylation (<a href="#reference8669">Buck and Chojkier, 2007</a>).
Interaction 19: Macrophage survival mediated by Cebpb-T217 phosphorylation
  • Type: Inhibition
  • Input Objects: Cebpb-T217
  • Output Objects: Cell death
  • GO Evidence Code: Inferred from Mutant Phenotype
  • Description: Interaction of anthrax LT inhibits upstream ERK1/2 activation and blocks phosphorylation of C/EBPbeta-217. Mutant double knockout of C/EBPbeta inhibits macrophage survival, while introduction of a dominant positive mimetic CebpbE217 restores macrophage survival, which establishes the requirement for C/EBP phosphorylation to block apoptosis (<a href="#reference8669">Buck and Chojkier, 2007</a>).
Interaction 20: MEKs phosphorylate MAPKs
  • Type: Activation
  • Input Objects: MEKK
  • Output Objects: Mapk1, Mapk3
  • GO Evidence Code: Inferred by Curator
Pathways