Uptake and function of anthrax toxins (Homo sapiens)

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2, 8, 13, 22, 24...16, 235, 10, 12, 17, 325, 10, 12, 17, 3212, 144, 915, 29, 3416, 2311, 287, 15, 21, 25, 30...15, 29, 347, 15, 19-21, 30...1-3, 18, 26...12, 246, 8, 124, 91-3, 18, 26...12, 2412, 246, 8, 12cytosolendosome lumenMAP2K3-3EF:LF:(PA63:ANTXR1oligomer)MAP2K1ANTXR2-1 PA83 Ca2+ EF:LF:(PA63:ANTXR1oligomer)PA63:ANTXR1 oligomerCa2+ ANTXR1-2 CALM1 Ca2+ Ca2+ ANTXR2-1 PA63 MAP2K7LFANTXR1-2 PA20Ca2+ PA83:ANTXR2CALM1:Ca2+MAP2K6-1(15-334)H+ANTXR1ANTXR2-1 ANTXR1-2 ANTXR2PDCD6IPMAP2K4(?-399)Zn2+ LF PA63 PA83:ANTXR1ANTXR1-1 EFcAMPPA83ANTXR1-2 ANTXR2-1 PA63 ANTXR2-4 MAP2K2PA63:ANTXR2 oligomerMAP2K2(11-400)PA83 LF LF Ca2+ MAP2K1(2-8)LF ANTXR2-4 ANTXR1-1 PPiCa2+ Zn2+ EF ANTXR2-4 MAP2K1(9-393)Ca2+ PA63:ANTXR1EF Zn2+ MAP2K6-1(1-14)EFANTXR1-1 MAP2K3-3(1-26)PA63:ANTXR2 oligomerZn2+ PA63 ANTXR2-1 Ca2+ PA63:ANTXR2Ca2+ MAP2K7(2-?)PA63 ANTXR1-1 ANTXR1-1 EF:LF:(PA63:ANTXR2oligomer)Ca2+ Ca2+ ANTXR2-4 ANTXR2-1 ANTXR2-4 PA63:ANTXR1 oligomerPA20MAP2K4(1-?)MAP2K2(1-10)ANTXR2-1 ANTXR2-4 ANTXR2-4 ANTXR1-2 PA63 EF MAP2K3-3(27-347)PA63 FURINEF:LF:(PA63:ANTXR2oligomer)Ca2+ MAP2K6-1EF ANTXR1-1 PA63 LFANTXR1-1 ANTXR1-2 FURINPA83 Zn2+ ANTXR1-2 Zn2+ PA63 LF Ca2+ LF PA63 MAP2K7(?-419)ATPMAP2K417, 3216, 232416, 236, 8251025256, 831226, 2716, 23716, 232420, 255719103520, 252419516, 2320, 2516, 2351916, 2320, 252520, 256, 825245256, 819, 2019516, 23242526, 2716, 2316, 2320, 25122420, 2516, 23102525252416, 23525103525241925710191917, 322525710


Description

Bacillus anthracis bacteria target cells in an infected human through the action of three secreted bacterial proteins, LF, EF, and PA (reviews: Turk 2007; Young and Collier 2007). LF (lethal factor) is a protease that cleaves and inactivates many MAP2K (MAP kinase kinase, MEK) proteins (Duesbery et al. 1998; Vitale et al. 2000), disrupting MAP kinase signaling pathways. EF (edema factor) is an adenylate cyclase that mediates the constitutive production of cAMP (Leppla 1982), a molecule normally generated transiently in tightly regulated amounts in response to extracellular signals. Both LF and EF depend on PA (protective antigen) to enter their target cells, a strategy characteristic of bacterial binary toxins (Barth et al. 2004). PA binds to the target cell receptors, is cleaved by furin or other cellular proteases, and thereupon forms an oligomer that exposes binding sites for LF and EF molecules (review: Young and Collier 2007). This complex is taken into the target cell by clathrin mediated endocytosis and delivered to endosomes. The low pH of the endosome causes the bacterial toxin complex to rearrange: the PA oligomer forms a pore in the endosome membrane through which EF and LF molecules enter the target cell cytosol. View original pathway at:Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 5210891
Reactome-version 
Reactome version: 66
Reactome Author 
Reactome Author: D'Eustachio, Peter

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Bibliography

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  30. Liu S, Crown D, Miller-Randolph S, Moayeri M, Wang H, Hu H, Morley T, Leppla SH.; ''Capillary morphogenesis protein-2 is the major receptor mediating lethality of anthrax toxin in vivo.''; PubMed
  31. Leppla SH.; ''Anthrax toxin edema factor: a bacterial adenylate cyclase that increases cyclic AMP concentrations of eukaryotic cells.''; PubMed
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  33. Wei W, Lu Q, Chaudry GJ, Leppla SH, Cohen SN.; ''The LDL receptor-related protein LRP6 mediates internalization and lethality of anthrax toxin.''; PubMed
  34. Abrami L, Liu S, Cosson P, Leppla SH, van der Goot FG.; ''Anthrax toxin triggers endocytosis of its receptor via a lipid raft-mediated clathrin-dependent process.''; PubMed
  35. Leduc R, Molloy SS, Thorne BA, Thomas G.; ''Activation of human furin precursor processing endoprotease occurs by an intramolecular autoproteolytic cleavage.''; PubMed

History

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CompareRevisionActionTimeUserComment
101364view11:25, 1 November 2018ReactomeTeamreactome version 66
100902view21:00, 31 October 2018ReactomeTeamreactome version 65
100443view19:34, 31 October 2018ReactomeTeamreactome version 64
99992view16:18, 31 October 2018ReactomeTeamreactome version 63
99546view14:53, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99180view12:42, 31 October 2018ReactomeTeamreactome version 62
93943view13:46, 16 August 2017ReactomeTeamreactome version 61
93532view11:26, 9 August 2017ReactomeTeamreactome version 61
87191view08:29, 19 July 2016EgonwOntology Term : 'disease pathway' added !
86632view09:22, 11 July 2016ReactomeTeamreactome version 56
83389view11:04, 18 November 2015ReactomeTeamVersion54
81575view13:06, 21 August 2015ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
ANTXR1-1 ProteinQ9H6X2-1 (Uniprot-TrEMBL)
ANTXR1-2 ProteinQ9H6X2-2 (Uniprot-TrEMBL)
ANTXR1ComplexR-HSA-5210019 (Reactome)
ANTXR2-1 ProteinP58335-1 (Uniprot-TrEMBL)
ANTXR2-4 ProteinP58335-4 (Uniprot-TrEMBL)
ANTXR2ComplexR-HSA-5209996 (Reactome)
ATPMetaboliteCHEBI:15422 (ChEBI)
CALM1 ProteinP0DP23 (Uniprot-TrEMBL)
CALM1:Ca2+ComplexR-HSA-3229180 (Reactome)
Ca2+ MetaboliteCHEBI:29108 (ChEBI)
EF ProteinP40136 (Uniprot-TrEMBL)
EF:LF:(PA63:ANTXR1 oligomer)ComplexR-HSA-5210915 (Reactome)
EF:LF:(PA63:ANTXR1 oligomer)ComplexR-HSA-5210940 (Reactome)
EF:LF:(PA63:ANTXR2 oligomer)ComplexR-HSA-5210937 (Reactome)
EF:LF:(PA63:ANTXR2 oligomer)ComplexR-HSA-5210954 (Reactome)
EFProteinP40136 (Uniprot-TrEMBL)
FURINProteinP09958 (Uniprot-TrEMBL)
H+MetaboliteCHEBI:15378 (ChEBI)
LF ProteinP15917 (Uniprot-TrEMBL)
LFComplexR-BAN-5211343 (Reactome)
LFComplexR-BAN-5211351 (Reactome)
MAP2K1(2-8)ProteinQ02750 (Uniprot-TrEMBL)
MAP2K1(9-393)ProteinQ02750 (Uniprot-TrEMBL)
MAP2K1ProteinQ02750 (Uniprot-TrEMBL)
MAP2K2(1-10)ProteinP36507 (Uniprot-TrEMBL)
MAP2K2(11-400)ProteinP36507 (Uniprot-TrEMBL)
MAP2K2ProteinP36507 (Uniprot-TrEMBL)
MAP2K3-3(1-26)ProteinP46734-3 (Uniprot-TrEMBL)
MAP2K3-3(27-347)ProteinP46734-3 (Uniprot-TrEMBL)
MAP2K3-3ProteinP46734-3 (Uniprot-TrEMBL)
MAP2K4(1-?)ProteinP45985 (Uniprot-TrEMBL)
MAP2K4(?-399)ProteinP45985 (Uniprot-TrEMBL)
MAP2K4ProteinP45985 (Uniprot-TrEMBL)
MAP2K6-1(1-14)ProteinP52564-1 (Uniprot-TrEMBL)
MAP2K6-1(15-334)ProteinP52564-1 (Uniprot-TrEMBL)
MAP2K6-1ProteinP52564-1 (Uniprot-TrEMBL)
MAP2K7(2-?)ProteinO14733 (Uniprot-TrEMBL)
MAP2K7(?-419)ProteinO14733 (Uniprot-TrEMBL)
MAP2K7ProteinO14733 (Uniprot-TrEMBL)
PA20ProteinP13423 (Uniprot-TrEMBL)
PA63 ProteinP13423 (Uniprot-TrEMBL)
PA63:ANTXR1 oligomerComplexR-HSA-5210928 (Reactome)
PA63:ANTXR1 oligomerComplexR-HSA-5210946 (Reactome)
PA63:ANTXR1ComplexR-HSA-5210006 (Reactome)
PA63:ANTXR2 oligomerComplexR-HSA-5210895 (Reactome)
PA63:ANTXR2 oligomerComplexR-HSA-5210953 (Reactome)
PA63:ANTXR2ComplexR-HSA-5210020 (Reactome)
PA83 ProteinP13423 (Uniprot-TrEMBL)
PA83:ANTXR1ComplexR-HSA-5210008 (Reactome)
PA83:ANTXR2ComplexR-HSA-5210007 (Reactome)
PA83ComplexR-BAN-5205716 (Reactome)
PDCD6IPProteinQ8WUM4 (Uniprot-TrEMBL)
PPiMetaboliteCHEBI:29888 (ChEBI)
Zn2+ MetaboliteCHEBI:29105 (ChEBI)
cAMPMetaboliteCHEBI:17489 (ChEBI)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ANTXR1R-HSA-5210921 (Reactome)
ANTXR2R-HSA-5210918 (Reactome)
ATPR-HSA-5211224 (Reactome)
CALM1:Ca2+ArrowR-HSA-5211224 (Reactome)
EF:LF:(PA63:ANTXR1 oligomer)ArrowR-HSA-5210923 (Reactome)
EF:LF:(PA63:ANTXR1 oligomer)ArrowR-HSA-5210944 (Reactome)
EF:LF:(PA63:ANTXR1 oligomer)R-HSA-5210944 (Reactome)
EF:LF:(PA63:ANTXR1 oligomer)R-HSA-5210947 (Reactome)
EF:LF:(PA63:ANTXR1 oligomer)mim-catalysisR-HSA-5210947 (Reactome)
EF:LF:(PA63:ANTXR2 oligomer)ArrowR-HSA-5210892 (Reactome)
EF:LF:(PA63:ANTXR2 oligomer)ArrowR-HSA-5210959 (Reactome)
EF:LF:(PA63:ANTXR2 oligomer)R-HSA-5210943 (Reactome)
EF:LF:(PA63:ANTXR2 oligomer)R-HSA-5210959 (Reactome)
EF:LF:(PA63:ANTXR2 oligomer)mim-catalysisR-HSA-5210943 (Reactome)
EFArrowR-HSA-5210943 (Reactome)
EFArrowR-HSA-5210947 (Reactome)
EFR-HSA-5210892 (Reactome)
EFR-HSA-5210923 (Reactome)
EFmim-catalysisR-HSA-5211224 (Reactome)
FURINmim-catalysisR-HSA-5210912 (Reactome)
FURINmim-catalysisR-HSA-5210935 (Reactome)
H+ArrowR-HSA-5210943 (Reactome)
H+ArrowR-HSA-5210947 (Reactome)
LFArrowR-HSA-5210943 (Reactome)
LFArrowR-HSA-5210947 (Reactome)
LFR-HSA-5210892 (Reactome)
LFR-HSA-5210923 (Reactome)
LFmim-catalysisR-HSA-5211340 (Reactome)
LFmim-catalysisR-HSA-5211356 (Reactome)
LFmim-catalysisR-HSA-5211387 (Reactome)
LFmim-catalysisR-HSA-5211391 (Reactome)
LFmim-catalysisR-HSA-5211400 (Reactome)
LFmim-catalysisR-HSA-5211405 (Reactome)
MAP2K1(2-8)ArrowR-HSA-5211340 (Reactome)
MAP2K1(9-393)ArrowR-HSA-5211340 (Reactome)
MAP2K1R-HSA-5211340 (Reactome)
MAP2K2(1-10)ArrowR-HSA-5211356 (Reactome)
MAP2K2(11-400)ArrowR-HSA-5211356 (Reactome)
MAP2K2R-HSA-5211356 (Reactome)
MAP2K3-3(1-26)ArrowR-HSA-5211400 (Reactome)
MAP2K3-3(27-347)ArrowR-HSA-5211400 (Reactome)
MAP2K3-3R-HSA-5211400 (Reactome)
MAP2K4(1-?)ArrowR-HSA-5211391 (Reactome)
MAP2K4(?-399)ArrowR-HSA-5211391 (Reactome)
MAP2K4R-HSA-5211391 (Reactome)
MAP2K6-1(1-14)ArrowR-HSA-5211405 (Reactome)
MAP2K6-1(15-334)ArrowR-HSA-5211405 (Reactome)
MAP2K6-1R-HSA-5211405 (Reactome)
MAP2K7(2-?)ArrowR-HSA-5211387 (Reactome)
MAP2K7(?-419)ArrowR-HSA-5211387 (Reactome)
MAP2K7R-HSA-5211387 (Reactome)
PA20ArrowR-HSA-5210912 (Reactome)
PA20ArrowR-HSA-5210935 (Reactome)
PA63:ANTXR1 oligomerArrowR-HSA-5210909 (Reactome)
PA63:ANTXR1 oligomerArrowR-HSA-5210947 (Reactome)
PA63:ANTXR1 oligomerR-HSA-5210923 (Reactome)
PA63:ANTXR1ArrowR-HSA-5210935 (Reactome)
PA63:ANTXR1R-HSA-5210909 (Reactome)
PA63:ANTXR2 oligomerArrowR-HSA-5210932 (Reactome)
PA63:ANTXR2 oligomerArrowR-HSA-5210943 (Reactome)
PA63:ANTXR2 oligomerR-HSA-5210892 (Reactome)
PA63:ANTXR2ArrowR-HSA-5210912 (Reactome)
PA63:ANTXR2R-HSA-5210932 (Reactome)
PA83:ANTXR1ArrowR-HSA-5210921 (Reactome)
PA83:ANTXR1R-HSA-5210935 (Reactome)
PA83:ANTXR2ArrowR-HSA-5210918 (Reactome)
PA83:ANTXR2R-HSA-5210912 (Reactome)
PA83R-HSA-5210918 (Reactome)
PA83R-HSA-5210921 (Reactome)
PDCD6IPArrowR-HSA-5210943 (Reactome)
PDCD6IPArrowR-HSA-5210947 (Reactome)
PPiArrowR-HSA-5211224 (Reactome)
R-HSA-5210892 (Reactome) The enzyme components of anthrax toxins EF (Edema Factor - Robertson et al. 1988) and LF (Lethal Factor - Bragg & Robertson 1989; Klimpel et al. 1994) bind to PA63:ANTXR2 (protective antigen, large fragment: Anthrax receptor 2) oligomers on the target cell surface. Binding of the two toxins to an oligomer is competitive and as many as four toxin molecules can bind to one oligomer (Elliott et al. 2000; Pimental et al. 2004).
R-HSA-5210909 (Reactome) ANTXR1 (Anthrax Receptor 1)-bound PA63 (protective antigen, large fragment) forms oligomers in the target cell plasma membrane. Initial studies indicated that these were heptamers (Lacy et al. 2004; Santelli et al. 2004; Wigelsworth et al. 2004; Young and Collier 2007). More recent work has established that octamers also form and suggests that the octaneric structure is more stable under physiological conditions (Kintzer et al. 2009, 2010). Formation of the latter structure is thus annotated here.
R-HSA-5210912 (Reactome) Furin or a related protease at the cell surface cleaves ANTXR2-bound PA83 (Anthrax protective antigen, full length) to yield PA63. The larger cleavage product, PA63, remains bound to the receptor while a smaller product, PA20, is released into the extracellular space (Klimpel et al, 1992; Koo et al. 2006; Molloy et al. 1992).
R-HSA-5210918 (Reactome) Extracellular PA83 (full length Protective Antigen - Petosa et al. 1997) produced by Bacillus anthracis binds to either of two isoforms of ANTXR2 (Anthrax Toxin Receptor 2, also known as CMG2 - Scobie et al. 2003) in the plasma membrane of a target human cell. The physiological ligand for ANTXR2 is not known, but this receptor has been shown to be the primary receptor involved in anthrax toxin pathogenesis (Liu et al. 2009). While some studies suggest that ANTXR2 is associated with palmitoylated LRP6 (low density lipoprotein receptor related protein 6 - Abrami et al. 2008) in the plasma membrane and that the latter protein can function as a co-receptor (Wei et al. 2006), the role of LRP6 in PA83 uptake remains uncertain (reviewed by van der Goot & Young 2009) and no function for LRP6 is annotated here.
R-HSA-5210921 (Reactome) Extracellular PA83 (full length Protective Antigen - Petosa et al. 1997) produced by Bacillus anthracis binds to either of two isoforms of ANTXR1 (Anthrax Toxin Receptor 1, also known as TEM8 - Bradley et al. 2001; Liu and Leppla 2003) in the plasma membrane of a target human cell. The physiological ligand for ANTXR1 is not known nor are the physiological roles of the two ANTRX1 isoforms. Although ANTXR1 can act as a relatively low affinity, PA83 receptor in tissue culture model systems, it does not play a primary role in anthrax toxin induced effects in mouse models (Liu et al. 2009). While some studies suggest that ANTXR1 is associated with palmitoylated LRP6 (low density lipoprotein receptor related protein 6 - Abrami et al. 2008) in the plasma membrane and that the latter molecule can function as a co-receptor (Wei et al. 2006), the role of LRP6 in PA83 uptake remains uncertain (reviewed by van der Goot & Young 2009) and no function for LRP6 is annotated here.
R-HSA-5210923 (Reactome) The enzyme components of anthrax toxins EF (Edema Factor - Robertson et al. 1988) and LF (Lethal Factor - Bragg & Robertson 1989; Klimpel et al. 1994) bind to PA63:ANTXR1 (protective antigen, large fragment: Anthrax receptor 1) oligomers on the target cell surface. Binding of the two toxins to an oligomer is competitive and as many as four toxin molecules can bind to one oligomer (Elliott et al. 2000; Pimental et al. 2004).
R-HSA-5210932 (Reactome) ANTXR2 (Anthrax Receptor 2)-bound PA63 (protective antigen, large fragment) forms oligomers in the target cell plasma membrane. Initial studies indicated that these were heptamers (Lacy et al. 2004; Santelli et al. 2004; Wigelsworth et al. 2004; Young and Collier 2007). More recent work has established that octamers also form and suggests that the octaneric structure is more stable under physiological conditions (Kintzer et al. 2009, 2010). Formation of the latter structure is thus annotated here.
R-HSA-5210935 (Reactome) Furin or a related protease at the cell surface cleaves ANTXR1-bound PA83 (Anthrax Protective Antigen, full-length). The larger cleavage product, PA63, remains bound to the receptor while a smaller product, PA20, is released into the extracellular space (Klimpel et al, 1992; Molloy et al. 1992).
R-HSA-5210943 (Reactome) Through the action of vacuolar ATPase the pH of the target cell early endosome is lowered. In this environment, PA63 (Anthrax protective antigen, large fragment) dissociates from its receptor and forms an oligomeric channel in the endosome membrane through which the anthrax EF (edema factor) and LF (lethal factor) pass (Milne et al. 1994). Entry of EF and LF into the target cell cytosol is thought to be mediated by back fusion of intraluminal vesicles with the late endosomal membrane and to be positively regulated by PDCD6IP / ALIX protein (Abrami et al. 2004).
R-HSA-5210944 (Reactome) Anthrax EF (edema factor) and LF (lethal factor) toxins bound to PA63:ANTXR1 (protective antigen, large fragment:Anthrax receptor 1) oligomer on the plasma membrane of the target cell, are localized into clathrin coated vesicles and transported to endosomes. Depletion of target cell ARAP3 (ArfGAP with RhoGAP domain, ankyrin repeat and PH domain 3) partly blocks endocytosis (Lu et al. 2004), but this effect may be indirect and has not been characterized at a molecular level (van der Goot & Young 2009).
R-HSA-5210947 (Reactome) Through the action of vacuolar ATPase the pH of the target cell early endosome is lowered. In this environment, PA63 (Anthrax protective antigen, large fragment) dissociates from its receptor and forms an oligomeric channel in the endosome membrane through which the anthrax EF (edema factor) and LF (lethal factor) pass (Milne et al. 1994). Entry of EF and LF into the target cell cytosol is thought to be mediated by back fusion of intraluminal vesicles with the late endosomal membrane and to be positively regulated by PDCD6IP / ALIX protein (Abrami et al. 2004).
R-HSA-5210959 (Reactome) Anthrax EF (edema factor) and LF (lethal factor) toxins bound to PA63:ANTXR2 (protective antigen, large fragment: Anthrax receptor 2) oligomer on the plasma membrane of the target cell, are localized into clathrin coated vesicles and transported to endosomes (Abrami et al. 2003). Depletion of target cell ARAP3 (ArfGAP with RhoGAP domain, ankyrin repeat and PH domain 3) partly blocks endocytosis (Lu et al. 2004), but this effect may be indirect and has not been characterized at a molecular level (van der Goot & Young 2009).
R-HSA-5211224 (Reactome) EF (edema factor), transported to the cytosol of the target cell, catalyzes the synthesis of cAMP from ATP, in a reaction that requires target cell calmodulin (Leppla 1984; Labruyere et al. 1990).
R-HSA-5211340 (Reactome) Anthrax LF (lethal factor), a zinc metalloprotease (Klimpel et al, 1994) in the target cell cytosol, cleaves MAP2K1 (MEK1, mitogen activated protein kinase kinase 1) at the N-terminus. While the kinase domain of MAP2K1 is unaffected, an aminoterminal docking domain is disrupted by the cleavage and the protein fails to interact normally with substrates (Duesbery et al. 1998; Vitale et al. 1998).
R-HSA-5211356 (Reactome) Anthrax LF (lethal factor) a zinc metalloprotease (Klimpel et al, 1994) in the target cell cytosol, cleaves MAP2K2 (MEK2, mitogen activated protein kinase kinase 2). While the kinase domain of MAP2K2 is unaffected, an aminoterminal docking domain is disrupted by the cleavage (Duesbery et al. 1998; Vitale et al. 1998).
R-HSA-5211387 (Reactome) Anthrax LF (lethal factor) a zinc metalloprotease (Klimpel et al, 1994) in the target cell cytosol, cleaves MAP2K7 (MEK7, mitogen activated protein kinase kinase 7) (Vitale et al. 2000).
R-HSA-5211391 (Reactome) Anthrax LF (lethal factor) a zinc metalloprotease (Klimpel et al, 1994) in the target cell cytosol, cleaves MAP2K4 (MEK4, mitogen activated protein kinase kinase 4) (Vitale et al. 2000).
R-HSA-5211400 (Reactome) Anthrax LF (lethal factor) a zinc metalloprotease (Klimpel et al, 1994) in the target cell cytosol, cleaves MAP2K3 (MEK3, mitogen activated protein kinase kinase 3), isoform 3 (Pellizzari et al. 1999).
R-HSA-5211405 (Reactome) Anthrax LF (lethal factor) a zinc metalloprotease (Klimpel et al, 1994) in the target cell cytosol, cleaves MAP2K6 (MEK6, mitogen activated protein kinase kinase 6), isoform 1 (Vitale et al. 2000).
cAMPArrowR-HSA-5211224 (Reactome)
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