Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models (Homo sapiens)

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2-4, 9, 16...10114178, 11, 13, 181091791718912, 18171417179Golgi lumencytosolmitochondrial matrixnucleoplasmmitochondrial intermembrane spacep-S43,S173,S294,S325-FOXO3p-T48,T67,S122,T130,S168,S214-CDC25CCDK5R1(99-307) ADPCa2+ADPCAPNS1 Ca2+ ADPATPFASLG(1-281)H2Op-S50,T69,S160,S321,S470-CDC25BCDK5:p25SOD2 geneFOXO3CDK5:p25ADPATPADPCDK5 ADPMyrG-CDK5R1(2-307)APP(672-713)LMNB1Ca2+ GOLGA2JUNATPCa2+CAPN2 ATPCAPNS1 p-S40,S116,S261-CDC25AADPCDC25CCDK5 ATPCAST CDC25C:YWHAECAPN2 Lamin ACDC25AADPCDK5R1(99-307) FASLG geneBCL2L11p-T90-PRDX1BCL2L11 genep-S37-GOLGA2SOD2CDC25BYWHAE ATPMyrG-CDK5R1(2-98)Calpain1,Calpain2:Ca2+:CASTCAPN1 CDK5R1(99-307)PRDX2CAPN2 CDK5p-S43,S173,S294,S325-FOXO3CDC25C p-S63,S73-JUNp-T89-PRDX2ATPCASTPRDX1CAPN1 ADPATPCAPN1 p-S22, S392-LMNA-1CAPNS2 Calpain1,Calpain2:Ca2+p-S23,S393-LMNB1YWHAEATPAPP geneCAPNS2 Calpain1,Calpain2CAPNS2 CAPNS1 ATPADP5181, 7186, 159


Description

Post-mitotic neurons do not have an active cell cycle. However, deregulation of Cyclin Dependent Kinase-5 (CDK5) activity in these neurons can aberrantly activate various components of cell cycle leading to neuronal death (Chang et al. 2012). Random activation of cell cycle proteins has been shown to play a key role in the pathogenesis of several neurodegenerative disorders (Yang et al. 2003, Lopes et al. 2009). CDK5 is not activated by the canonical cyclins, but binds to its own specific partners, CDK5R1 and CDK5R2 (aka p35 and p39, respectively) (Tsai et al. 1994, Tang et al. 1995). Expression of p35 is nearly ubiquitous, whereas p39 is largely expressed in the central nervous system. A variety of neurotoxic insults such as beta-amyloid (A-beta), ischemia, excitotoxicity and oxidative stress disrupt the intracellular calcium homeostasis in neurons, thereby leading to the activation of calpain, which cleaves p35 into p25 and p10 (Lee et al. 2000). p25 has a six-fold longer half-life compared to p35 and lacks the membrane anchoring signal, which results in its constitutive activation and mislocalization of the CDK5:p25 complex to the cytoplasm and the nucleus. There, CDK5:p25 is able to access and phosphorylate a variety of atypical targets, triggering a cascade of neurotoxic pathways that culminate in neuronal death. One such neurotoxic pathway involves CDK5-mediated random activation of cell cycle proteins which culminate in neuronal death. Exposure of primary cortical neurons to oligomeric beta-amyloid (1-42) hyper-activates CDK5 due to p25 formation, which in turn phosphorylates CDC25A, CDC25B and CDC25C. CDK5 phosphorylates CDC25A at S40, S116 and S261; CDC25B at S50, T69, S160, S321 and S470; and CDC25C at T48, T67, S122, T130, S168 and S214. CDK5-mediated phosphorylation of CDC25A, CDC25B and CDC25C not only increases their phosphatase activities but also facilitates their release from 14-3-3 inhibitory binding. CDC25A, CDC25B and CDC25C in turn activate CDK1, CDK2 and CDK4 kinases causing neuronal death. Consistent with this mechanism, higher CDC25A, CDC25B and CDC25C activities were observed in human Alzheimer's disease (AD) clinical samples, as compared to age-matched controls. Inhibition of CDC25 isoforms confers neuroprotection to beta-amyloid toxicity, which underscores the contribution of this pathway to AD pathogenesis View original pathway at:Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 8862803
Reactome-version 
Reactome version: 63
Reactome Author 
Reactome Author: Shah, Kavita

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Bibliography

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  4. Sun KH, de Pablo Y, Vincent F, Shah K.; ''Deregulated Cdk5 promotes oxidative stress and mitochondrial dysfunction.''; PubMed Europe PMC Scholia
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History

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CompareRevisionActionTimeUserComment
101198view11:09, 1 November 2018ReactomeTeamreactome version 66
100736view20:33, 31 October 2018ReactomeTeamreactome version 65
100280view19:10, 31 October 2018ReactomeTeamreactome version 64
99826view15:54, 31 October 2018ReactomeTeamreactome version 63
99383view14:32, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99082view12:39, 31 October 2018ReactomeTeamreactome version 62
93602view11:28, 9 August 2017ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
ADPMetaboliteCHEBI:16761 (ChEBI)
APP geneGeneProductENSG00000142192 (Ensembl)
APP(672-713)ProteinP05067 (Uniprot-TrEMBL)
ATPMetaboliteCHEBI:15422 (ChEBI)
BCL2L11 geneGeneProductENSG00000153094 (Ensembl)
BCL2L11ProteinO43521 (Uniprot-TrEMBL)
CAPN1 ProteinP07384 (Uniprot-TrEMBL)
CAPN2 ProteinP17655 (Uniprot-TrEMBL)
CAPNS1 ProteinP04632 (Uniprot-TrEMBL)
CAPNS2 ProteinQ96L46 (Uniprot-TrEMBL)
CAST ProteinP20810 (Uniprot-TrEMBL)
CASTProteinP20810 (Uniprot-TrEMBL)
CDC25AProteinP30304 (Uniprot-TrEMBL)
CDC25BProteinP30305 (Uniprot-TrEMBL)
CDC25C ProteinP30307 (Uniprot-TrEMBL)
CDC25C:YWHAEComplexR-HSA-8863673 (Reactome)
CDC25CProteinP30307 (Uniprot-TrEMBL)
CDK5 ProteinQ00535 (Uniprot-TrEMBL)
CDK5:p25ComplexR-HSA-8863434 (Reactome)
CDK5:p25ComplexR-HSA-8863585 (Reactome)
CDK5ProteinQ00535 (Uniprot-TrEMBL)
CDK5R1(99-307) ProteinQ15078 (Uniprot-TrEMBL)
CDK5R1(99-307)ProteinQ15078 (Uniprot-TrEMBL)
Ca2+ MetaboliteCHEBI:29108 (ChEBI)
Ca2+MetaboliteCHEBI:29108 (ChEBI)
Calpain1, Calpain2:Ca2+ComplexR-HSA-8863399 (Reactome)
Calpain1,Calpain2:Ca2+:CASTComplexR-HSA-8868137 (Reactome)
Calpain1,Calpain2ComplexR-HSA-8863618 (Reactome)
FASLG geneGeneProductENSG00000117560 (Ensembl)
FASLG(1-281)ProteinP48023 (Uniprot-TrEMBL)
FOXO3ProteinO43524 (Uniprot-TrEMBL)
GOLGA2ProteinQ08379 (Uniprot-TrEMBL)
H2OMetaboliteCHEBI:15377 (ChEBI)
JUNProteinP05412 (Uniprot-TrEMBL)
LMNB1ProteinP20700 (Uniprot-TrEMBL)
Lamin AProteinP02545-1 (Uniprot-TrEMBL)
MyrG-CDK5R1(2-307)ProteinQ15078 (Uniprot-TrEMBL)
MyrG-CDK5R1(2-98)ProteinQ15078 (Uniprot-TrEMBL)
PRDX1ProteinQ06830 (Uniprot-TrEMBL)
PRDX2ProteinP32119 (Uniprot-TrEMBL)
SOD2 geneGeneProductENSG00000112096 (Ensembl)
SOD2ProteinP04179 (Uniprot-TrEMBL)
YWHAE ProteinP62258 (Uniprot-TrEMBL)
YWHAEProteinP62258 (Uniprot-TrEMBL)
p-S22, S392-LMNA-1ProteinP02545-1 (Uniprot-TrEMBL)
p-S23,S393-LMNB1ProteinP20700 (Uniprot-TrEMBL)
p-S37-GOLGA2ProteinQ08379 (Uniprot-TrEMBL)
p-S40,S116,S261-CDC25AProteinP30304 (Uniprot-TrEMBL)
p-S43,S173,S294,S325-FOXO3ProteinO43524 (Uniprot-TrEMBL)
p-S50,T69,S160,S321,S470-CDC25BProteinP30305 (Uniprot-TrEMBL)
p-S63,S73-JUNProteinP05412 (Uniprot-TrEMBL)
p-T48,T67,S122,T130,S168,S214-CDC25CProteinP30307 (Uniprot-TrEMBL)
p-T89-PRDX2ProteinP32119 (Uniprot-TrEMBL)
p-T90-PRDX1ProteinQ06830 (Uniprot-TrEMBL)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-8863007 (Reactome)
ADPArrowR-HSA-8863011 (Reactome)
ADPArrowR-HSA-8863014 (Reactome)
ADPArrowR-HSA-8868260 (Reactome)
ADPArrowR-HSA-8868340 (Reactome)
ADPArrowR-HSA-8868344 (Reactome)
ADPArrowR-HSA-8868567 (Reactome)
ADPArrowR-HSA-8868573 (Reactome)
ADPArrowR-HSA-8868666 (Reactome)
ADPArrowR-HSA-8870558 (Reactome)
APP geneR-HSA-8870710 (Reactome)
APP(672-713)ArrowR-HSA-8863009 (Reactome)
APP(672-713)ArrowR-HSA-8870710 (Reactome)
ATPR-HSA-8863007 (Reactome)
ATPR-HSA-8863011 (Reactome)
ATPR-HSA-8863014 (Reactome)
ATPR-HSA-8868260 (Reactome)
ATPR-HSA-8868340 (Reactome)
ATPR-HSA-8868344 (Reactome)
ATPR-HSA-8868567 (Reactome)
ATPR-HSA-8868573 (Reactome)
ATPR-HSA-8868666 (Reactome)
ATPR-HSA-8870558 (Reactome)
BCL2L11 geneR-HSA-8870686 (Reactome)
BCL2L11ArrowR-HSA-8870686 (Reactome)
CASTR-HSA-8868134 (Reactome)
CDC25AR-HSA-8863014 (Reactome)
CDC25BR-HSA-8863007 (Reactome)
CDC25C:YWHAEArrowR-HSA-8863674 (Reactome)
CDC25CR-HSA-8863011 (Reactome)
CDC25CR-HSA-8863674 (Reactome)
CDK5:p25ArrowR-HSA-8863013 (Reactome)
CDK5:p25ArrowR-HSA-8863587 (Reactome)
CDK5:p25R-HSA-8863587 (Reactome)
CDK5:p25TBarR-HSA-8863674 (Reactome)
CDK5:p25mim-catalysisR-HSA-8863007 (Reactome)
CDK5:p25mim-catalysisR-HSA-8863011 (Reactome)
CDK5:p25mim-catalysisR-HSA-8863014 (Reactome)
CDK5:p25mim-catalysisR-HSA-8868260 (Reactome)
CDK5:p25mim-catalysisR-HSA-8868340 (Reactome)
CDK5:p25mim-catalysisR-HSA-8868344 (Reactome)
CDK5:p25mim-catalysisR-HSA-8868567 (Reactome)
CDK5:p25mim-catalysisR-HSA-8868573 (Reactome)
CDK5:p25mim-catalysisR-HSA-8868666 (Reactome)
CDK5:p25mim-catalysisR-HSA-8870558 (Reactome)
CDK5R-HSA-8863013 (Reactome)
CDK5R1(99-307)ArrowR-HSA-8863012 (Reactome)
CDK5R1(99-307)R-HSA-8863013 (Reactome)
Ca2+ArrowR-HSA-8863009 (Reactome)
Ca2+R-HSA-8863008 (Reactome)
Ca2+R-HSA-8863009 (Reactome)
Calpain1, Calpain2:Ca2+ArrowR-HSA-8863008 (Reactome)
Calpain1, Calpain2:Ca2+R-HSA-8868134 (Reactome)
Calpain1, Calpain2:Ca2+mim-catalysisR-HSA-8863012 (Reactome)
Calpain1,Calpain2:Ca2+:CASTArrowR-HSA-8868134 (Reactome)
Calpain1,Calpain2:Ca2+:CASTTBarR-HSA-8863012 (Reactome)
Calpain1,Calpain2R-HSA-8863008 (Reactome)
FASLG geneR-HSA-8870698 (Reactome)
FASLG(1-281)ArrowR-HSA-8870698 (Reactome)
FOXO3R-HSA-8870558 (Reactome)
GOLGA2R-HSA-8868260 (Reactome)
H2OR-HSA-8863012 (Reactome)
JUNR-HSA-8868666 (Reactome)
LMNB1R-HSA-8868340 (Reactome)
Lamin AR-HSA-8868344 (Reactome)
MyrG-CDK5R1(2-307)R-HSA-8863012 (Reactome)
MyrG-CDK5R1(2-98)ArrowR-HSA-8863012 (Reactome)
PRDX1R-HSA-8868567 (Reactome)
PRDX2R-HSA-8868573 (Reactome)
R-HSA-8863007 (Reactome) CDK5, activated by binding to p25 phosphorylates CDC25B protein tyrosine phosphatase on serine and threonine residues S50, T69, S160, S321 and S470. In neurons, CDK25B localizes to both nucleus and cytosol and CDK5-mediated phosphorylation does not change its localization. Once activated by CDK5, CDC25B promotes activation of CDK1, CDK2 and CDK4 (Chang et al. 2012).
R-HSA-8863008 (Reactome) Binding of calcium ions to the calpain dimer composed of the calpain catalytic subunit of 80 kDa and a calpain regulatory subunit of 30 kDa enables conformation change that results in formation of a functional catalytic center and also promotes relocalization of the calpain complex to the plasma membrane (Lin et al. 1997, Strobl et al. 2000, Schad et al. 2002). Calpain complexes involving the neuronally expressed mu-calpain (CAPN1) and m-calpain (CAPN2) catalytic subunits (Lee et al. 2000) are shown in this activation reaction.
R-HSA-8863009 (Reactome) Beta amyloid increases influx of extracellular calcium (Ca2+) through the plasma membrane, thus increasing the cytosolic Ca2+ concentration. The mechanism has not been completely elucidated (Lee et al. 2000, Abramov et al. 2004).
R-HSA-8863011 (Reactome) CDK5 activated by binding to p25 phosphorylates CDC25C protein tyrosine phosphatase at serine and threonine residues T48, T67, S122, T130, S168, and S214. CDK5-mediated phosphorylation of CDC25C interferes with 14-3-3-epsilon (YWHAE) mediated retention of CDC25C in the cytosol. Once activated by CDK5, CDC25C promotes activation of CDK1 (Chang et al. 2012).
R-HSA-8863012 (Reactome) A variety of neurotoxic insults such as beta-amyloid (A-beta), ischemia, excitotoxicity and oxidative stress disrupt the intracellular calcium homeostasis in neurons, thereby leading to the activation of calpain, which cleaves p35 into p25 and p10 (Lee et al. 2000). p25 has a six-fold longer half-life compared to p35 and lacks the membrane anchoring signal, which results in its constitutive activation and mislocalization of the CDK5:p25 complex to the cytoplasm and the nucleus.

Calpain-mediated cleavage of p35 to p25 is inhibited by calpastatin (CAST). CAST levels are decreased in Alzheimer disease (Sato et al. 2011).

R-HSA-8863013 (Reactome) p25 has a 5-10 fold longer half-life compared to p35 and lacks the membrane anchoring signal, which results in its constitutive activation and mislocalization of the CDK5:p25 complex to the cytoplasm and the nucleus (Patrick et al. 1999). As CDK5 deregulation triggers nuclear envelope dispersion (Chang et al. 2011), with timing being uncertain, all phosphorylation events catalyzed by the CDK5:p25 complex are shown to occur in the cytosol.
R-HSA-8863014 (Reactome) CDK5, activated by binding to p25, phosphorylates CDC25A protein tyrosine phosphatase at serine residues S40, S116 and S261. CDC25A mainly localizes to the nucleus in neurons and CDK5-mediated phosphorylation does not change its localization. Once activated by CDK5, CDC25A promotes activation of CDK1, CDK2 and CDK4 (Chang et al. 2012).
R-HSA-8863587 (Reactome) The complex of CDK5 and p25 can translocate to the nucleus (Patrick et al. 1999). Nuclear envelope fragmentation, initiated by CDK5:p25-mediate phosphorylation of lamin A and B1, increases access of the CDK5:p25 complex to nuclear proteins (Chang et al. 2011).
R-HSA-8863674 (Reactome) Binding of CDC25C to 14-3-3-epsilon (YWHAE), which promotes retention of CDC25C in the cytosol, is inhibited by CDK5-mediated phosphorylation of CDC25C (Chang et al. 2012).
R-HSA-8868134 (Reactome) The proteolytic activity of calpain complexes is inhibited by binding to calpastatin (CAST) (Takano et al. 1995). Based on detailed structural studies of recombinant rat proteins, CAST associates with calcium-bound calpain heterodimers and occupies both sides of the calpain active site cleft (Hanna et al. 2008). CAST levels are reduced in Alzheimer disease (Sato et al. 2011).
R-HSA-8868260 (Reactome) Golgi fragmentation is observed in neurodegenerative diseases, including Alzheimer's disease. The underlying mechanism, based on a mouse AD model, is the phosphorylation of the Golgi membrane protein GOLGA2 (GM130) by the CDK5:p25 complex. CDK5:p25 phosphorylates GOLGA2 (GM130) on a conserved residue S37, phosphorylated by CDK1 in mitotic prophase (Lowe et al. 1998), triggering Golgi apparatus disassembly in Alzheimer's disease (Sun et al. 2008). Please note that S37 of GOLGA2 is sometimes labeled as S25 in the literature because the recombinant Golga2 construct used in the original study of mitotic Golgi fragmentation (Lowe et al. 1998) lacked 12 N-terminal amino acids of Golga2.
R-HSA-8868340 (Reactome) Alzheimer's disease (AD), like many other neurodegenerative diseases, is characterized by nuclear envelope fragmentation. Based on a mouse AD model, nuclear fragmentation is initiated by phosphorylation of nuclear lamins by p25-activated CDK5. The CDK5:p25 complex phosphorylates lamin B1 (LMNB1) at serine residues S23 and S393. Nuclear envelope fragmentation increases access of the CDK5:p25 complex to nuclear proteins and precedes neuronal death (Chang et al. 2011).
R-HSA-8868344 (Reactome) Alzheimer's disease (AD), like many other neurodegenerative diseases, is characterized by nuclear envelope fragmentation. Based on a mouse AD model, nuclear fragmentation is initiated by phosphorylation of nuclear lamins by p25-activated CDK5. The CDK5:p25 complex phosphorylates lamin A (LMNA-1) at serine residues S22 and S392, with S392 being the major CDK5 target site. Nuclear envelope fragmentation increases access of the CDK5:p25 complex to nuclear proteins and precedes neuronal death (Chang et al. 2011).
R-HSA-8868567 (Reactome) Oxidative stress, manifested through accumulation of reactive oxygen species in the cell, is one of the hallmarks of Alzheimer's disease. Based on mouse model studies, CDK5, aberrantly activated by binding to p25, phosphorylates the peroxide reductase PRDX1 on a conserved threonine residue T90, thus inactivating it and contributing to ROS accumulation (Sun et al. 2008).
R-HSA-8868573 (Reactome) Oxidative stress, manifested through accumulation of reactive oxygen species in the cell, is one of the hallmarks of Alzheimer's disease. Based on mouse model studies, CDK5, aberrantly activated by binding to p25, phosphorylates the peroxide reductase PRDX2 on a conserved threonine residue T89, thus inactivating it and contributing to ROS accumulation (Sun et al. 2008).
R-HSA-8868666 (Reactome) Based on mouse model studies, the JUN transcription factor undergoes biphasic activation in Alzheimer's disease. JUN is phosphorylated directly by p25-bound CDK5 at serine residues S63 and S73. CDK5:p25-mediated increase in the level of reactive oxygen species (ROS) triggers activation of JNK kinases (MAPK8, MAPK9, MAPK10), which phosphorylate JUN at S63 and S73 at a later time point (Sun et al. 2009).

Aberrant activation of CDK5 by p25 binding also triggers activation of MKK6 (MAP2K6), a p38 MAP kinase. Levels of phosphorylated MAP2K6 are increased in Alzheimer's disease. Activation of p38 MAP kinase(s) results in increased JUN expression (Chang et al. 2010).

R-HSA-8870558 (Reactome) CDK5, aberrantly activated by binding to p25, phosphorylates transcription factor FOXO3 on serine residues S43, S173, S294 and S325 (Shi et al. 2016).
R-HSA-8870628 (Reactome) CDK5-mediated phosphorylation of the transcription factor FOXO3 promotes translocation of FOXO3 from the cytosol to the nucleus (Shi et al. 2016).
R-HSA-8870686 (Reactome) Transcription of the pro-apoptotic BCL2L11 (BIM) gene is stimulated by FOXO3 downstream of CDK5-mediated FOXO3 phosphorylation (Shi et al. 2016).
R-HSA-8870698 (Reactome) Transcription of the FASLG (FasL) gene, encoding the death receptor ligand, is stimulated by FOXO3 phosphorylated by aberrantly activated CDK5 (Shi et al. 2016).
R-HSA-8870703 (Reactome) Experiments using human cord blood CD4(+) T cells show 22 protein spots and 20 protein spots, upregulated and downregulated proteins respectively, following Interleukin-12 stimulation (Rosengren et.al, 2005). Among the down-regulated proteins is :Superoxide dismutase [Mn], mitochondrial(SOD2).
R-HSA-8870710 (Reactome) Transcription of the APP gene is increased by FOXO3, downstream of FOXO3 phosphorylation by aberrantly activated CDK5 (Shi et al. 2016).
SOD2 geneR-HSA-8870703 (Reactome)
SOD2ArrowR-HSA-8870703 (Reactome)
YWHAER-HSA-8863674 (Reactome)
p-S22, S392-LMNA-1ArrowR-HSA-8868344 (Reactome)
p-S23,S393-LMNB1ArrowR-HSA-8868340 (Reactome)
p-S37-GOLGA2ArrowR-HSA-8868260 (Reactome)
p-S40,S116,S261-CDC25AArrowR-HSA-8863014 (Reactome)
p-S43,S173,S294,S325-FOXO3ArrowR-HSA-8870558 (Reactome)
p-S43,S173,S294,S325-FOXO3ArrowR-HSA-8870628 (Reactome)
p-S43,S173,S294,S325-FOXO3ArrowR-HSA-8870686 (Reactome)
p-S43,S173,S294,S325-FOXO3ArrowR-HSA-8870698 (Reactome)
p-S43,S173,S294,S325-FOXO3ArrowR-HSA-8870703 (Reactome)
p-S43,S173,S294,S325-FOXO3ArrowR-HSA-8870710 (Reactome)
p-S43,S173,S294,S325-FOXO3R-HSA-8870628 (Reactome)
p-S50,T69,S160,S321,S470-CDC25BArrowR-HSA-8863007 (Reactome)
p-S63,S73-JUNArrowR-HSA-8868666 (Reactome)
p-T48,T67,S122,T130,S168,S214-CDC25CArrowR-HSA-8863011 (Reactome)
p-T89-PRDX2ArrowR-HSA-8868573 (Reactome)
p-T90-PRDX1ArrowR-HSA-8868567 (Reactome)
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