SMAD activation via TGFB activates SMAD7 gene expression.

NFKB activates SMAD7 gene transcription.

ROS activates MEK by blocking the MEK inhibitors.

Raf phosphorylates and activates MEK.

IL4 is secreted by DCs.

IL4 is secreted by TH2.

The transcription factor NFKB upregulaes CFLIP.

CASP3 cleaves and inactivates P21.

GSK3B phosphorylates P21, leading to its degradation.

P53 activity leads to increased transcriptional activation of P21.

SMAD activates the p21 promoter.

TNFR activation stimulates TRAF2-driven activation of MEKK1.

TGFR indirectly activates MEKK1.

CERAMIDE directly binds to and activates MEKK1.

CTL cells produce IFNG.

TH1 cells produce IFNG.

P21 directly binds and inhibits CASP8.

CFLIP inhibits CASP8 by preventing cleavage of procaspase-8.

FADD recruits CASP8 to the TRADD protein complex.

EP2 activates PI3K directly and through the activation of RAS.

PTEN dephosphorylates phosphatidylinositol (3,4,5)-trisphosphate (PIP3), produced by PI3K, in order to inactivate PI3K.

RAS interacts directly with the catalytic subunit of PI3K.

BCL2 inhibits TBID insertion into the mitochondrial membrane.

CASP8 cleaves BID to create TBID.

IKB is a family of inhibitors that sequestors NFKB in the cytoplasm.

EP2 activation leads to the phosphorylation and inhibition of GSK3B.

AKT phosphorylates and inactivates GSK3B.

Activation of the ERK/MAPK signaling cascade results in the activation of FOS.

Activation of TNFR results in the recruitment and activation of IKK.

S1P is a cofactor for TRAF2, which has been simplified to TNFR in this model.

AKT is an upstream activator of IKK in the AKT/I kappa B kinase pathway.

IL10 activates TREG differentiation through STAT3 signaling.

Dendritic cells present antigen to naive T cells.

IL6 supresses TREG differentiation.

FAS recruits and activates FADD.

TNFR recruits FADD.

TNFR activation stimulates COX2 production.

S1P is a cofactor for TRAF2, which has been simplified to TNFR in this model.

The transcription factor STAT3 upregulaes BCL2 production.

BCL2 is down-regulated by P53.

PP2A dephosphorylates and inactivates BCL2.

The transcription factor NFKB upregulaes BCL2 production.

ASK1 activates MAPK kinase 4, which leads to JNK activation.

MEKK1 activates MAPK kinase 4, which leads to JNK activation.

TNFA is secreted by macrophages.

IAP proteins contain several functional units called BIRs that inhibits the catalytic function of different caspases, including CASP9.

Cytochrome c is released from the mitochondria and forms a complex with Apaf-1 in the cytosol. This complex, called the apoptosome, recruits pro-caspase 9 to create active CASP9.

P21 directly binds and inhibits CASP9.

IL10 inhibits the maturation of DCs.

TNFA enhances DC survival.

CCL2 binds to CCR2, leading to nuclear translocation of NFkB and subsequent DC maturation.

BCL2 inhibits caspase activity that would lead to MOMP activation.

TBID translocates from the cytoplasmic membrane to the mitochondria and induces apoptotic signals, leading to the activation of MOMP.

BAX forms proteolipid pores in the outer mitochondrial membrame, leading to MOMP activation.

CERAMIDE forms channels in the outer membranes of isolated mitochondria and works synergistcally with BAX to activate MOMP.

P53 activates SMASE transcription.

FADD indirectly activates SMASE.

SPHK1 phosphorylates CERAMIDE to form SIP.

SMASE produces CERAMIDE by hydrolysis of sphingomyelins.

EP2 indirectly activates RAS.

GP130 indirectly activates RAS.

CASP3 cleaves and inactivates AKT.

PI3K produces phosphatidylinositol (3,4,5)-trisphosphate (PIP3) (not depicted in model), which recruits and activates AKT.

PP2A dephosorylates and inactivates AKT.

RAS recruits and activates RAF.

Ceramide-activated protein kinase (CAPK), condensed to CERAMIDE in this model, phosphorolates and activates RAF.

The interaction between IL6 and its receptor activates GP130.

Addition of IFNG is needed to induce proliferation and differentiation of naive T cells to CTLs.

TGFB inhibits the expression of cytolitic gene products, including perforin, granzyme A, granzyme B, Fas ligand, and interferon gamma.

IL4 induces differentiation of TH2 cells.

TH2 cells are inhibited by the TH1 cytokine, IFNG.

TGFB inhibits TH2 cells function through transcriptional repression. .

JUN transcription is upregulated by BCATENIN.

JNK phosphorylates and activates JUN.

GSK3B phosphorylates and inactivates JUN.

JUN is a downstream target of the ERK/MAPK pathway.

TBID activates BAX by targeting the α1 helix. This allows for mitochondrial targeting of BAX.

P53 upregulates BAX gene expression and can directly associate with BAX proteins.

Dephosphorylation of Bax by PP2A is needed for BAX activation.

AKT phosphorylates BAX, which concentrates the protein in the cytoplasm.

STAT3 upregulates SOCS production.

The transcription factors NFKB and STAT3 upregulae IAP production.

SMAC directly interacts with IAP's BIR domain.

The transcription factors NFKB and STAT3 upregulae IAP production.

JAK phosphorylates STAT3. This leads to the dimerization and actiavation of STAT3.

MOMP stimulates the release of CYTC.

PGE2 binds to and activates EP2.

MOMP stimulates the release of SMAC.

TH1 differentiation is inhibited by the TH2 cytokines, IL10 and IL4.

TH1 differentiation is inhibited by the TH2 cytokines, IL10 and IL4.

IFNG activates differentiation into TH1 cells.

IL 12 directs naive CD4+ T cells to differentiate into TH1 cells.

TGFB inhibits TH1 function through transcriptional repression.

P53 binds upstream of the PTEN gene for transactivation of PTEN.

JUN inhibits PTEN expression by binding to a variant AP-1 site found in the PTEN promoter.

NFKB lowers transcriptional expression of PTEN.

IAP proteins contain several functional units called BIRs that inhibits the catalytic function of different caspases, including CASP3.

CASP9 cleaves and activates CASP3.

CASP8 directly activates CASP3.

DC secretes IL12.

MAC secretes IL12.

TNFR activation stimulates ROS production.

SOD is an anti-oxidative enzyme.

IL6 is mostly secreted by MAC, but DC can also secret IL6.

IL6 is mostly secreted by MAC.

Intestinal epithelial cells (IECs) produce IL6 through the activation of NFKB.

TGFB is secreted by TREG.

Cells exposed to oxidated stress strongly activate ASK1.

P21 binds to and inactivates ASK1.

CTLs express FAS on the cell surface.

TNFA binds to TNFR.

SPHK1 produces S1P.

TM and GSK3B are able to phosphorylate MDM2, leading to P53 mediated ubiquitation and degradation.

TM and GSK3B are able to phosphorylate MDM2, leading to P53 mediated ubiquitation and degradation.

P53 upregulates MDM2 transcription. AKT is needed for the nuclear translocation of MDM2.

P53 upregulates MDM2. AKT is needed for the nuclear translocation of MDM2.

Oxidation of ATM directly activates ATM in the absence of DNA double-stranded breaks.

CASP3 activates mitochondrial apoptosis.

GSK3B forms a complex with APC and phosphorylates BCATENIN, leading to BCATENIN degradation.

GSK3B forms a complex with APC and phosphorylates BCATENIN, leading to BCATENIN degradation.

PP2A is negatively regulated by mTOR, which has been condensed to AKt in this model.

CERAMIDE binds to and activates PP2A.

After activation from TNFB, TGFR activates SMAD by phosphorylating the C-terminal regulatory residues.

JUN downregulates SMAD activity by acting as a co-repressor.

IL10 inhibits the production of proinflammatory cytokines and chemokines by MAC.

IFNG stimulates MAC activation as well as their microbicidal effector functions.

CCL2 is chemotactic for MAC.

ATM phosphorylates and activates P53.

JNK phosphorylates and stabilizes P53.

PTEN enhances P53 transactivation.

MDM2 binds to P53 and inhibits its ability to regulate its target genes. MDM2 also promotes the rapid degradation of P53.

TH2 secretes IL10.

TREG secretes IL10.

P21 inhibits CDK1 and CDK2, leading to cell cycle arrest.

CASP3 mediates apoptosis.

FOS stabilizes CYCLIND1 in order to promote cellular prioliferation.

CYCLIND1 promotes cell cycle progression.

MEK phosphorylates ERK.

Activated IKK leads to the phosphorylation and degradation of IKB.

TNFR recruits and activates SPHK1.

ERK phosphorylates and activates SPHK1.

The transcription factor NFKB upregulates CCL2 expression.

COX2 produces PGE2.

STAT3 upregulates SOD transcription.

NFKB upregulates SOD transcription.

Cytokine activation of GP130 leads to receptor dimerization and subsequent activation of asociated JAK proteins.

SOCS binds to and inhibits JAK.

SMAD7 inhibits TGFR's ability to phosphorylate SMAD2 and SMAD3..

TGFB binds to TGFR.

STAT3 upregulates CYCLIND1 transcription.

BCATENIN activates CYCLIND1 transcription.

GSK3B phosphorylates and inhibits CYCLIND1.

JUN upregulates CYCLIND1 transcription.