CDK2 (in complex with Cyclin E) phosphorylates pRB to progress the cell into S phase. Formation of the CDK2:CyclinE complex is dependent on the partial phosphorylation of pRB (in this model pRB represents the phosphorylated form of pRB) by CDK4 and CDK6.

CDK6 (in complex with Cyclin D) phosphorylates pRB.

CDK4 (in complex with Cyclin D) phosphorylates pRB.

The BIR3 domain of XIAP forms a heterodimer with Cas9 monomers, thus preventing Cas9 catalytic activity.

The release of Cytc leads to the proteolytic activation of procaspase-9 by Apaf-1, which produces Cas9.

AKT inhibits Cas9 by blocking Cytc release into the cytosol as well as inhibiting Cytc activation of Cas9.

MDM induces proteasome degradation of p53.

MDM induces proteasome degradation of p53.

Experimental evidence demonstrates that p53 is incapable of binding to DNA in the absence of DNAPK, insinuating that DNAPK is required for p-53 activation in response to DNA damage.

JNK converts p53 from a transactivator to a repressor of Wip1, a p53 signaling inhibitor.

ATM is activated in response to DNA damage, specifically in the form of double-strand breaks.

ATM activity is up-regulated with apoptotic progression. As a result, activation of ATM occurs concurrently with caspase-3 activation.

p53 upregulates Fas following DNA damage.

FasL binds to its receptor, Fas.

RAC indirectly activates the same downstream target as MEKK2.

Unphosphorylated pRB inhibits progression from G1 to S phase by blocking transcription of S phase proteins. When pRB is phophorylated (pRB in this model represents the phosphorylated form), the cell cycle is able to progress from G1 to S phase.

CI_PARP activation induces apoptosis.

c-Src-mediated transcriptional activation of NFκB requires tyrosine phosphorylation of IκBα.

Only phosphorylated Stat3 is able to interact with phosphorylated NF-kappa-B p65.

X activates pNFkB.

Inhibition of Prot prevents cleavage of IκBα and decreases NFκB activity.

NFKB binds to Bclxl.

BclxL expression can be inhibited by blocking STAT3 activation from JAKs, demonstrating that STAT3 plays a role in Bclxl expression.

Bclxl is an antiapoptotic protein while p53 is a known tumor suppressor protein that can mediate cell death.

BAD binds to and inhibits Bclxl.

Bclxl is a antiapoptotic protein while BAX promotes mitochondrial apoptosis. In multiple myeloma cells, there is higher expression of Bclxl and lower expression of BAX.

MDM iinhibits p53, the positive regulator of p21.

AKT phosphorylates p27, leading to its relocalization to the cytoplasm.

p53 transcriptionally activates p21 expression.

The CYCD:CDK4 complex sequesters unbound p27 and prevents its inhibitory effect on CYCE:CDK2.

MYC inhibits p21 transcription by repressing the p21 promoter.

MEK1 phosphorylates MEKK.

MYC indirectly upregulates CYCE activity through activation of E2F.

Binding of FasL to Fas promotes oligomerization of Cas8 through activation of FADD.

FLIP is recruited and partially processed by death-induced signaling complexes. A portion of the FLIP protein is retained, which in turn inhibits recruitment of caspase-8.

Binding of FasL to Fas promotes oligomerization of Cas8 through activation of FADD.

SHP1 binds to the EPO receptor and dephosphorylates the associated JAK2 proteins.

IL6 binding to its receptor induces gp130-homodimerization. This in turn leads to JAK2 phosphorylation.

IL6 binding to its receptor induces gp130-homodimerization. This in turn leads to JAK2 phosphorylation.

JNK phosphorylates cJun on its N-terminal transactivation domain at Ser63 and Ser73.

p21 is a CDK inhibitor.

CYCD forms a complex with CDK4.

p27 is a CDK inhibitor.

MKK4 phosphorylates JNK.

Treatment with proteasome inhibitors led to a steady increase in JNK activity, implying that Prot is a negative regulator of JNK.

DNA damage causes cellular stress.

Proteolytic activities of proteasomes are important for repairing DNA damage. Prot prevents the buildup of DNA damage and cellular stress caused by that damage.

AKT phosphorylates p27, leading to its relocalization to the cytoplasm.

p53 binds to the p27 promoter to activates p27 expression.

The CYCD:CDK4 complex sequesters unbound p27 and prevents its inhibitory effect on CYCE:CDK2.

MYC is an upstream regulator of CDKs and functionally antagonizes p27 activity.

TRAF3 inhibits NIK by interacting with a TRAF2–cIAP complex to direct cIAP-mediated K48-linked polyubiquitylation of NIK.

MAPK phosphorylates MEK1.

CYCD forms a complex with CDK6.

TNFAR indirectly activates RIP.

TNFA indirectly activates RIP through binding of its receptor, TNFAR.

Bort induces phosphorylation of RIP.

The formation of pores in the mitochondrial membrane by BAX leads to the release of Cytc.

STRESS indirectly induces RAC activation.

Akt signaling promotes the phosphorylation and movement of the MDM into the nucleus.

p53 transcriptionally upregulates MDM.

ATM phosphorylates serine 394 of MDM. This reduces MDM's ability to induce p53 degradation.

ERK indirectly upregulates CYCD expression.

AKT up regulates CYCD expression by phosphorylating and inactivating glycogen synthase kinase 3β. This prevents the degradation of CYCD.

MYC knockout cells saw a 12-fold reduction in CYCD-CDK4 activity, indicating that MYC is important for CYCD's role in promoting cell division.

Bortezomib is a potent, selective, and reversible inhibitor of the proteasome

RAF phosphorylates MEK1.

Activation of TNFAR leads to the recruitment of CIAP to the receptor.

cJun has been shown to directly activate the FasL promoter.

Fas indirectly upregulates FasL expression.

p53 neutralizes the inhibitory effects of Bclxl and BCL2 on Bax.

Truncated BID translocates to the mitochondria where it then induces a conformational change and oligomerization of BAX.

Bclxl inhibits Bax by competing for binding to membranes.

BCL2 induces conformational changes in the mitochondrial membrane to bind membrane-inserted BAX monomers in order to inhibit BID-mediated activation of BAX.

The formation of pores in the mitochondrial membrane by BAX leads to the sequential activation of the caspase cascade.

Downregulation of gp130 by proteasome inhibitor PS-341 is dependent on caspase activation and is suspected to be mediated by caspase-3 specifically.

MEKK2 phosphorylates MKK4.

NFκB activation upregulates FLIP.

AKT phosphorylates BAD.

STAT3 plays a role in cell survival, while Cas 3 promotes apoptosis.

BAX induces apoptotic pores in the mitochondrial outer membrane to induce cell death.

IKK phosphorylates IkB.

IKK is a negative regulator of pSTAT3 which expresses dominance over JAK1 and JAK2.

JAK2 and JAK1 phosphorylate STAT3 at Tyr705, resulting in translocation of activated STAT3 dimers to the nucleus.

JAK2 and JAK1 phosphorylate STAT3 at Tyr705, resulting in translocation of activated STAT3 dimers to the nucleus.

JAK2 and JAK1 phosphorylate STAT3 at Tyr705, resulting in translocation of activated STAT3 dimers to the nucleus.

JNK induces ser-727 phosphorylation of STAT3 and can negatively regulate the tyrosine phosphorylation of STAT3.

Inhibition of STAT3 signaling suppresses MYC expression, suggesting that STAT3 positively regulates MYC experssion.

MEKK expression stimulated the transactivation of MYC.

ERK stabilizes MYC through phosphorylation of MYC at Ser62.

SHP1 is required for Ras-dependent activation of the MAPK pathway, but not required for activation of RAF.

IL6 binding to its receptor induces gp130-homodimerization. This in turn leads to RAS activation.

IL6 binding to its receptor induces gp130-homodimerization. This in turn leads to RAS activation.

IL6 binding to its receptor induces gp130-homodimerization. This in turn leads to activation of the PI3K/AKT pathway.

IL6 binding to its receptor induces gp130-homodimerization. This in turn leads to activation of the PI3K/AKT pathway.

STRESS activates BID.

Fas indirectly activates BID through caspase-8.

Cas8 cleaves and activates BID.

Bclxl inhibits BID-mediated activation of Bax by competing for binding to membranes.

BCL2 induces conformational changes in the mitochondrial membrane to bind membrane-inserted BAX monomers in order to inhibit BID-mediated activation of BAX.

Akt phosphorylates IKKα on T23.

RIP is suspected to activate IKK by recruiting the IKK kinase to the TNF-R1 complex.

NIK is required for IKK activation and seems to function as an IKK-activating kinase as well as a scaffold linking IKK and p100.

NFKB and XIAP are apart of a positive feedback loop where NFKB activates XIAP, which in turn activates NFKB.

XIAP binds to and inactivates caspase-9. Smac prevents XIAP-mediated inhibition of caspase-9 activity by disrupting the interaction of the linker peptide of caspase-9 with the BIR3 domain iof XIAP.

Inhibition of STAT3 decrease XIAP expression, suggesting that STAT3 up-regulates XIAP expression.

Expression of p53 reduced XIAP protein in neurons, suggesting that p53 down-regulates XIAP expression.

MM cell adhesion to bone marrow stromal cells upregulates transcription and secretion of IL6 via a NFKB-dependent pathway.

RAS binds to RAF and recruits it to the cell membrane. Here, RAF is phosphorylated to activate its enzymatic activity.

PTEN lcontains a p53 binding element directly upstream of the PTEN gene that is necessary for inducible transactivation of PTEN by p53.

p21 is a CDK inhibitor.

CYCE forms a complex CDK2.

ATM mediates DNAPK phosphorylation at Thr-2609.

Proteolytic activities of proteasomes are important for a number of cellular processes, including DNA repair. Inhibition of the proteasome causes by stress leads to the accumulation of DNA damage.

Cas3 cleaves a protein important for cellular repair, DNA-PKc, thus inhibiting DNA repair.

SHP1 is plays a role in the dephosphorylation of JAK1.

IL6 binding to its receptor induces gp130-homodimerization. This in turn leads to JAK1 phosphorylation.

IL6 binding to its receptor induces gp130-homodimerization. This in turn leads to JAK1 phosphorylation.

In response to ligands such as CD40L, CIAPs target TRAF3 for proteasomal degradation.

Cas3 cleaves C1_PARP.

ERK is activated by MAPK.

PTEN deposphorylates PIP3.

PIP3 is involved in a positve feedback loop that sustains its own activity.

PIP3 potentially activates AKT by recruiting it to the plasma membrane and altering its conformation to induce subsequent phosphorylation by PDK1.

NFKB transcriptionally regulates BCL2.

pSTAT3 directly associates with the BCL2 promoter to upregulate BCL2 expression.

p53 is a proapoptotic protein that can counteract the antiapoptotic effects of BCL2.

BAD heterodimerizes with BCL2.

XIAP can polyubiquitylate Cas3, leading to its proteasome-dependent degradation.

Cas9 cleaves and activates Cas3.

Cas8 cleaves and activates Cas3.