The Mitogen-Activated Protein Kinase (MAPK) network consists of tightly interconnected signalling pathways involved in diverse cellular processes, such as cell cycle, survival, apoptosis and differentiation. Although several studies reported the involvement of these signalling cascades in cancer deregulations, the precise mechanisms underlying their influence on the balance between cell proliferation and cell death (cell fate decision) in pathological circumstances remain elusive. Based on an extensive analysis of published data, we have built a comprehensive and generic reaction map for the MAPK signalling network, using CellDesigner software. In order to explore the MAPK responses to different stimuli and better understand their contributions to cell fate decision, we have considered the most crucial components and interactions and encoded them into a logical model, using the software GINsim. Our logical model analysis particularly focuses on urinary bladder cancer, where MAPK network deregulations have often been associated with specific phenotypes. To cope with the combinatorial explosion of the number of states, we have applied novel algorithms for model reduction and for the compression of state transition graphs, both implemented into the software GINsim. The results of systematic simulations for different signal combinations and network perturbations were found globally coherent with published data. In silico experiments further enabled us to delineate the roles of specific components, cross-talks and regulatory feedbacks in cell fate decision. Finally, tentative proliferative or anti-proliferative mechanisms can be connected with established bladder cancer deregulations, namely Epidermal Growth Factor Receptor (EGFR) over-expression and Fibroblast Growth Factor Receptor 3 (FGFR3) activating mutations. Bird Shannyn birdgirl@arcticmail.com University of Nebraska-Lincoln 2017-04-28T15:06:55Z 2017-07-25T20:06:24Z

Refer to an FGFR3 stimulus.

 2017-04-28T15:39:33Z

Agents that damage DNA.

 2017-04-28T15:39:33Z

Refer an EGFR stimulus.

 2017-04-28T15:39:33Z

TGFBR_stimulus refers to a stimulus known to cause TGFBR activation.

 2017-05-11T19:56:02Z

Name: Cyclin-dependent kinase inhibitor 1A

Gene Name: CDKN1A

UNIPROT ID: P38936

Gene ID: 1026

 2017-05-11T19:56:02Z

Name: Phosphatase and tensin homolog

Gene Name: PTEN

UNIPROT ID: P60484

Gene ID: 5728

 2017-05-11T19:56:02Z

Name: Protein sprouty homolog 2

Gene Name: SPRY2

UNIPROT ID: O43597

Gene ID: 10253

 2017-05-11T19:56:02Z

Name: Apoptosis regulator Bcl-2

Gene Name: BCL2

UNIPROT ID: P10415

Gene ID: 596

 2017-04-28T15:39:33Z

Name: Cyclic AMP-dependent transcription factor ATF-2

Gene Name: ATF2

UNIPROT ID: P15336

Gene ID: 1386

 2017-04-28T15:39:33Z

Name: Mothers against decapentaplegic homolog 2, 3, and 4

Gene Name: SMAD2, SMAD3, SMAD4

UNIPROT ID: Q15796, P84022, Q13485

Gene ID: 4087, 4088, 4089

 2017-05-11T19:56:02Z

Cell growth arrest

 2017-04-28T16:04:02Z

Name: Proto-oncogene c-Fos

Gene Name: FOS

UNIPROT ID: P01100

Gene ID: 2353

 2017-04-28T15:45:53Z

Name: Mitogen-activated protein kinase kinase kinase 7

Gene Name: MAP3K7

UNIPROT ID: O43318

Gene ID: 6885

 2017-05-11T19:56:02Z

Name: Son of sevenless homolog 1 and 2

Gene Name: SOS1, SOS2

UNIPROT ID: Q07889, Q07890

Gene ID: 6654, 6655

 2017-05-11T19:56:02Z

Name: Mitogen-activated protein kinase 11, 12, 13, and 14

Gene Name: MAPK11, MAPK12, MAPK13, MAPK14

UNIPROT ID: Q15759, P53778, O15264, Q16539

Gene ID: 5600, 6300, 5603, 1432

 2017-05-17T10:05:58Z

Name: Myc-associated factor X

Gene Name: MAX

UNIPROT ID: P61244

Gene ID: 4149

 2017-04-28T16:26:26Z

Name: Protein kinase C alpha, beta, and gamma

Gene Name: PRKCA, PRKCB, PRKCG

UNIPROT ID: P17252, P05771, P05129

Gene ID: 5578, 5579, 5582

 2017-05-11T19:56:02Z

Name: Mitogen-activated protein kinase kinase kinase 4

Gene Name: MAP3K4

UNIPROT ID: Q9Y6R4

Gene ID: 4216

 2017-05-11T19:56:02Z

Name: Protein phosphatase 2 catalytic subunit alpha

Gene Name: PPP2CA

UNIPROT ID: P67775

Gene ID: 5515

 2017-05-11T19:56:02Z

Name: Fibroblast growth factor receptor substrate 2

Gene Name: FRS2

UNIPROT ID: Q8WU20

Gene ID: 10818

 2017-04-28T15:53:48Z

Name: Forkhead box protein O3

Gene Name: FOXO3

UNIPROT ID: O43524

Gene ID: 2309

 2017-04-28T15:51:13Z

Name: ETS domain-containing protein Elk-1

Gene Name: ELK1

UNIPROT ID: P19419

Gene ID: 2002

 2017-04-28T15:51:13Z

Name: Epidermal growth factor receptor

Gene Name: EGFR

UNIPROT ID: P00533

Gene ID: 1956

 2017-05-11T19:56:02Z

Name: Ribosomal protein S6 kinase beta 1 and 2

Gene Name: RPS6KB1 and RPS6KB2

UNIPROT ID: P23443, Q9UBS0

Gene ID: 6198, 6199

 2017-05-11T19:56:02Z

Name: V-myc avian myelocytomatosis viral oncogene homolog

Gene Name: MYC

UNIPROT ID: P01109

Gene ID: 420332

 2017-05-11T19:56:02Z

Gene Name: AKT1, AKT2, and AKT3

UNIPROT ID: P31749, P31751, Q9Y243

Name: Serine/threonine-protein kinase AKT family

Gene ID: 207, 208, 10000

 2017-05-11T19:56:02Z

Name: Dual specificity protein phosphatase 1

Gene Name: DUSP1

UNIPROT ID: P28562

Gene ID: 1843

 2017-05-11T19:56:02Z

Name: Ribosomal protein S6 kinase alpha 4 and 5

Gene Name: RPS6KA4, RPS6KA5

UNIPROT ID: O75676, O75582

Gene ID: 8986, 9252

 2017-04-28T16:26:26Z

Name: GRB2-associated-binding protein 1

Gene Name: GAB1

UNIPROT ID: Q13480

Gene ID: 2549

 2017-05-11T19:56:02Z

Name: Growth factor receptor-bound protein 2

Gene Name: GRB2

UNIPROT ID: P62993

Gene ID: 2885

 2017-05-11T19:56:02Z

Name: Mitogen-activated protein kinase 8, 9, and 10

Gene Name: MAPK8, MAPK9, MAPK10

UNIPROT ID: P45983, P45984, P53779

Gene ID: 5599, 5601, 5602

 2017-04-28T16:26:26Z

Name: Mitogen-activated protein kinases 1 and 3

Gene Name: MAPK1, MAPK3

UNIPROT ID: P28482, P27361

Gene ID: 5594, 5595

 2017-05-11T19:56:02Z

Name: Phospholipase C, gamma 1 and 2

Gene Name: PLCG1, PLCG2

UNIPROT ID: P19174, P16885

Gene ID: 5335, 5336

 2017-05-11T19:56:02Z

Name: Cyclin-dependent kinase inhibitor 2A

Gene Name: CDKN2A

UNIPROT ID: P42771

Gene ID: 1029

 2017-04-28T16:27:16Z

Name: Mitogen-activated protein kinase kinase kinase 1, 2, and 3

Gene Name: MAP3K1, MAP3K2, MAP3K3

UNIPROT ID: Q13233, Q9Y2U5, Q99759

Gene ID: 4214, 10746, 4215

 2017-05-11T19:56:02Z

Name: Ribosomal protein S6 kinase alpha-1, 2, 3, and 6

Gene Name: RPS6KA1, RPS6KA2, RPS6KA3, RPS6KA6

UNIPROT ID: Q15418, Q15349, P51812, Q9UK32

Gene ID: 6195, 6196, 6197, 27330

 2017-05-11T19:56:02Z

Name: Growth arrest and DNA damage-inducible protein GADD45 alpha, beta, and gamma

Gene Name: GADD45A, GADD45B, GADD45G

UNIPROT ID: P24522, O75293, O95257

Gene ID: 1647, 4616, 10912

 2017-04-28T16:26:26Z

Name: GTPase HRas, GTPase KRas, and GTPase NRas

Gene Name: HRAS, KRAS, NRAS

UNIPROT ID: P01112, P01116, P01111

Gene ID: 3265, 3845, 4893

 2017-05-11T19:56:02Z

Name: Activator protein 1

Gene Name: JUN/FOS/ATF2

UNIPROT ID: P05412/P01100/ P15336

Gene ID: 3725/2353/1386

AP1 is a heterodimer of either JUN and FOS or ATF2

 2017-04-28T16:26:26Z

Name: Serine-protein kinase ATM

Gene Name: ATM

UNIPROT ID: Q13315

Gene ID: 472

 2017-05-17T10:05:58Z

Programmed cell death

 2017-04-28T15:39:33Z

Cell proliferation (increase in cell numbers)

 2017-05-11T19:56:02Z

Name: Transforming growth factor beta receptor 1, 2, and 3

Gene Name: TGFBR1, TGFBR2, TGFBR3

UNIPROT ID: P36897, P37173, Q03167

Gene ID: 7046, 7048, 7049

 2017-05-11T19:56:02Z

Name: Proto-oncogene c-Jun

Gene Name: JUN

UNIPROT ID: P05412

Gene ID: 3725

 2017-04-28T16:26:26Z

Name: E3 ubiquitin-protein ligase Mdm2

Gene Name: MDM2

UNIPROT ID: Q00987

Gene ID: 4193

 2017-05-17T10:05:58Z

Name: Serine/threonine-protein kinase TAO1, TAO2, and TAO3

Gene Name: TAOK1, TAOK2, and TAOK3

UNIPROT ID: Q7L7X3, Q9UL54, Q9H2K8

Gene ID: 57551, 9344

 2017-05-11T19:56:02Z

Name: Mitogen-activated protein kinase kinase 1 and 2

Gene Name: MAP2K1, MAP2K2

UNIPROT ID: Q02750, P36507

Gene ID: 5604, 5605

 2017-04-28T16:26:26Z

Name: Cellular tumor antigen p53

Gene Name: TP53

UNIPROT ID: P04637

Gene ID: 7157

 2017-05-17T10:05:58Z

Name: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform

Gene Name: PIK3CA

UNIPROT ID: P42336

Gene ID: 5290

 2017-05-11T19:56:02Z

Name: Pyruvate dehydrogenase kinase, isozyme 1

Gene Name: PDK1

UNIPROT ID: Q15118

Gene ID: 5163

 2017-05-11T19:56:02Z

Name: V-raf-1 murine leukemia viral oncogene homolog 1, Serine/threonine-protein kinase B-raf, and Serine/threonine-protein kinase A-Raf

Gene ID: RAF1, BRAF, ARAF

UNIPROT ID: P04049, P15056, P10398

Gene ID: 5894, 673, 369

 2017-05-11T19:56:02Z

Name: Fibroblast growth factor receptor 3

Gene Name: FGFR3

UNIPROT ID: P22607

Gene ID: 2261

 2017-05-11T19:56:02Z

Name: Cyclic AMP-responsive element-binding protein 1

Gene Name: CREB1

UNIPROT ID: P16220

Gene ID: 1385

 2017-04-28T15:51:13Z

p53 and not AKT activate p21.

AKT inhibits p21 through phosphorylation.

p53 activates p21 transcriptionally.

 S_48 1 S_23 1

p53 activates PTEN.

Increased p53 activity is associated with increased PTEN activity.

 S_48 1

ERK activates SPRY.

ERK activates SPRY through phosphorylation on Tyr55.

 S_29 1

CREB activates BCL2 in the presence of AKT.

BCL2 is a target gene of CREB.

AKT activates BCL2 through phosphorylation.

 S_53 1 S_23 1

JNK and p38 are positive regulators of ATF2.

JNK activates ATF2 through phosphorylation at Thr69 and Ser71.

p38 activates ATF2 through phosphorylation at Thr69 and Ser71.

 S_12 1 S_28 1

TGFBR activates SMAD.

Increased TGFBR activity is associated with increased SMAD activity.

 S_43 1

p21 activates Growth_Arrest.

p21 is a cyclin-dependent kinase inhibitor that activates Growth_Arrest.

 S_1 1

ERK upregulates FOS in the presence of RSK and either CREB or ELK1.

Phosphorylation by ERK and RSK activate FOS.

Phosphorylation by ERK and RSK activate FOS.

ELK1 encourages FOS activation.

CREB targets FOS, encouraging activation.

 S_29 1 S_34 1 S_19 1 S_53 1

TGFBR activates TAK1.

TGFBR activates TAK1 through phosphorylation.

 S_43 1

GRB2 and NOT RSK activates SOS.

RSK is known to be involved in SOS phosphorylation and is associated with downregulation of SOS.

Increased GRB2 activity is associated with increased SOS activity.

 S_27 1 S_34 1

MAP3K1_3 and MTK1 activate p38. MAP3K1_3 activate p38, when DUSP1 is inactive. MTK1 activates p38, when DUSP1 is inactive. TAK1 adn MTK1 activate p38. TAK1 and MAP3K1_3 activate p38. TAK1 and TAOK activate p38. TAK1 activates p38, when DUSP1 is inactive. TAOK and MAP3K1_3 activate p38. TAOK and MTK1 activate p38. TAOK activates p38, when DUSP1 is inactive.

TAK1 activates p38 through phosphorylation.

Increased DUSP1 activity is associated with decreased p38 activity.

Increased MTK1 activity is associated with increased p38 activity.

Increased MAP3K1_3 activity is associated with increased p38 activity.

Increased TAOK activity is associated with increased p38 activity.

 S_32 1 S_15 1 S_46 1 S_15 1 S_10 1 S_15 1 S_10 1 S_24 1 S_46 1 S_24 1 S_46 1 S_32 1 S_10 1 S_32 1 S_15 1 S_24 1 S_10 1 S_46 1 S_32 1 S_24 1

p38 activates MAX.

p38 activates MAX through phosphorylation.

 S_12 1

PLCG activates PKC.

PLCG activates PKC through phosphorylation and formation of secondary messengers, diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3).

 S_30 1

GADD 45 activate MTK1.

Increased GADD45 activity is associated with increased MTK1 activity.

 S_36 1

p38 activates PPP2CA.

p38 activates PPP2CA through dephosphorylation.

 S_12 1

FGFR3 and not GRB2 and not SPRY activate FRS2.

GRB2 encourages ubiquitation, which degrades FRS2.

SPRY sequesters GRB2, causing negative feedback.

FGFR3 encourages phosphorylation of Shp2 on a tyrosine residue, forming a complex with GRB2. The complexes are recruited, which activates FRS2.

 S_52 1 S_4 1 S_27 1

FOXO3 is activated by JNK and downregulated by AKT, which expresses dominance over JNK.

By encouraging phosphorylation at Ser82 of MST1, MST1 phosphorylates FOXO3 at Ser207, which promotes cell death.

By phosphorylating FOXO3 a binding site is created, where other proteins can bind, inhibiting FOXO3 activity.

 S_28 1 S_23 1

ERK, JNK, and p38 are all activators of ELK1.

JNK target ELK1 in the nucleus.

ERK activates ELK1 through phosphorylation.

p38 targets ELK1 in the nucleus.

 S_12 1 S_28 1 S_29 1

EGFR is activated by SPRY and EGFR_stimulus. PKC and GRB2 negatively regulate EGFR and express dominance over SPRY and EGRF_stimulus.

GRB2 promotes ubiquitation and degradation of EGFR.

A possible inhibitory mechanism

SPRY sequesters Cb1, which encourages positive feedback. It also sequesters GRB2, which also activates EGFR.

EGFR_stimulus is a stimulus that activates EGFR.

 S_4 1 S_14 1 S_27 1 S_35 1 S_14 1 S_27 1

PDK1 and ERK activate p70.

ERK activates p70 by causing cascade reactions.

PDK1 targets p70, causing activation.

 S_50 1 S_29 1

MSK and MAX activate MYC. MSK and AKT activate MYC.

MAX is known to trans-activate MYC.

AKT activates MYC through phosphorylation.

MSK encourages chromatic to relax, which induces MYC activity.

 S_25 1 S_23 1 S_25 1 S_13 1

AKT is activated by PDK1 and inhibited by PTEN, which expresses dominance over PDK1.

Increased levels of PTEN is associated with decreased AKT activity.

PDK1 activates AKT through phosphorylation.

 S_50 1 S_2 1

CREB positively regulates DUSP1.

DUSP1 is a target gene of CREB.

 S_53 1

ERK or p38 activate MSK.

ERK activates MSK in vivoly via phosphorylation.

p38 activates MSK in vivoly via phosphorylation.

 S_29 1 S_12 1

GRB2 or PI3K activate GAB1.

GRB2 activates GAB1 through recruitment.

PI3K recruits GAB1, resulting in a positive feedback loop.

 S_49 1 S_27 1

EGFR, FRS2 or TGFBR activate GRB2.

EGFR activates GRB2 through tyrosine phosphorylation.

FRS2 activates GRB2 throught tyrosine phosphorylation.

TGFBR activates GRB2 through phosphorylation.

 S_20 1 S_43 1 S_17 1

MAP3K1_3 activates JNK, when DUSP1 is inactive. MAP3K1_3 adn MTK1 activate JNK. MTK1 activates JNK, when DUSP1 is inactive. TAK1 and MTK1 activate JNK. TAK1 and MAP3K1_3 activate JNK. TAK1 activates JNK, when DUSP1 is inactive. TAK1 and TAOK activate JNK. TAOK and MTK1 activate JNK. TAOK and MAP3K1_3 activate JNK. TAOK activates JNK, when DUSP1 is inactive.

TAK1 activates JNK through phosphorylation.

DUSP1 inhibits JNK, preferentially.

Increased JNK activity is associated with increased MTK1 activity.

MAP3K1_3 activates JNK through coupling and Ras-dependent mechanisms.

TAOK functions upstream of JNK, activating JNK.

 S_46 1 S_15 1 S_10 1 S_46 1 S_15 1 S_24 1 S_10 1 S_15 1 S_10 1 S_32 1 S_32 1 S_15 1 S_10 1 S_24 1 S_46 1 S_24 1 S_46 1 S_32 1 S_32 1 S_24 1

MEK1_2 activates ERK.

When MEK1_2 is activated, it causes a phosphorylation cascade, activating ERK.

 S_47 1

EGFR or FGFR3 activate PLCG.

EGFR activates PLCG through tyrosine phosphorylation.

FGFR3 activates PLCG through binding and phosphorylation.

 S_20 1 S_52 1

MYC activates p14.

Increased MYC activity is associated with increased p14 activity.

 S_22 1

RAS activates MAP3K1_3.

RAS binds to MAP3K1_3 in a GTP-dependent manner.

 S_37 1

ERK activates RSK.

ERK activates RSK through phosphorylation.

 S_29 1

SMAD or p53 activate GADD45.

SMAD is known to encourage p38 activation, in presence of TGFbeta. GADD45 is induced by TGFbeta.

p53 is known to trans-activate the gene.

 S_7 1 S_48 1

PLCG or SOS activate RAS.

Increased PLCG activity is associated with increased RAS activity.

Increased SOS activity is associated with increased RAS activity.

 S_11 1 S_30 1

JUN activates AP1 in the presence of either ATF2 or FOS.

JUN is part of the AP1 heterodimer.

FOS can be part of the AP1 heterodimer.

ATF2 can be part of the AP1 heterodimer.

 S_44 1 S_9 1 S_6 1

DNA_damage activates ATM.

In response to stress (DNA_damage), ATM autophosphorylates at Ser1981.

 S_33 1

FOXO3 activates Apoptosis in the presence of p53. ERK and BCL2 are negative regulators of Apoptosis which express dominance over FOXO3.

When BCL2 is unbound, it encourages cell survival.

By activating PUMA, FOXO3 helps lead to apoptosis.

Caspase 9 is phosophorylated on Thr125 by ERK, which causes anti -apoptotic reactions.

p53 transactivates PUMa, which leads to apoptosis.

 S_18 1 S_48 1 S_5 1 S_29 1

p70 and MYC and not p21 activate proliferation.

Activation of p70 is known to cause cell growth.

p21 is a cyclin- dependent inhibitor of the cell cycle.

MYC is known to lead to Ef2-induced cell cycle progression.

 S_21 1 S_22 1 S_1 1

TGFBR_stimulus activates TGFBR.

TGFBR_stimulus refers to a stimulus known to cause TGFBR activation.

 S_39 1

JNK activates JUN.

JNK activates JUN through phosphorylation on Ser63 and Ser73.

 S_28 1

AKT or p53 and not p14 activate MDM2.

AKT recruites survival signals, activating MDM2.

p14 inhibts MDM2 through transcription.

p53 activates MDM2 through an autoregulatory feedback loop mechanism dependent on ubiquitation.

 S_23 1 S_31 1 S_48 1 S_31 1

ATM activates TAOK.

ATM activates TAOK via phosphorylation.

 S_40 1

MAP3K1_3 or RAF and not AP1 or not PPP2CA activate MEK1_2.

RAF activates MEK1_2 through a phosphorylation cascade.

PPP2CA inhibits MEK1_2 through dephosphorylation.

AP1 inhibits MEK1_2, by inhibiting phosphorylation.

Increased MAP3K1_3 activity is associated with increased MEK1_2 activity.

 S_51 1 S_38 1 S_16 1 S_32 1 S_38 1 S_16 1

ATM and p38 activate p53. ATM activates p53, when MDM2 is inactive. p38 activates p53, when MDM2 is inactive.

By phosphorylation at ser15, ATM activates p53.

p38 activates p53 via phosphorylation.

MDM2 and p53 are involved in an autoregulatory feedback loop. Increased levels o fp53 activate MDM2, which then causes degradation of p53 through ubiquitation.

 S_12 1 S_45 1 S_40 1 S_12 1 S_40 1 S_45 1

GAB1 or RAS and SOS activate PI3K.

Increased SOS activity is associated with increased PI3K activity.

Increased RAS activity is associated with increased PI3K activity.

GAB2 activates PI3K through binding and a positive feedback loop mechanism.

 S_37 1 S_11 1 S_26 1

PI3k activate PDK1.

Increased PI3K activity is associated with increased PDK1 activity.

 S_49 1

PKC or RAS and not AKT or not ERK activate RAF.

PKC activate RAF through phosphorylation.

ERK inhibits RAF through feedback phosphorylation.

Phosphorylated AKT inhibit RAF.

RAS activates RAF through phosphorylation.

 S_14 1 S_29 1 S_23 1 S_37 1 S_29 1 S_23 1

FGFR3_stimulus activates FGFR3. GRB2 and PKC are negative regulators of FGFR3 which express dominance over FGFR3_stimulus.

By promoting ubiquitation, GRB2 encourages FGFR3 degradation.

By encouraging phosphorylation, PKC causes internalization and degradation of FGFR3.

FGFR3_stimulus refers to a stimulus that causes FGFR3 activation.

 S_3 1 S_27 1 S_14 1

CREB is activated by MSK.

MSK activates CREB by encouraging mitogen-stimulated phosphorylation.

 S_25 1