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BIOMD0000000396 - Sivakumar2011 - Notch Signaling Pathway

 

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Reference Publication
Publication ID: 21978399
Sivakumar KC, Dhanesh SB, Shobana S, James J, Mundayoor S.
A systems biology approach to model neural stem cell regulation by notch, shh, wnt, and EGF signaling pathways.
OMICS 2011 Oct; 15(10): 729-737
Bioinformatics Facility, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India.  [more]
Model
Original Model: BIOMD0000000396.origin
Submitter: KC Sivakumar
Submission ID: MODEL1101270000
Submission Date: 27 Jan 2011 04:36:26 UTC
Last Modification Date: 08 Apr 2016 17:16:54 UTC
Creation Date: 02 Nov 2011 14:45:45 UTC
Encoders:  Vijayalakshmi Chelliah
   KC Sivakumar
set #1
bqmodel:isDerivedFrom PANTHER Pathway P00045
set #2
bqbiol:occursIn Cell Type Ontology neuronal stem cell
set #3
bqbiol:hasTaxon Taxonomy Mammalia
set #4
bqbiol:isVersionOf Gene Ontology Notch signaling pathway
Notes
Sivakumar2011 - Notch Signaling Pathway

Notch is a transmembrane receptor that mediates local cell-cell communication and coordinates a signaling cascade. It plays a key role in modulating cell fate decisions throughout the development of invertebrate and vertebrate species and the misregulation leads to a number of human diseases.

References:

This model is described in the article:

Sivakumar KC, Dhanesh SB, Shobana S, James J, Mundayoor S.
Omics: a Journal of Integrative Biology. 2011; 15(10):729-737

Abstract:

The Notch, Sonic Hedgehog (Shh), Wnt, and EGF pathways have long been known to influence cell fate specification in the developing nervous system. Here we attempted to evaluate the contemporary knowledge about neural stem cell differentiation promoted by various drug-based regulations through a systems biology approach. Our model showed the phenomenon of DAPT-mediated antagonism of Enhancer of split [E(spl)] genes and enhancement of Shh target genes by a SAG agonist that were effectively demonstrated computationally and were consistent with experimental studies. However, in the case of model simulation of Wnt and EGF pathways, the model network did not supply any concurrent results with experimental data despite the fact that drugs were added at the appropriate positions. This paves insight into the potential of crosstalks between pathways considered in our study. Therefore, we manually developed a map of signaling crosstalk, which included the species connected by representatives from Notch, Shh, Wnt, and EGF pathways and highlighted the regulation of a single target gene, Hes-1, based on drug-induced simulations. These simulations provided results that matched with experimental studies. Therefore, these signaling crosstalk models complement as a tool toward the discovery of novel regulatory processes involved in neural stem cell maintenance, proliferation, and differentiation during mammalian central nervous system development. To our knowledge, this is the first report of a simple crosstalk map that highlights the differential regulation of neural stem cell differentiation and underscores the flow of positive and negative regulatory signals modulated by drugs.

To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Model
Publication ID: 21978399 Submission Date: 27 Jan 2011 04:36:26 UTC Last Modification Date: 08 Apr 2016 17:16:54 UTC Creation Date: 02 Nov 2011 14:45:45 UTC
Mathematical expressions
Reactions
r30 r31 r8 r9
r10 r11 r13 r16
r17 r18 r21 r25
r26 r28 r29 re16
Physical entities
Compartments Species
default Fringe fucose Delta
a7_degraded Neuralized Complex_br_(Delta/N_sub_ext)
Neurotic Serrate Complex_br_(Serrate/N_sub_ext)
s76 s77 dapt
gama secretase    
cytosol NI_sub_c_sub_t N_sub_tm TACE
Numb Notch Notch
Complex_br_(Serrate/Notch) NI_sub_c_sub_s a25_degraded
LNXp80 Complex_br_(Notch/Delta)  
nucleus Mastermind Su(H) CoR
Complex_br_(Su(H)/CoR) CoA NI_sub_c_sub_s
Complex_br_(Mastermind/Su(H)/_br_CoA/NI_sub_c_sub_s) NI_sub_c_sub_s Sel 10
Ub a46_degraded E(spl)-C genes
     
Global parameters
kcatp_r8 kM_r8_s15 kcatn_r8 kM_r8_s19
kM_r8_s63 kcatp_r9 kM_r9_s7 kcatn_r9
kM_r9_s22 kass_r10 kdiss_r10 kI_r10_s25
kcatp_r11 kM_r11_s32 kcatn_r11 kM_r11_s26
kM_r11_s28 kass_r13 kdiss_r13 kcatp_r16
kcatn_r16 kM_r16_s39 ki_r16_s39 kass_r17
kdiss_r17 kcatp_r18 kcatn_r18 kM_r18_s4
ki_r18_s4 kass_r21 kdiss_r21 kI_r21_s2
kcatp_r25 kM_r25_s53 kcatn_r25 kM_r25_s60
kM_r25_s15 kcatp_r26 kM_r26_s25 kcatn_r26
kM_r26_s64 kcatp_r28 kcatn_r28 kM_r28_s41
ki_r28_s41 kcatp_r29 kM_r29_s67 kcatn_r29
kM_r29_s18 kM_r29_s15 kass_r30 kass_r31
kdiss_r31 kass_re16 kdiss_re16 kI_re16_s81
Reactions (16)
 
 r30 [Complex_br_(Su(H)/CoR)] → [E(spl)-C genes];  
 
 r31 [Complex_br_(Mastermind/Su(H)/_br_CoA/NI_sub_c_sub_s)] → [E(spl)-C genes];  
 
 r8 [NI_sub_c_sub_t] ↔ [N_sub_tm] + [NI_sub_c_sub_s];   {gama secretase}
 
 r9 [Delta] ↔ [a7_degraded];   {Neuralized}
 
 r10 [NI_sub_c_sub_s] ↔ [NI_sub_c_sub_s];   {Numb}
 
 r11 [Complex_br_(Su(H)/CoR)] ↔ [Su(H)] + [CoR];   {NI_sub_c_sub_s}
 
 r13 [NI_sub_c_sub_s] + [Su(H)] + [Mastermind] + [CoA] ↔ [Complex_br_(Mastermind/Su(H)/_br_CoA/NI_sub_c_sub_s)];  
 
 r16 [NI_sub_c_sub_s] + [Ub] ↔ [NI_sub_c_sub_s];   {Sel 10}
 
 r17 [NI_sub_c_sub_s] ↔ [a46_degraded];  
 
 r18 [Notch] + [fucose] ↔ [Notch];   {Neurotic}
 
 r21 [Notch] + [Serrate] ↔ [Complex_br_(Serrate/Notch)];   {Fringe}
 
 r25 [Complex_br_(Serrate/Notch)] ↔ [Complex_br_(Serrate/N_sub_ext)] + [NI_sub_c_sub_t];   {TACE}
 
 r26 [Numb] ↔ [a25_degraded];   {LNXp80}
 
 r28 [Delta] + [Notch] ↔ [Complex_br_(Notch/Delta)];   {Fringe}
 
 r29 [Complex_br_(Notch/Delta)] ↔ [Complex_br_(Delta/N_sub_ext)] + [NI_sub_c_sub_t];   {TACE}
 
 re16 [s76] + [s77] ↔ [gama secretase];   {dapt}
 
   Spatial dimensions: 3.0  Compartment size: 1.0
 
 Fringe
Compartment: default
Initial amount: 5.0
 
 fucose
Compartment: default
Initial amount: 5.0
 
 Delta
Compartment: default
Initial amount: 5.0
 
 a7_degraded
Compartment: default
Initial amount: 0.0
 
 Neuralized
Compartment: default
Initial amount: 0.5
 
 Complex_br_(Delta/N_sub_ext)
Compartment: default
Initial amount: 0.0
 
 Neurotic
Compartment: default
Initial amount: 5.0
 
 Serrate
Compartment: default
Initial amount: 5.0
 
 Complex_br_(Serrate/N_sub_ext)
Compartment: default
Initial amount: 0.0
 
 s76
Compartment: default
Initial amount: 5.0
 
 s77
Compartment: default
Initial amount: 5.0
 
 dapt
Compartment: default
Initial amount: 0.0
 
 gama secretase
Compartment: default
Initial amount: 0.0
 
 cytosol Spatial dimensions: 3.0  Compartment size: 1.0
 
 NI_sub_c_sub_t
Compartment: cytosol
Initial amount: 5.0
 
 N_sub_tm
Compartment: cytosol
Initial amount: 0.0
 
 TACE
Compartment: cytosol
Initial amount: 0.5
 
 Numb
Compartment: cytosol
Initial amount: 0.64
 
 Notch
Compartment: cytosol
Initial amount: 5.0
 
 Notch
Compartment: cytosol
Initial amount: 0.0
 
 Complex_br_(Serrate/Notch)
Compartment: cytosol
Initial amount: 0.0
 
 NI_sub_c_sub_s
Compartment: cytosol
Initial amount: 0.0
 
 a25_degraded
Compartment: cytosol
Initial amount: 0.0
 
 LNXp80
Compartment: cytosol
Initial amount: 0.33
 
 Complex_br_(Notch/Delta)
Compartment: cytosol
Initial amount: 0.0
 
 nucleus Spatial dimensions: 3.0  Compartment size: 1.0
 
 Mastermind
Compartment: nucleus
Initial amount: 0.5
 
 Su(H)
Compartment: nucleus
Initial amount: 5.0
 
 CoR
Compartment: nucleus
Initial amount: 5.0
 
 Complex_br_(Su(H)/CoR)
Compartment: nucleus
Initial amount: 0.0
 
 CoA
Compartment: nucleus
Initial amount: 0.5
 
 NI_sub_c_sub_s
Compartment: nucleus
Initial amount: 0.0
 
 Complex_br_(Mastermind/Su(H)/_br_CoA/NI_sub_c_sub_s)
Compartment: nucleus
Initial amount: 0.0
 
 NI_sub_c_sub_s
Compartment: nucleus
Initial amount: 0.0
 
 Sel 10
Compartment: nucleus
Initial amount: 0.6
 
 Ub
Compartment: nucleus
Initial amount: 0.5
 
 a46_degraded
Compartment: nucleus
Initial amount: 0.0
 
 E(spl)-C genes
Compartment: nucleus
Initial amount: 0.0
 
Global Parameters (56)
 
   kcatp_r8
Value: 0.5
Constant
 
   kM_r8_s15
Value: 1.0
Constant
 
   kcatn_r8
Value: 1.5
Constant
 
   kM_r8_s19
Value: 2.0
Constant
 
   kM_r8_s63
Value: 1.5
Constant
 
   kcatp_r9
Value: 1.5
Constant
 
   kM_r9_s7
Value: 1.0
Constant
 
   kcatn_r9
Value: 0.04
Constant
 
   kM_r9_s22
Value: 0.05
Constant
 
   kass_r10
Value: 2.0
Constant
 
   kdiss_r10
Value: 0.01
Constant
 
   kI_r10_s25
Value: 1.0
Constant
 
   kcatp_r11
Value: 0.5
Constant
 
   kM_r11_s32
Value: 1.0
Constant
 
   kcatn_r11
Value: 0.5
Constant
 
   kM_r11_s26
Value: 1.5
Constant
 
   kM_r11_s28
Value: 1.0
Constant
 
   kass_r13
Value: 0.5
Constant
 
   kdiss_r13
Value: 2.0
Constant
 
   kcatp_r16
Value: 1.0
Constant
 
   kcatn_r16
Value: 1.0
Constant
 
   kM_r16_s39
Value: 1.0
Constant
 
   ki_r16_s39
Value: 1.0
Constant
 
   kass_r17
Value: 1.5
Constant
 
   kdiss_r17
Value: 1.5
Constant
 
   kcatp_r18
Value: 1.0
Constant
 
   kcatn_r18
Value: 1.5
Constant
 
   kM_r18_s4
Value: 1.0
Constant
 
   ki_r18_s4
Value: 1.5
Constant
 
   kass_r21
Value: 1.5
Constant
 
   kdiss_r21
Value: 1.5
Constant
 
   kI_r21_s2
Value: 1.5
Constant
 
   kcatp_r25
Value: 1.0
Constant
 
   kM_r25_s53
Value: 1.5
Constant
 
   kcatn_r25
Value: 1.5
Constant
 
   kM_r25_s60
Value: 1.25
Constant
 
   kM_r25_s15
Value: 1.5
Constant
 
   kcatp_r26
Value: 0.5
Constant
 
   kM_r26_s25
Value: 1.7
Constant
 
   kcatn_r26
Value: 1.0
Constant
 
   kM_r26_s64
Value: 1.61
Constant
 
   kcatp_r28
Value: 1.71
Constant
 
   kcatn_r28
Value: 1.48
Constant
 
   kM_r28_s41
Value: 1.64
Constant
 
   ki_r28_s41
Value: 1.28
Constant
 
   kcatp_r29
Value: 1.86
Constant
 
   kM_r29_s67
Value: 1.61
Constant
 
   kcatn_r29
Value: 1.78
Constant
 
   kM_r29_s18
Value: 0.15
Constant
 
   kM_r29_s15
Value: 1.87
Constant
 
   kass_r30
Value: 1.95
Constant
 
   kass_r31
Value: 0.055
Constant
 
   kdiss_r31
Value: 2.0
Constant
 
   kass_re16
Value: 0.004
Constant
 
   kdiss_re16
Value: 2.0
Constant
 
   kI_re16_s81
Value: 0.00594
Constant
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000396

Curator's comment: (updated: 02 Nov 2011 14:43:36 GMT)

Figure 1A of the reference publication has been reproduced here. The model was simulated using Copasi v4.7 (Build 34).

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