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BIOMD0000000395 - Sivakumar2011 - Hedgehog 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: BIOMD0000000395.xml.origin
Submitter: KC Sivakumar
Submission ID: MODEL1101270001
Submission Date: 27 Jan 2011 04:39:11 UTC
Last Modification Date: 30 May 2014 16:29:53 UTC
Creation Date: 02 Nov 2011 14:45:21 UTC
Encoders:  Vijayalakshmi Chelliah
   KC Sivakumar
set #1
bqbiol:isVersionOf Gene Ontology smoothened signaling pathway
set #2
bqbiol:occursIn Taxonomy Mammalia
set #3
bqbiol:occursIn Cell Type Ontology CL:0000047
set #4
bqmodel:isDerivedFrom PANTHER Pathway P00025
Notes
Sivakumar2011 - Hedgehog Signaling Pathway

This is the current model for the Hedgehog signaling pathway. The best data for mechanism of signaling has been worked out in Drosophila, so this model is based largely on Drosophila data. Hedgehog target genes vary from tissue to tissue, so the identities of individual target genes have not been listed. The main difference between the Drosophila and mammalian Hedgehog signaling pathways is the fact that there are three mammalian homologs of Cubitus interruptus, Gli1 Gli2 and Gli3. Some or all of the mammalian homologs may be proteolytically processed, but the data are controversial. There are two mammalian Ptc genes and three mammalian Hedgehog genes as well. The pathway for Sonic Hedgehog appears to be most similar to the Drosophila hedgehog pathway.

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 04:39:11 UTC Last Modification Date: 30 May 2014 16:29:53 UTC Creation Date: 02 Nov 2011 14:45:21 UTC
Mathematical expressions
Reactions
r52 r55 r7 r14
r51 r53 re24 r15
r23 r54 r26 r25
Physical entities
Compartments Species
default Hedgehog    
Receiving cell ATP ADP Patched
Complex_br_(Patched/Hedgehog) Complex_br_(Costal2/Fused/_br_Smoothened) Complex_br_(Costal2/Smoothened/_br_Fused)
Microtubule smoothened complex
MIcrotubule sag Complex_br_(Su(fu)/Cubitus)
lipid raft Complex_br_(Costal2/Fused/_br_Smoothened) Complex_br_(Costal2/Fused/../microtubule) Complex_br_(Su(fu)/Fused/../_br_Smoothened)
     
nucleus Hedgehog target gene Sap18 CBP
Cubitus_space_interruptus Complex_br_(Cubitus_space_interruptus_space_repressor/Su(fu)) Complex_br_(Sap18/Su(fu)/_br_Cubitus_space_interruptus_space_repressor)
Complex_br_(CBP/Cubitus)    
Global parameters
kass_r7 kdiss_r7 kcatp_r14 kM_r14_s69
kcatn_r14 kM_r14_s46 kass_r25 kdiss_r25
kass_r26 kdiss_r26 kass_r51 kdiss_r51
kass_r52 kdiss_r52 kcatp_r53 kM_r53_s70
kcatn_r53 kass_r54 kdiss_r54 kass_r55
kass_r15_s21 kdiss_r15_s21 kass_re24_s157 kass_r23_s21
kdiss_r23_s21      
Reactions (12)
 
 r52 [Complex_br_(Sap18/Su(fu)/_br_Cubitus_space_interruptus_space_repressor)] → [Hedgehog target gene];  
 
 r55 [Complex_br_(CBP/Cubitus)] → [Hedgehog target gene];  
 
 r7 [Hedgehog] + [Patched] ↔ [Complex_br_(Patched/Hedgehog)];  
 
 r14 [Complex_br_(Costal2/Fused/_br_Smoothened)] ↔ [Complex_br_(Costal2/Fused/_br_Smoothened)];   {Complex_br_(Patched/Hedgehog)}
 
 r51 [Sap18] + [Complex_br_(Cubitus_space_interruptus_space_repressor/Su(fu))] ↔ [Complex_br_(Sap18/Su(fu)/_br_Cubitus_space_interruptus_space_repressor)];  
 
 r53 [Cubitus_space_interruptus] ↔ [Cubitus_space_interruptus];   {Complex_br_(Costal2/Smoothened/_br_Fused)}
 
 re24 [smoothened] + [complex] → [Complex_br_(Costal2/Fused/../microtubule)];   {sag}
 
 r15 [Complex_br_(Costal2/Fused/_br_Smoothened)] + [ATP] ↔ [Complex_br_(Costal2/Smoothened/_br_Fused)] + [ADP];   {Complex_br_(Patched/Hedgehog)}
 
 r23 [Complex_br_(Costal2/Fused/../microtubule)] ↔ [Microtubule] + [Complex_br_(Su(fu)/Fused/../_br_Smoothened)];   {Complex_br_(Patched/Hedgehog)}
 
 r54 [Cubitus_space_interruptus] + [CBP] ↔ [Complex_br_(CBP/Cubitus)];  
 
 r26 [Complex_br_(Su(fu)/Cubitus)] ↔ [Cubitus_space_interruptus];  
 
 r25 [Complex_br_(Su(fu)/Fused/../_br_Smoothened)] ↔ [Complex_br_(Su(fu)/Cubitus)] + [Complex_br_(Costal2/Fused/_br_Smoothened)];  
 
   Spatial dimensions: 3.0  Compartment size: 1.0
 
 Hedgehog
Compartment: default
Initial amount: 5.0
 
 Receiving cell Spatial dimensions: 3.0  Compartment size: 1.0
 
 ATP
Compartment: Receiving cell
Initial amount: 2.0
 
 ADP
Compartment: Receiving cell
Initial amount: 0.0
 
 Patched
Compartment: Receiving cell
Initial amount: 5.0
 
 Complex_br_(Patched/Hedgehog)
Compartment: Receiving cell
Initial amount: 0.0
 
 Complex_br_(Costal2/Fused/_br_Smoothened)
Compartment: Receiving cell
Initial amount: 0.0
 
 Complex_br_(Costal2/Smoothened/_br_Fused)
Compartment: Receiving cell
Initial amount: 0.0
 
 Microtubule
Compartment: Receiving cell
Initial amount: 0.0
 
 smoothened
Compartment: Receiving cell
Initial amount: 3.0
 
 complex
Compartment: Receiving cell
Initial amount: 3.0
 
 MIcrotubule
Compartment: Receiving cell
Initial amount: 0.0
 
 sag
Compartment: Receiving cell
Initial amount: 0.5
 
 Complex_br_(Su(fu)/Cubitus)
Compartment: Receiving cell
Initial amount: 0.0
 
 lipid raft Spatial dimensions: 3.0  Compartment size: 1.0
 
 Complex_br_(Costal2/Fused/_br_Smoothened)
Compartment: lipid raft
Initial amount: 0.0
 
 Complex_br_(Costal2/Fused/../microtubule)
Compartment: lipid raft
Initial amount: 0.0
 
 Complex_br_(Su(fu)/Fused/../_br_Smoothened)
Compartment: lipid raft
Initial amount: 0.0
 
 nucleus Spatial dimensions: 3.0  Compartment size: 1.0
 
 Hedgehog target gene
Compartment: nucleus
Initial amount: 0.0
 
 Sap18
Compartment: nucleus
Initial amount: 2.5
 
 CBP
Compartment: nucleus
Initial amount: 2.0
 
 Cubitus_space_interruptus
Compartment: nucleus
Initial amount: 0.0
 
 Complex_br_(Cubitus_space_interruptus_space_repressor/Su(fu))
Compartment: nucleus
Initial amount: 2.5
 
 Complex_br_(Sap18/Su(fu)/_br_Cubitus_space_interruptus_space_repressor)
Compartment: nucleus
Initial amount: 0.0
 
 Complex_br_(CBP/Cubitus)
Compartment: nucleus
Initial amount: 0.0
 
Global Parameters (25)
 
   kass_r7
Value: 1.13
Constant
 
   kdiss_r7
Value: 1.122
Constant
 
   kcatp_r14
Value: 1.146
Constant
 
   kM_r14_s69
Value: 1.03
Constant
 
   kcatn_r14
Value: 1.75
Constant
 
   kM_r14_s46
Value: 0.215
Constant
 
   kass_r25
Value: 1.27
Constant
 
   kdiss_r25
Value: 0.73
Constant
 
   kass_r26
Value: 1.33
Constant
 
   kdiss_r26
Value: 0.61
Constant
 
   kass_r51
Value: 1.23
Constant
 
   kdiss_r51
Value: 0.46
Constant
 
   kass_r52
Value: 0.6
Constant
 
   kdiss_r52
Value: 1.67
Constant
 
   kcatp_r53
Value: 1.29
Constant
 
   kM_r53_s70
Value: 0.79
Constant
 
   kcatn_r53
Value: 1.62
Constant
 
   kass_r54
Value: 1.28
Constant
 
   kdiss_r54
Value: 0.71
Constant
 
   kass_r55
Value: 1.56
Constant
 
   kass_r15_s21
Value: 1.53
Constant
 
   kdiss_r15_s21
Value: 0.89
Constant
 
   kass_re24_s157
Value: 1.0
Constant
 
   kass_r23_s21
Value: 1.0
Constant
 
   kdiss_r23_s21
Value: 1.0
Constant
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000395

Curator's comment: (updated: 02 Nov 2011 14:41:10 GMT)

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

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