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BIOMD0000000394 - Sivakumar2011 - EGF Receptor 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: BIOMD0000000394.origin
Submitter: KC Sivakumar
Submission ID: MODEL1101270003
Submission Date: 27 Jan 2011 04:42:05 UTC
Last Modification Date: 08 Apr 2016 17:15:18 UTC
Creation Date: 02 Nov 2011 14:44:52 UTC
Encoders:  Vijayalakshmi Chelliah
   KC Sivakumar
set #1
bqmodel:isDerivedFrom PANTHER Pathway P00018
set #2
bqbiol:occursIn Cell Type Ontology neuronal stem cell
set #3
bqbiol:occursIn Taxonomy Mammalia
set #4
bqbiol:isVersionOf Gene Ontology epidermal growth factor receptor signaling pathway
Notes
Sivakumar2011 - EGF Receptor Signaling Pathway

EGFR belongs to the human epidermal receptor (HER) family of receptor tyrosine kinases, which consists of four closely related receptors (EGFR (HER1, erbB1), HER2 (neu, erbB2), HER3 (erbB3), and HER4 (erbB4)) that mediate cellular signaling pathways involved in growth and proliferation in response to the binding of a variety of growth factor ligands. There are currently six known endogenous ligands for EGFR: EGF, transforming growth factor- (TGF-), amphiregulin, betacellulin, heparin-binding EGF (HB-EGF), and epiregulin.Upon ligand binding, the EGFR forms homo- or heterodimeric complexes (usually with HER2), which leads to activation of the receptor tyrosine kinase, via autophosphorylation.

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 04:42:05 UTC Last Modification Date: 08 Apr 2016 17:15:18 UTC Creation Date: 02 Nov 2011 14:44:52 UTC
Mathematical expressions
Reactions
r8 r9 r11 r14
r15 r17 r6 r7
r4 re11    
Physical entities
Compartments Species
default EGF erlotinib  
Cytosol Akt Akt MEK1_minus_2
MEK1_minus_2 ERK1_minus_2 ERK1_minus_2
RKIP RKIP PP2A
14_minus_3_minus_3 Mitogenesis_br_Differentiation Raf_minus_1
Raf_minus_1 EGFR Ras
GDP GTP PKC
EGFR Complex_br_(EGFR/../_br_GAP) Complex(Grb2/../PLC)
Global parameters
kcatp_r8_s124 kM_r8_s124_s23 kcatn_r8_s124 kM_r8_s124_s24
kcatp_r8_s31 kM_r8_s31_s23 kcatn_r8_s31 kM_r8_s31_s24
kI_r8_s22 kI_r8_s29 kI_r8_s33 kcatp_r9
kM_r9_s25 kcatn_r9 kM_r9_s26 kcatp_r11
kM_r11_s29 kcatn_r11 kM_r11_s30 kcatp_r14
kM_r14_s27 kcatn_r14 kM_r14_s28 kass_r15
kdiss_r15 kass_r17_s3 kdiss_r17_s3 kI_re11_s142
kass_r6_s144 kdiss_r6_s144 kass_r7_s144 kdiss_r7_s144
kass_r4_s144 kdiss_r4_s144 Vp_re11 kM_re11_s129
kM_re11_s147 ki_re11_s129    
Reactions (10)
 
 r8 [Raf_minus_1] ↔ [Raf_minus_1];   {Akt} , {RKIP} , {Ras} , {14_minus_3_minus_3} , {PP2A}
 
 r9 [MEK1_minus_2] ↔ [MEK1_minus_2];   {Raf_minus_1}
 
 r11 [RKIP] ↔ [RKIP];   {PKC}
 
 r14 [ERK1_minus_2] ↔ [ERK1_minus_2];   {MEK1_minus_2}
 
 r15 [ERK1_minus_2] ↔ [Mitogenesis_br_Differentiation];  
 
 r17 2.0 × [EGFR] ↔ [EGFR];   {EGF}
 
 r6 [PKC] ↔ [PKC];   {Complex_br_(EGFR/../_br_GAP)}
 
 r7 [Akt] ↔ [Akt];   {Complex_br_(EGFR/../_br_GAP)}
 
 r4 [Ras] + [GDP] ↔ [Ras] + [GTP];   {Complex_br_(EGFR/../_br_GAP)}
 
 re11 [EGFR] + [Complex(Grb2/../PLC)] → [Complex_br_(EGFR/../_br_GAP)];   {erlotinib}
 
   Spatial dimensions: 3.0  Compartment size: 1.0
 
 EGF
Compartment: default
Initial amount: 5.0
 
 erlotinib
Compartment: default
Initial amount: 0.5
 
 Cytosol Spatial dimensions: 3.0  Compartment size: 1.0
 
 Akt
Compartment: Cytosol
Initial amount: 5.0
 
 Akt
Compartment: Cytosol
Initial amount: 0.0
 
 MEK1_minus_2
Compartment: Cytosol
Initial amount: 5.0
 
 MEK1_minus_2
Compartment: Cytosol
Initial amount: 0.0
 
 ERK1_minus_2
Compartment: Cytosol
Initial amount: 5.0
 
 ERK1_minus_2
Compartment: Cytosol
Initial amount: 0.0
 
 RKIP
Compartment: Cytosol
Initial amount: 5.0
 
 RKIP
Compartment: Cytosol
Initial amount: 0.0
 
 PP2A
Compartment: Cytosol
Initial amount: 5.0
 
 14_minus_3_minus_3
Compartment: Cytosol
Initial amount: 5.0
 
 Mitogenesis_br_Differentiation
Compartment: Cytosol
Initial amount: 1.0
 
 Raf_minus_1
Compartment: Cytosol
Initial amount: 5.0
 
 Raf_minus_1
Compartment: Cytosol
Initial amount: 0.0
 
 EGFR
Compartment: Cytosol
Initial amount: 5.0
 
 Ras
Compartment: Cytosol
Initial amount: 5.0
 
 GDP
Compartment: Cytosol
Initial amount: 0.5
 
 GTP
Compartment: Cytosol
Initial amount: 0.0
 
 PKC
Compartment: Cytosol
Initial amount: 2.0
 
 EGFR
Compartment: Cytosol
Initial amount: 0.0
 
 Complex_br_(EGFR/../_br_GAP)
Compartment: Cytosol
Initial amount: 0.0
 
 Complex(Grb2/../PLC)
Compartment: Cytosol
Initial amount: 5.0
 
Global Parameters (38)
 
   kcatp_r8_s124
Value: 0.511
Constant
 
   kM_r8_s124_s23
Value: 0.47
Constant
 
   kcatn_r8_s124
Value: 1.083
Constant
 
   kM_r8_s124_s24
Value: 0.786
Constant
 
   kcatp_r8_s31
Value: 0.727
Constant
 
   kM_r8_s31_s23
Value: 0.614
Constant
 
   kcatn_r8_s31
Value: 0.636
Constant
 
   kM_r8_s31_s24
Value: 1.367
Constant
 
   kI_r8_s22
Value: 0.583
Constant
 
   kI_r8_s29
Value: 1.219
Constant
 
   kI_r8_s33
Value: 0.293
Constant
 
   kcatp_r9
Value: 2.0
Constant
 
   kM_r9_s25
Value: 0.626
Constant
 
   kcatn_r9
Value: 0.693
Constant
 
   kM_r9_s26
Value: 0.463
Constant
 
   kcatp_r11
Value: 0.787
Constant
 
   kM_r11_s29
Value: 1.459
Constant
 
   kcatn_r11
Value: 0.566
Constant
 
   kM_r11_s30
Value: 1.021
Constant
 
   kcatp_r14
Value: 0.558
Constant
 
   kM_r14_s27
Value: 0.038
Constant
 
   kcatn_r14
Value: 0.725
Constant
 
   kM_r14_s28
Value: 1.65
Constant
 
   kass_r15
Value: 2.0
Constant
 
   kdiss_r15
Value: 0.074
Constant
 
   kass_r17_s3
Value: 0.73
Constant
 
   kdiss_r17_s3
Value: 1.13
Constant
 
   kI_re11_s142
Value: 1.0
Constant
 
   kass_r6_s144
Value: 1.0
Constant
 
   kdiss_r6_s144
Value: 1.0
Constant
 
   kass_r7_s144
Value: 1.0
Constant
 
   kdiss_r7_s144
Value: 1.0
Constant
 
   kass_r4_s144
Value: 1.0
Constant
 
   kdiss_r4_s144
Value: 1.0
Constant
 
   Vp_re11
Value: 1.0
Constant
 
   kM_re11_s129
Value: 1.0
Constant
 
   kM_re11_s147
Value: 1.0
Constant
 
   ki_re11_s129
Value: 1.0
Constant
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000394

Curator's comment: (updated: 02 Nov 2011 14:40:45 GMT)

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

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