Sivakumar2011_NeuralStemCellDifferentiation_Crosstalk
This model is generated by integrating BIOMD0000000394 (EGFR), BIOMD0000000395 (Hedgehog), BIOMD0000000396 (Notch) and BIOMD0000000397 (Wnt), to investigate the signalling crosstalk between the four pathways.

This model is described in the article:

Sivakumar KC, Dhanesh SB, Shobana S, James J, Mundayoor S.
OMICS 2011 Oct; 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.

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4.0 s57 PROTEIN pr21 s57 PROTEIN pr22 s72 PROTEIN pr26 s72 PROTEIN pr25 s85 PROTEIN pr29 s85 PROTEIN pr30 s100 PROTEIN pr34 s100 PROTEIN pr35 s111 PROTEIN pr36 s111 PROTEIN pr37 s135 PROTEIN pr42 s135 PROTEIN pr43 s146 PROTEIN pr46 s146 PROTEIN pr47 SQUARE inactive inactive inactive inactive inactive inactive inactive inactive inactive inactive inactive inactive inactive inactive inactive inactive inactive inactive inactive inactive inactive inactive inactive inactive inactive inactive inactive inactive inactive inactive inactive inactive inactive inactive inactive inactive inactive inactive inactive inactive inactive inactive Chelliah Vijayalakshmi viji@ebi.ac.uk EMBL-EBI Sivakumar KC sivakumar.kc@gmail.com Rajiv Gandhi Centre for Biotechnology 2011-11-02T14:54:21Z 2016-04-08T17:17:33Z nucleus inside PROTEIN pr21 inside COMPLEX Notch inside PROTEIN pr22 inside PROTEIN pr23 inside DRUG DAPT inside PROTEIN pr26 inside COMPLEX Complex NICD-RBP inside GENE gn1 inside PROTEIN pr29 inside PROTEIN pr30 inside COMPLEX Complex Shh Ptch1 inside PROTEIN pr31 inside DRUG SAG inside PROTEIN pr34 inside PROTEIN pr35 inside COMPLEX Complex EGF-EGFR inside DRUG Erlotinib inside PROTEIN pr36 inside PROTEIN pr37 inside COMPLEX Complex Wnt-Frzzl inside PROTEIN pr42 inside PROTEIN pr43 inside COMPLEX Complex Dishevelled-FRAT-CK2 inside PROTEIN pr46 inside PROTEIN pr47 inside COMPLEX Complex GSK3B-Bcatenin inside DRUG 6 bromoindirubin 3`oxime reversible thermodynamically independent convenience kinetics DISSOCIATION 0.2944444444444445,0.29444444444444473 csa10 sa62 sa63 sa66 sa67 kI_re29_s61 kI_re29_s61 s61 s60 kV_re29_s60 s57 kM_re29_s60_s57 2 kG_s57 kM_re29_s60_s57 kG_s53 kM_re29_s60_s53 kG_s58 kM_re29_s60_s58 s53 kM_re29_s60_s53 s58 kM_re29_s60_s58 2 kG_s53 kM_re29_s60_s53 kG_s58 kM_re29_s60_s58 kG_s57 kM_re29_s60_s57 s57 kM_re29_s60_s57 1 s53 kM_re29_s60_s53 1 s58 kM_re29_s60_s58 mass action rate law for second order forward, first order reverse, reversible reactions, two reactants, continuous scheme HETERODIMER_ASSOCIATION 0.5,0.0 0.5,0.0 0.9256878374903574,-0.26227822062226824 0.5,0.0 0.5,0.0 -0.32666666666666666,0.6533333333333334 sa62 sa70 csa11 kass_re31 s53 s68 kdiss_re31 s72 mass action rate law for first order forward, first order reverse, reversible reactions, continuous scheme STATE_TRANSITION 0.8476715072608907,-0.35933900851276923 csa11 sa73 kass_re32 s72 kdiss_re32 s73 mass action rate law for second order forward, first order reverse, reversible reactions, two reactants, continuous scheme HETERODIMER_ASSOCIATION 0.29444444444444473,0.4111111111111111 sa76 sa77 csa12 kass_re33 s81 s83 kdiss_re33 s85 mass action rate law for second order forward, first order reverse, reversible reactions, two reactants, continuous scheme HETERODIMER_ASSOCIATION 0.46777546777546775,0.498960498960499 0.46777546777546863,-0.4989604989604963 0.5,0.0 0.5,0.0 0.35714285714285676,0.2857142857142857 sa85 sa86 csa13 sa89 kI_re36_s101 kI_re36_s101 s101 kass_re36 s96 s98 kdiss_re36 s100 mass action rate law for first order forward, first order reverse, reversible reactions, continuous scheme STATE_TRANSITION 0.7939513849632563,0.4044657998869414 csa13 sa73 kass_re37 s100 kdiss_re37 s73 mass action rate law for second order forward, first order reverse, reversible reactions, two reactants, continuous scheme HETERODIMER_ASSOCIATION 0.2944444444444443,0.4111111111111112 sa90 sa91 csa14 kass_re38 s107 s109 kdiss_re38 s111 reversible rapid-equilibrium random order ternary-complex mechanism with one product HETERODIMER_ASSOCIATION 0.29444444444444606,0.4111111111111114 sa98 sa99 csa16 csa14 kcatp_re40 ki_re40_s124 kM_re40_s124 s111 s122 s124 kcatn_re40 kM_re40_s124 s111 s135 1 s122 ki_re40_s124 s124 ki_re40_s124 s122 s124 ki_re40_s124 kM_re40_s124 s135 kM_re40_s124 mass action rate law for second order forward, first order reverse, reversible reactions, two reactants, continuous scheme HETERODIMER_ASSOCIATION 0.27006369426751675,0.527388535031847 sa106 sa107 csa18 sa110 csa16 kI_re42_s147 kI_re42_s147 s147 kI_re42_s135 kI_re42_s135 s135 kass_re42 s142 s144 kdiss_re42 s146 mass action rate law for first order forward, first order reverse, reversible reactions, continuous scheme STATE_TRANSITION 0.19635996740269301,-0.19123753347044858 0.6831464162365635,0.30858783810004264 sa107 sa73 kass_re43 s144 kdiss_re43 s73 kinetics of non-modulated unireactant enzymes STATE_TRANSITION 0.5,0.0 0.5,0.0 sa80 sa81 csa12 s85 kass_re34_s85 s88 kdiss_re34_s85 s88 s89 kass_re34_s89 s88 kdiss_re34_s89 s88 mass action rate law for first order forward, first order reverse, reversible reactions, continuous scheme STATE_TRANSITION 0.7408771629261603,0.4381531608703102 sa81 sa73 sa83 s89 kass_re35_s89 s88 kdiss_re35_s89 s73