# This model follows Figure 2 of Grabner et al. (Nat. Rev. Cancer 6:347-359).
# It model describes formation of a signaling complex in a nucleus. All signaling steps are very sketchy, but
# it's easy to add additional biomolecules and their components. The model includes several compartments but
# does not consider any spatial effects. It predicts translocation of ICN to nucleus and formation of ICN-CSL-MAML complex.


begin parameters  # These are unchanged during simulation: initial concentrations and rate constants
ICN_tot 	100
Notch_tot   100
Fringe_tot  100
Furin_tot   100
OFUT1_tot 	100
DSL_tot 	100

CSL_tot     100
MAML_tot    100

kp1   0.1
km1   0.1
end parameters

begin species    # Species that exist before simulation

# I divide Notch receptor into 2 molecules: Notch and ICN. Both have location attribute and several binding sites.

Notch(location~ER,DSLbind,Ibind)	   Notch_tot 	# Initial concentration before simulation


# Translocation, fucosalisation, cleavage and heterodimerization 
# are lumped into translocation steps. These details can be restored 
# if any need arises, say to include Fringe and Furin explicitely.

ICN(location~ER,Nbind,CSLbind,MAMLbind)                 ICN_tot 

OFUT1                 OFUT1_tot
Fringe                Fringe_tot
Furin                 Furin_tot
DSL(Nbind)            DSL_tot

CSL(Ibind,MAMLbind)      CSL_tot
MAML(Cbind,Ibind)     MAML_tot

end species

begin reaction rules

1  Fucosylation and translocation from ER to Golgi (G):\
Notch(location~ER,Ibind) + ICN(location~ER,Nbind,CSLbind) + OFUT1 -> Notch(location~G,Ibind!1).ICN(location~G,Nbind!1,CSLbind) + OFUT1 kp1 

2  Glycosylation, S1 cleavage, translocation from Golgi to Membrane (M) and heterodimerization:\
Notch(location~G).ICN(location~G,CSLbind) + Furin + Fringe -> Notch(location~M).ICN(location~M,CSLbind) + Furin + Fringe  kp1

3  DSL binding:\
Notch(location~M,DSLbind) + DSL(Nbind) <-> Notch(location~M,DSLbind!1).DSL(Nbind!1)  kp1,km1

4  S2, S3 cleavage, ICN dissociation and translocation to Nucleus (N):\
Notch(location~M,DSLbind!2,Ibind!3).ICN(location~M,Nbind!3) ->  Notch(location~M,DSLbind!2,Ibind) + ICN(location~N,Nbind)  kp1

5  Binding CSL to ICN:\
ICN(location~N,CSLbind,MAMLbind) + CSL(Ibind,MAMLbind) <-> ICN(location~N,CSLbind!1,MAMLbind).CSL(Ibind!1,MAMLbind)  kp1,km1

5  Binding MAML to CSL-ICN:\
ICN(location~N,CSLbind!1,MAMLbind).CSL(Ibind!1,MAMLbind) + MAML(Cbind,Ibind) <-> \
ICN(location~N,CSLbind!1,MAMLbind!2).CSL(Ibind!1,MAMLbind!3).MAML(Cbind!3,Ibind!2)  kp1,km1

end reaction rules



begin observables

Notch_ICN_Complex	      Notch.ICN
Nucleus_complex         ICN.CSL.MAML

end observables


generate_network({overwrite=>1});