#TODO: in Lig: replace site l with site l1, l2 begin model begin parameters Lig_tot 6.0e3 Rec_tot 4.0e2 Lyn_tot 2.8e1 Fyn_tot 4.0e2 Syk_tot 4.0e2 kp1 1.32845238e-7 km1 0 kp2 2.5e-1 km2 0 kpL 5e-2 kmL 20 kpLs 5e-2 kmLs 0.12 kpF 5e-2 kmF 20 kpS 6e-2 kmS 0.13 kpSs 6e-2 kmSs 0.13 pLb 30 pLbs 100 pLg 1 pLgs 3 pLS 30 pLSs 100 pSS 100 pSSs 200 pLF 30 pLFs 100 dm 20 dc 20 end parameters begin seed species Lig(l1,l2) Lig_tot Lyn(U,SH2,a~Y) Lyn_tot Fyn(SH2,a~Y,t~Y) Fyn_tot Syk(tSH2,l~Y,a~Y) Syk_tot Rec(a,b~Y,g~Y) Rec_tot end seed species begin reaction rules # Ligand-receptor binding Rec(a) + Lig(l1,l2) <-> Rec(a!1).Lig(l1!1,l2) kp1, km1 Rec(a) + Lig(l2,l1) <-> Rec(a!1).Lig(l2!1,l1) kp1, km1 # Receptor-aggregation Rec(a) + Lig(l1,l2!+) <-> Rec(a!2).Lig(l1!2,l2!+) kp2,km2 Rec(a) + Lig(l2,l1!+) <-> Rec(a!2).Lig(l2!2,l1!+) kp2,km2 # Constitutive Lyn-receptor binding Rec(b~Y) + Lyn(U,SH2) <-> Rec(b~Y!1).Lyn(U!1,SH2) kpL, kmL # Transphosphorylation of beta by constitutive Lyn Lig(l1!1,l2!2).Lyn(U!3,SH2).Rec(a!2,b~Y!3).Rec(a!1,b~Y) -> Lig(l1!1,l2!2).Lyn(U!3,SH2).Rec(a!2,b~Y!3).Rec(a!1,b~pY) pLb Lig(l2!1,l1!2).Lyn(U!3,SH2).Rec(a!2,b~Y!3).Rec(a!1,b~Y) -> Lig(l2!1,l1!2).Lyn(U!3,SH2).Rec(a!2,b~Y!3).Rec(a!1,b~pY) pLb # Transphosphorylation of gamma by constitutive Lyn Lig(l1!1,l2!2).Lyn(U!3,SH2).Rec(a!2,b~Y!3).Rec(a!1,g~Y) -> Lig(l1!1,l2!2).Lyn(U!3,SH2).Rec(a!2,b~Y!3).Rec(a!1,g~pY) pLg Lig(l2!1,l1!2).Lyn(U!3,SH2).Rec(a!2,b~Y!3).Rec(a!1,g~Y) -> Lig(l2!1,l1!2).Lyn(U!3,SH2).Rec(a!2,b~Y!3).Rec(a!1,g~pY) pLg # Lyn-receptor binding through SH2 domain Rec(b~pY) + Lyn(U,SH2) <-> Rec(b~pY!1).Lyn(U,SH2!1) kpLs, kmLs # Fyn-receptor binding through SH2 domain Rec(b~pY) + Fyn(SH2) <-> Rec(b~pY!1).Fyn(SH2!1) kpF, kmF # Transphosphorylation of beta by SH2-bound Lyn Lig(l1!1,l2!2).Lyn(U,SH2!3).Rec(a!2,b~pY!3).Rec(a!1,b~Y) -> Lig(l1!1,l2!2).Lyn(U,SH2!3).Rec(a!2,b~pY!3).Rec(a!1,b~pY) pLbs Lig(l2!1,l1!2).Lyn(U,SH2!3).Rec(a!2,b~pY!3).Rec(a!1,b~Y) -> Lig(l2!1,l1!2).Lyn(U,SH2!3).Rec(a!2,b~pY!3).Rec(a!1,b~pY) pLbs # Transphosphorylation of gamma by SH2-bound Lyn Lig(l1!1,l2!2).Lyn(U,SH2!3).Rec(a!2,b~pY!3).Rec(a!1,g~Y) -> Lig(l1!1,l2!2).Lyn(U,SH2!3).Rec(a!2,b~pY!3).Rec(a!1,g~pY) pLgs Lig(l2!1,l1!2).Lyn(U,SH2!3).Rec(a!2,b~pY!3).Rec(a!1,g~Y) -> Lig(l2!1,l1!2).Lyn(U,SH2!3).Rec(a!2,b~pY!3).Rec(a!1,g~pY) pLgs # Syk-receptor binding through tSH2 domain Rec(g~pY) + Syk(tSH2) <-> Rec(g~pY!1).Syk(tSH2!1) kpS, kmS # Transphosphorylation of Lyn by constitutive Lyn Lig(l1!1,l2!2).Lyn(U!3,SH2).Rec(a!2,b~Y!3).Rec(a!1,b~pY!4).Lyn(SH2!4,a~Y) -> \ Lig(l1!1,l2!2).Lyn(U!3,SH2).Rec(a!2,b~Y!3).Rec(a!1,b~pY!4).Lyn(SH2!4,a~pY) pLS Lig(l2!1,l1!2).Lyn(U!3,SH2).Rec(a!2,b~Y!3).Rec(a!1,b~pY!4).Lyn(SH2!4,a~Y) -> \ Lig(l2!1,l1!2).Lyn(U!3,SH2).Rec(a!2,b~Y!3).Rec(a!1,b~pY!4).Lyn(SH2!4,a~pY) pLS # Transphosphorylation of Lyn by SH2-bound Lyn Lig(l1!1,l2!2).Lyn(U,SH2!3).Rec(a!2,b~pY!3).Rec(a!1,b~pY!4).Lyn(SH2!4,a~Y) -> \ Lig(l1!1,l2!2).Lyn(U,SH2!3).Rec(a!2,b~pY!3).Rec(a!1,b~pY!4).Lyn(SH2!4,a~pY) pLSs Lig(l2!1,l1!2).Lyn(U,SH2!3).Rec(a!2,b~pY!3).Rec(a!1,b~pY!4).Lyn(SH2!4,a~Y) -> \ Lig(l2!1,l1!2).Lyn(U,SH2!3).Rec(a!2,b~pY!3).Rec(a!1,b~pY!4).Lyn(SH2!4,a~pY) pLSs # Transphosphorylation of Fyn by constitutive Lyn Lig(l1!1,l2!2).Lyn(U!3,SH2).Rec(a!2,b~Y!3).Rec(a!1,b~pY!4).Fyn(SH2!4,a~Y) -> \ Lig(l1!1,l2!2).Lyn(U!3,SH2).Rec(a!2,b~Y!3).Rec(a!1,b~pY!4).Fyn(SH2!4,a~pY) pLF Lig(l2!1,l1!2).Lyn(U!3,SH2).Rec(a!2,b~Y!3).Rec(a!1,b~pY!4).Fyn(SH2!4,a~Y) -> \ Lig(l2!1,l1!2).Lyn(U!3,SH2).Rec(a!2,b~Y!3).Rec(a!1,b~pY!4).Fyn(SH2!4,a~pY) pLF # Transphosphorylation of Fyn by SH2-bound Lyn # KaSa has discovered that the following rule is wrong # Lyn has to be bound via SH2, not via U (since it is bound to a site with state pY) #Lig(l!1,l!2).Lyn(U!3,SH2).Rec(a!2,b~pY!3).Rec(a!1,b~pY!4).Fyn(SH2!4,a~Y) #-> \ #Lig(l!1,l!2).Lyn(U!3,SH2).Rec(a!2,b~pY!3).Rec(a!1,b~pY!4).Fyn(SH2!4,a~pY) pLFs #correct rule: Lig(l1!1,l2!2).Lyn(U,SH2!3).Rec(a!2,b~pY!3).Rec(a!1,b~pY!4).Fyn(SH2!4,a~Y) -> \ Lig(l1!1,l2!2).Lyn(U,SH2!3).Rec(a!2,b~pY!3).Rec(a!1,b~pY!4).Fyn(SH2!4,a~pY) pLFs Lig(l2!1,l1!2).Lyn(U,SH2!3).Rec(a!2,b~pY!3).Rec(a!1,b~pY!4).Fyn(SH2!4,a~Y) -> \ Lig(l2!1,l1!2).Lyn(U,SH2!3).Rec(a!2,b~pY!3).Rec(a!1,b~pY!4).Fyn(SH2!4,a~pY) pLFs # Transphosphorylation of Syk by constitutive Lyn Lig(l1!1,l2!2).Lyn(U!3,SH2).Rec(a!2,b~Y!3).Rec(a!1,g~pY!4).Syk(tSH2!4,l~Y) -> \ Lig(l1!1,l2!2).Lyn(U!3,SH2).Rec(a!2,b~Y!3).Rec(a!1,g~pY!4).Syk(tSH2!4,l~pY) pLS Lig(l2!1,l1!2).Lyn(U!3,SH2).Rec(a!2,b~Y!3).Rec(a!1,g~pY!4).Syk(tSH2!4,l~Y) -> \ Lig(l2!1,l1!2).Lyn(U!3,SH2).Rec(a!2,b~Y!3).Rec(a!1,g~pY!4).Syk(tSH2!4,l~pY) pLS # Transphosphorylation of Syk by SH2-bound Lyn Lig(l1!1,l2!2).Lyn(U,SH2!3).Rec(a!2,b~pY!3).Rec(a!1,g~pY!4).Syk(tSH2!4,l~Y) -> \ Lig(l1!1,l2!2).Lyn(U,SH2!3).Rec(a!2,b~pY!3).Rec(a!1,g~pY!4).Syk(tSH2!4,l~pY) pLSs Lig(l2!1,l1!2).Lyn(U,SH2!3).Rec(a!2,b~pY!3).Rec(a!1,g~pY!4).Syk(tSH2!4,l~Y) -> \ Lig(l2!1,l1!2).Lyn(U,SH2!3).Rec(a!2,b~pY!3).Rec(a!1,g~pY!4).Syk(tSH2!4,l~pY) pLSs # Transphosphorylation of Syk by Syk not phosphorylated on aloop Lig(l1!1,l2!2).Syk(tSH2!3,a~Y).Rec(a!2,g~pY!3).Rec(a!1,g~pY!4).Syk(tSH2!4,a~Y) -> \ Lig(l1!1,l2!2).Syk(tSH2!3,a~Y).Rec(a!2,g~pY!3).Rec(a!1,g~pY!4).Syk(tSH2!4,a~pY) pSS Lig(l2!1,l1!2).Syk(tSH2!3,a~Y).Rec(a!2,g~pY!3).Rec(a!1,g~pY!4).Syk(tSH2!4,a~Y) -> \ Lig(l2!1,l1!2).Syk(tSH2!3,a~Y).Rec(a!2,g~pY!3).Rec(a!1,g~pY!4).Syk(tSH2!4,a~pY) pSS # Transphosphorylation of Syk by Syk phosphorylated on aloop Lig(l1!1,l2!2).Syk(tSH2!3,a~pY).Rec(a!2,g~pY!3).Rec(a!1,g~pY!4).Syk(tSH2!4,a~Y) -> \ Lig(l1!1,l2!2).Syk(tSH2!3,a~pY).Rec(a!2,g~pY!3).Rec(a!1,g~pY!4).Syk(tSH2!4,a~pY) pSSs Lig(l2!1,l1!2).Syk(tSH2!3,a~pY).Rec(a!2,g~pY!3).Rec(a!1,g~pY!4).Syk(tSH2!4,a~Y) -> \ Lig(l2!1,l1!2).Syk(tSH2!3,a~pY).Rec(a!2,g~pY!3).Rec(a!1,g~pY!4).Syk(tSH2!4,a~pY) pSSs # Dephosphorylation of Rec beta Rec(b~pY)-> Rec(b~Y) dm # Dephosphorylation of Rec gamma Rec(g~pY)-> Rec(g~Y) dm # Dephosphorylation of Syk at membrane Syk(tSH2!+,l~pY)-> Syk(tSH2!+,l~Y) dm Syk(tSH2!+,a~pY)-> Syk(tSH2!+,a~Y) dm # Dephosphorylation of Syk in cytosol Syk(tSH2,l~pY)-> Syk(tSH2,l~Y) dc Syk(tSH2,a~pY)-> Syk(tSH2,a~Y) dc end reaction rules end model ## actions ## generate_network({overwrite=>1,max_iter=>100})