# kappa version of Schoeberl et al, 2002 with the negative feedback of Brightman & Fell, 2000 # 5/05/07 # phase -> activated dimers # external dimers: 'EGF_EGFR' EGF(r), EGFR(L,CR) <-> EGF(r!1), EGFR(L!1,CR) 'EGFR_EGFR' EGFR(L!_,CR), EGFR(L!_,CR) <-> EGFR(L!_,CR!1), EGFR(L!_,CR!1) # simplified phos (internal or external) 'EGFR@992' EGFR(CR!_,Y992~u) -> EGFR(CR!_,Y992~p) 'EGFR@1068' EGFR(CR!_,Y1068~u) -> EGFR(CR!_,Y1068~p) 'EGFR@1148' EGFR(CR!_,Y1148~u) -> EGFR(CR!_,Y1148~p) # simplified dephos (internal or external) '992_op' EGFR(Y992~p) -> EGFR(Y992~u) '1068_op' EGFR(Y1068~p) -> EGFR(Y1068~u) '1148_op' EGFR(Y1148~p) -> EGFR(Y1148~u) # phase -> internalization, degradation and recycling # internalization: 'int_monomer' EGF(r!1), EGFR(L!1,CR) -> EGF(r!1), EGFR(L!1,CR) @ 0.02 'int_dimer' EGF(r!1), EGFR(L!1,CR!2), EGF(r!3), EGFR(L!3,CR!2) -> \ EGF(r!1), EGFR(L!1,CR!2), EGF(r!3), EGFR(L!3,CR!2) @ 0.02 # dissociation: 'EGFR_EGFR_op' EGFR(L!_,CR!1), EGFR(L!_,CR!1) -> EGFR(L!_,CR), EGFR(L!_,CR) 'EGF_EGFR_op' EGF(r!1), EGFR(L!1,CR) -> EGF(r), EGFR(L,CR) # degradation: #'deg_EGF' EGF(r) -> #'deg_EGFR' EGFR(L,CR) -> # recycling: 'rec_EGFR' EGFR(L,Y992~u,Y1068~u,Y1148~u) -> EGFR(L,Y992~u,Y1068~u,Y1148~u) # phase -> SoS and RasGAP recruitment 'EGFR_RasGAP' EGFR(Y992~p), RasGAP(SH2) <-> EGFR(Y992~p!1), RasGAP(SH2!1) 'EGFR_Grb2' EGFR(Y1068~p), Grb2(SH2) <-> EGFR(Y1068~p!1), Grb2(SH2!1) 'Grb2_SoS' Grb2(SH3), SoS(a,SS~u) -> Grb2(SH3!1), SoS(a!1,SS~u) 'Grb2_SoS_op' Grb2(SH3!1), SoS(a!1) -> Grb2(SH3), SoS(a) 'EGFR_Shc' EGFR(Y1148~p), Shc(PTB) <-> EGFR(Y1148~p!1), Shc(PTB!1) 'Shc_Grb2' Shc(Y318~p), Grb2(SH2) <-> Shc(Y318~p!1), Grb2(SH2!1) 'Shc@318' EGFR(CR!_,Y1148~p!1), Shc(PTB!1,Y318~u) -> EGFR(CR!_,Y1148~p!1), Shc(PTB!1,Y318~p) 'Shc@318_op' Shc(Y318~p) -> Shc(Y318~u) # phase -> active Ras # activate: 'long arm SoS_Ras' EGFR(Y1148~p!1), Shc(PTB!1,Y318~p!2), Grb2(SH2!2,SH3!3), SoS(a!3,b), Ras(S1S2~gdp) -> \ EGFR(Y1148~p!1), Shc(PTB!1,Y318~p!2), Grb2(SH2!2,SH3!3), SoS(a!3,b!4), Ras(S1S2~gdp!4) 'short arm SoS_Ras' EGFR(Y1068~p!1), Grb2(SH2!1,SH3!2), SoS(a!2,b), Ras(S1S2~gdp) -> \ EGFR(Y1068~p!1), Grb2(SH2!1,SH3!2), SoS(a!2,b!3), Ras(S1S2~gdp!3) 'Ras GTP' SoS(b!1), Ras(S1S2~gdp!1) -> SoS(b!1), Ras(S1S2~gtp!1) 'SoS_Ras_op' SoS(b!1), Ras(S1S2!1) -> SoS(b), Ras(S1S2) # deactivate: 'direct RasGAP_Ras' EGFR(Y992~p!1), RasGAP(SH2!1,s), Ras(S1S2~gtp) -> \ EGFR(Y992~p!1), RasGAP(SH2!1,s!2), Ras(S1S2~gtp!2) 'Ras GDP' RasGAP(s!1), Ras(S1S2~gtp!1) -> RasGAP(s!1), Ras(S1S2~gdp!1) 'RasGAP_Ras_op' RasGAP(s!1), Ras(S1S2!1) -> RasGAP(s), Ras(S1S2) 'intrinsic Ras GDP' Ras(S1S2~gtp) -> Ras(S1S2~gdp) # phase -> active Raf # activation: 'Ras_Raf' Ras(S1S2~gtp), Raf(x~u) -> Ras(S1S2~gtp!1), Raf(x~u!1) 'Raf' Ras(S1S2~gtp!1), Raf(x~u!1) -> Ras(S1S2~gtp!1), Raf(x~p!1) 'Ras_Raf_op' Ras(S1S2~gtp!1), Raf(x!1) -> Ras(S1S2~gtp), Raf(x) # deactivation: 'PP2A1_Raf' PP2A1(s), Raf(x~p) -> PP2A1(s!1), Raf(x~p!1) 'Raf_op' PP2A1(s!1), Raf(x~p!1) -> PP2A1(s!1), Raf(x~u!1) 'PP2A1_Raf_op' PP2A1(s!1), Raf(x!1) -> PP2A1(s), Raf(x) # phase -> active MEK # activation: 'Raf_MEK@222' Raf(x~p), MEK(S222~u) -> Raf(x~p!1), MEK(S222~u!1) 'MEK@222' Raf(x~p!1), MEK(S222~u!1) -> Raf(x~p!1), MEK(S222~p!1) 'Raf_MEK@222_op' Raf(x~p!1), MEK(S222!1) -> Raf(x~p), MEK(S222) 'Raf_MEK@218' Raf(x~p), MEK(S218~u) -> Raf(x~p!1), MEK(S218~u!1) 'MEK@218' Raf(x~p!1), MEK(S218~u!1) -> Raf(x~p!1), MEK(S218~p!1) 'Raf_MEK@218_op' Raf(x~p!1), MEK(S218!1) -> Raf(x~p), MEK(S218) # deactivation: 'PP2A2_MEK@222' PP2A2(s), MEK(S222~p) -> PP2A2(s!1), MEK(S222~p!1) 'MEK@222_op' PP2A2(s!1), MEK(S222~p!1) -> PP2A2(s!1), MEK(S222~u!1) 'PP2A2_MEK@222_op' PP2A2(s!1), MEK(S222!1) -> PP2A2(s), MEK(S222) 'PP2A2_MEK@218' PP2A2(s), MEK(S218~p) -> PP2A2(s!1), MEK(S218~p!1) 'MEK@218_op' PP2A2(s!1), MEK(S218~p!1) -> PP2A2(s!1), MEK(S218~u!1) 'PP2A2_MEK@218_op' PP2A2(s!1), MEK(S218!1) -> PP2A2(s), MEK(S218) # phase -> active ERK # activation: 'MEK_ERK@185' MEK(s,S218~p,S222~p), ERK(T185~u) -> MEK(s!1,S218~p,S222~p), ERK(T185~u!1) 'ERK@185' MEK(s!1,S218~p,S222~p), ERK(T185~u!1) -> MEK(s!1,S218~p,S222~p), ERK(T185~p!1) 'MEK_ERK@185_op' MEK(s!1), ERK(T185!1) -> MEK(s), ERK(T185) 'MEK_ERK@187' MEK(s,S218~p,S222~p), ERK(Y187~u) -> MEK(s!1,S218~p,S222~p), ERK(Y187~u!1) 'ERK@187' MEK(s!1,S218~p,S222~p), ERK(Y187~u!1) -> MEK(s!1,S218~p,S222~p), ERK(Y187~p!1) 'MEK_ERK@187_op' MEK(s!1), ERK(Y187!1) -> MEK(s), ERK(Y187) # deactivation: 'MKP_ERK@185' MKP3(s), ERK(T185~p) -> MKP3(s!1), ERK(T185~p!1) 'ERK@185_op' MKP3(s!1), ERK(T185~p!1) -> MKP3(s!1), ERK(T185~u!1) 'MKP_ERK@185_op' MKP3(s!1), ERK(T185!1) -> MKP3(s), ERK(T185) 'MKP_ERK@187' MKP3(s), ERK(Y187~p) -> MKP3(s!1), ERK(Y187~p!1) 'ERK@187_op' MKP3(s!1), ERK(Y187~p!1) -> MKP3(s!1), ERK(Y187~u!1) 'MKP_ERK@187_op' MKP3(s!1), ERK(Y187!1) -> MKP3(s), ERK(Y187) # negative feedback 'SoS_ERK' SoS(SS~u), ERK(s,T185~p,Y187~p) -> SoS(SS~u!1), ERK(s!1,T185~p,Y187~p) 'SoS_ERK_op' SoS(SS!1), ERK(s!1) -> SoS(SS), ERK(s) 'SoS@SS' SoS(SS~u!1), ERK(s!1,T185~p,Y187~p) -> SoS(SS~p!1), ERK(s!1,T185~p,Y187~p) 'SoS@SS_op' SoS(SS~p) -> SoS(SS~u) # rates here... # initial solution (much smaller, for basic testing) %init: 10*(EGF(r)) %init: 100*(EGFR(L,CR,Y992~u,Y1068~u,Y1148~u)) %init: 100*(Shc(PTB,Y318~u)) %init: 100*(Grb2(SH2,SH3!1),SoS(a!1,b,SS~u)) %init: 200*(RasGAP(SH2,s)) %init: 100*(Ras(S1S2~gdp)) %init: 100*(Raf(x~u)) %init: 40*(PP2A1(s)) %init: 50*(PP2A2(s)) %init: 200*(MEK(s,S222~u,S218~u)) %init: 200*(ERK(s,T185~u,Y187~u)) %init: 50*(MKP3(s)) #%obs: EGFR(Y992~p?,Y1068~p?,Y1148~p?) %obs: Ras(S1S2~gtp?) %obs: Raf(x~p?) %obs: MEK(S218~p?,S222~p?) %obs: ERK(T185~p?,Y187~p?) #%story: 'Ras GTP' %story: 'SoS_ERK'