begin model

begin parameters
  # Tie Module
  Tie2_0        1
  Tie1_0        1
  Tie1Tie2_0    1 
  Ang1_4_0      1
  Ang2_2_0      1
  Ang2_3_0      1
  Ang2_4_0      1
  VEPTP_0       1
  sTie2_0       1  
  sTie1_0       1               
  
  PTEN_0    1
  PIP2_0    1
  PI3K_0    1
  Akt_0     1
  PDK1_0    1

  RhoA_0        1
  mDia_0        1
  Src_0         1 
  VECadherin_0  1
  ABIN2_0       1


  # Affinities
  kD_ang1         1 # nM
  kD_ang2         1 # nM

  # Ang1 Kinetics
  koffang1tie2    1   # s-1
  konang1tie2     koffang1tie2/kD_ang1

  # Ang2 Kinetics
  koffang2tie2    1   # s-1
  konang2tie2     koffang2tie2/kD_ang2

  # Diffusion Limits
  kontie2diff     1
  kofftie2diff    1

  konstie2diff    1
  koffstie2diff   1


  # kinteic parameters
  # Ang1 Binding
  konang1tie2_1   konang1tie2  # nM-1s-1
  koffang1tie2_1  koffang1tie2 # s-1
  konang1tie2_2   kontie2diff   # nM-1s-1
  koffang1tie2_2  kofftie2diff  # s-1
  konang1tie2_3   kontie2diff   # nM-1s-1
  koffang1tie2_3  kofftie2diff  # s-1
  konang1tie2_4   kontie2diff   # nM-1s-1
  koffang1tie2_4  kofftie2diff  # s-1

  # Ang2 Binding
  konang2_2tie2_1   konang2tie2    # nM-1s-1
  koffang2_2tie2_1  koffang2tie2   # s-1
  konang2_2tie2_2   kontie2diff     # nM-1s-1
  koffang2_2tie2_2  kofftie2diff    # s-1

  konang2_3tie2_1   konang2tie2    # nM-1s-1
  koffang2_3tie2_1  koffang2tie2   # s-1
  konang2_3tie2_2   kontie2diff     # nM-1s-1
  koffang2_3tie2_2  kofftie2diff    # s-1
  konang2_3tie2_3   kontie2diff     # nM-1s-1
  koffang2_3tie2_3  kofftie2diff    # s-1

  konang2_4tie2_1   konang2tie2    # nM-1s-1
  koffang2_4tie2_1  koffang2tie2   # s-1
  konang2_4tie2_2   kontie2diff     # nM-1s-1
  koffang2_4tie2_2  kofftie2diff    # s-1
  konang2_4tie2_3   kontie2diff     # nM-1s-1
  koffang2_4tie2_3  kofftie2diff    # s-1
  konang2_4tie2_4   kontie2diff     # nM-1s-1
  koffang2_4tie2_4  kofftie2diff    # s-1

  # Phosphorylation
  kpang1tie2       1    # s-1
  kdpang1tie2      1 # s-1
  kpang2tie2       1    # s-1
  kdpang2tie2      1 # s-1

  # Tie2 Junctional Localization
  ksjang1tie2   1
  kjsang1tie2   1
  ksjang2tie2   1
  kjsang2tie2   1

  # Tie1 Junctional Localization
  ksjtie1     1
  kjstie1     1

  # Tie1Tie2 binding at Junction
  konang1tie1tie2_4_j     1
  koffang1tie1tie2_4_j    1
  konang2tie1tie2_4_j     1
  koffang2tie1tie2_4_j    1
  
  # Tie1 phosphorylation at Junction
  kptie1ang1_j        1
  kdpatie1ang1_j      1
  kptie1ang2_j        1
  kdpatie1ang2_j      1


  # Dephosphorylation
  konveptp          1 # ?, nM -1 s-1
  koffveptp         1    # ?, s-1
  kactveptp_ang1    1 # s-1
  kactveptp_ang2  	1


  kintang1dptie   1
  kintang1ptie    1

  kintang2dptie   1
  kintang2ptie    1

  # Internalization
  kintang1tie2_1      kintang1dptie # s-1
  kintang1tie2_2      kintang1dptie # s-1
  kintang1tie2_3      kintang1dptie # s-1
  kintang1tie2_4      kintang1dptie # s-1
  kintang1p1tie2_4    kintang1ptie # s-1
  kintang1p2tie2_4    kintang1ptie # s-1
  kintang1p3tie2_4    kintang1ptie # s-1
  kintang1p4tie2_4    kintang1ptie # s-1


  kintang2_2tie2_1    kintang2dptie # s-1
  kintang2_2tie2_2    kintang2dptie # s-1

  kintang2_3tie2_1    kintang2dptie # s-1
  kintang2_3tie2_2    kintang2dptie # s-1
  kintang2_3tie2_3    kintang2dptie # s-1

  kintang2_4tie2_1    kintang2dptie # s-1
  kintang2_4tie2_2    kintang2dptie # s-1
  kintang2_4tie2_3    kintang2dptie # s-1
  kintang2_4tie2_4    kintang2dptie # s-1
  kintang2_4p1tie2_4  kintang2ptie # s-1
  kintang2_4p2tie2_4  kintang2ptie # s-1
  kintang2_4p3tie2_4  kintang2ptie # s-1
  kintang2_4p4tie2_4  kintang2ptie # s-1



  # Degradation and Replenishment
  kdegptie2         1 # s-1, fit
  krectie2          1 # recycling, fit!
  ksyntie2          1      # nM s-1
  ksyntie1        	1 #nM s-1


  # Binding to sTie2
  # Ang1 Binding
  konang1stie2_1   konang1tie2  # nM-1s-1
  koffang1stie2_1  koffang1tie2 # s-1
  konang1stie2_2   konstie2diff  # nM-1s-1
  koffang1stie2_2  koffstie2diff # s-1
  konang1stie2_3   konstie2diff  # nM-1s-1
  koffang1stie2_3  koffstie2diff # s-1
  konang1stie2_4   konstie2diff  # nM-1s-1
  koffang1stie2_4  koffstie2diff # s-1

  # Ang2 Binding
  konang2_2stie2_1   konang2tie2    # nM-1s-1
  koffang2_2stie2_1  koffang2tie2   # s-1
  konang2_2stie2_2   konstie2diff    # nM-1s-1
  koffang2_2stie2_2  koffstie2diff   # s-1

  konang2_3stie2_1   konang2tie2    # nM-1s-1
  koffang2_3stie2_1  koffang2tie2   # s-1
  konang2_3stie2_2   konstie2diff    # nM-1s-1
  koffang2_3stie2_2  koffstie2diff   # s-1
  konang2_3stie2_3   konstie2diff    # nM-1s-1
  koffang2_3stie2_3  koffstie2diff   # s-1

  konang2_4stie2_1   konang2tie2    # nM-1s-1
  koffang2_4stie2_1  koffang2tie2   # s-1
  konang2_4stie2_2   konstie2diff    # nM-1s-1
  koffang2_4stie2_2  koffstie2diff   # s-1
  konang2_4stie2_3   konstie2diff    # nM-1s-1
  koffang2_4stie2_3  koffstie2diff   # s-1
  konang2_4stie2_4   konstie2diff    # nM-1s-1
  koffang2_4stie2_4  koffstie2diff   # s-1

  # heterodimerization
  kontie1tie2     1
  kofftie1tie2    1

  # Binding to Tie1Tie2
  konang1_4tie1tie2   koffang1tie2/kD_ang1    # nM-1s-1
  koffang1_4tie1tie2  koffang1tie2    # s-1
  kdissang1tie1tie2   1   #??

  koffang2_2tie1tie2  koffang2tie2
  konang2_2tie1tie2   koffang2tie2/kD_ang2
  koffang2_3tie1tie2  koffang2tie2
  konang2_3tie1tie2   koffang2tie2/kD_ang2
  koffang2_4tie1tie2  koffang2tie2
  konang2_4tie1tie2   koffang2tie2/kD_ang2

  # Cleavage and Degradation
  kcleavetie2       1
  kcleavetie1       1
  kdegsTie2         1
  kdegstie1         1

  # Akt Activation
  kactPI3KTie2      1
  kinactPI3KTie2    1

  kPIP2gen          1

  kmPIP2PI3K        1
  kcatPI3KPIP2      1

  kmPIP3PTEN        1
  kcatPTENPIP3      1

  konPDK1PIP3       1
  koffPDK1PIP3      1
  konAKTPIP3        1
  koffAKTPIP3       1

  kpmTORAKT         1
  kpAKTPDK1         1
  kdp473AKTPPase    1
  kdp308AKTPPase    1

  # rhoa,mdia
  kprhoa        0.1
  kdprhoa       0.1

  konrhoamdia   0.1
  koffrhoamdia  0.1

  konmdiasrc    0.1
  koffmdiasrc   0.1
  
  kpsrc         0.1
  kdpsrc        0.1
  
  kpvecad       0.1
  kdpvecad      0.1
  kintvecad     0.1
  krecvecad     0.1
  kdegvecad     0.1

  kactabin2     0.1
  kinactabin2   0.1
end parameters


begin molecule types
  Tie2(tie1bs,loc~s~i~j~sol,veptpbs,pY~p~dp,ang1bs,ang2bs)
  Tie1(pY~dp~p,tie2bs,loc~s~i~j~sol)
  Ang1_4(tie2bs,tie2bs,tie2bs,tie2bs)
  Ang2_2(tie2bs,tie2bs)
  Ang2_3(tie2bs,tie2bs,tie2bs)
  Ang2_4(tie2bs,tie2bs,tie2bs,tie2bs)
  VEPTP(tie2bs)
  
  PTEN(PIP3docking)
  PI(PIsite~3P~4P)
  PI3K(state~active~inactive)
  Akt(PHakt,T308~S~pS,S473~S~pS)
  PDK1(PHpdk1,aktbd)

  RhoA(G~GDP~GTP,mDiabs) 
  mDia(RhoAbs,srcbs)
  Src(mDiabs,Y1~Y~pY)
  VECadherin(S665~S~pS,c~j~i)
  ABIN2(state~inactive~active)
  
  I()
  Trash()
end molecule types

begin seed species
  Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang1bs,ang2bs) Tie2_0
  Ang1_4(tie2bs,tie2bs,tie2bs,tie2bs) Ang1_4_0
  Ang2_2(tie2bs,tie2bs) Ang2_2_0
  Ang2_3(tie2bs,tie2bs,tie2bs) Ang2_3_0
  Ang2_4(tie2bs,tie2bs,tie2bs,tie2bs) Ang2_4_0
  VEPTP(tie2bs) VEPTP_0
  Tie2(tie1bs,loc~sol,veptpbs,pY~dp,ang1bs,ang2bs) sTie2_0
  Tie1(pY~dp,loc~sol,tie2bs) sTie1_0
  Tie1(pY~dp,loc~s,tie2bs) Tie1_0
  Tie1(pY~dp,loc~s,tie2bs!1).Tie2(tie1bs!1,loc~s,veptpbs,pY~dp,ang1bs,ang2bs) Tie1Tie2_0
  
  PTEN(PIP3docking)            PTEN_0
  PI(PIsite~3P)                PIP2_0
  PI3K(state~inactive)  PI3K_0
  Akt(PHakt,T308~S,S473~S)   Akt_0
  PDK1(PHpdk1,aktbd)    PDK1_0

  RhoA(G~GDP,mDiabs)      RhoA_0
  mDia(RhoAbs,srcbs)      mDia_0
  Src(mDiabs,Y1~Y)        Src_0
  VECadherin(S665~S,c~j)  VECadherin_0
  ABIN2(state~inactive)  ABIN2_0

  I() 1
  Trash() 1
end seed species

begin observables
  Molecules pTie2 Tie2(pY~p)								#1 
  Molecules intTie2 Tie2(loc~i)                             #2 
  Molecules surfTie2 Tie2(loc~s)                            #3 
  Molecules psurfTie2 Tie2(loc~s,pY~p)                      #4 
  Molecules pintTie2 Tie2(loc~i,pY~p)                       #5 
  Molecules totalTie2 Tie2                                  #6 
  Molecules sTie2 Tie2(loc~sol)                             #7 
  Molecules Tie1Tie2 Tie1(pY~dp,loc~s,tie2bs!+)             #8 
  Molecules surfTie1 Tie1(pY~dp,loc~s,tie2bs)               #9 
  Molecules sTie1 Tie1(loc~sol)                             #10
  Molecules jTie2 Tie2(loc~j)                               #11
  Molecules tsurfTie1 Tie1(loc~s)                           #12
  Molecules jTie1 Tie1(loc~j)                               #13
  Molecules freepip2 PI(PIsite~3P)                          #14
  Molecules freepip3 PI(PIsite~4P)                          #15
  Molecules ppAkt Akt(T308~pS,S473~pS)                      #16
  Molecules freeSrc Src(mDiabs)                             #17
  Molecules pSrc Src(Y1~pY)                                 #18
  Molecules pVECadherin VECadherin(S665~pS)                 #19
  Molecules aABIN2 ABIN2(state~active)                      #20
  Molecules totalAkt Akt                                    #21
  Molecules RhoAGTP RhoA(G~GTP)  							#22
  Molecules RhoAmDia mDia(RhoAbs!+)							#23
  Molecules mDiaSrc Src(mDiabs!+) 							#24
  Molecules totalTie1 Tie1							        #25
end observables

# Ang/Tie Binding: Rules 1-13
begin reaction rules
  # Ang1 Binding (ligand-induced)
  # 1
  Ang1_4(tie2bs,tie2bs,tie2bs,tie2bs) + \
  Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang1bs,ang2bs) <-> \
  Ang1_4(tie2bs!1,tie2bs,tie2bs,tie2bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang1bs!1,ang2bs) konang1tie2_1,koffang1tie2_1

  # 2
  Ang1_4(tie2bs!1,tie2bs,tie2bs,tie2bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang1bs!1,ang2bs) + Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang1bs,ang2bs) <-> \
  Ang1_4(tie2bs!1,tie2bs!2,tie2bs,tie2bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang1bs!1,ang2bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang1bs!2,ang2bs) konang1tie2_2,koffang1tie2_2

  # 3
  Ang1_4(tie2bs!1,tie2bs!2,tie2bs,tie2bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang1bs!1,ang2bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang1bs!2,ang2bs) + \
  Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang1bs,ang2bs) <-> \
  Ang1_4(tie2bs!1,tie2bs!2,tie2bs!3,tie2bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang1bs!1,ang2bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang1bs!2,ang2bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang1bs!3,ang2bs) konang1tie2_3,koffang1tie2_3

  # 4
  Ang1_4(tie2bs!1,tie2bs!2,tie2bs!3,tie2bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang1bs!1,ang2bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang1bs!2,ang2bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang1bs!3,ang2bs) + \
  Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang1bs,ang2bs) <-> \
  Ang1_4(tie2bs!1,tie2bs!2,tie2bs!3,tie2bs!4).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang1bs!1,ang2bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang1bs!2,ang2bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang1bs!3,ang2bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang1bs!4,ang2bs) konang1tie2_4,koffang1tie2_4

  # Ang2 Binding
  # dimer
  # 5
  Ang2_2(tie2bs,tie2bs) + \
  Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang2bs,ang1bs) <-> \
  Ang2_2(tie2bs!1,tie2bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang2bs!1,ang1bs) konang2_2tie2_1,koffang2_2tie2_1

  # 6
  Ang2_2(tie2bs!1,tie2bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang2bs!1,ang1bs) + \
  Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang2bs,ang1bs) <-> \
  Ang2_2(tie2bs!1,tie2bs!2).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang2bs!1,ang1bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang2bs!2,ang1bs) konang2_2tie2_2,koffang2_2tie2_2

  # trimer
  # 7
  Ang2_3(tie2bs,tie2bs,tie2bs) + \
  Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang2bs,ang1bs) <-> \
  Ang2_3(tie2bs!1,tie2bs,tie2bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang2bs!1,ang1bs) konang2_3tie2_1,koffang2_3tie2_1

  # 8
  Ang2_3(tie2bs!1,tie2bs,tie2bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang2bs!1,ang1bs) + \
  Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang2bs,ang1bs) <-> \
  Ang2_3(tie2bs!1,tie2bs!2,tie2bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang2bs!1,ang1bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang2bs!2,ang1bs) konang2_3tie2_2,koffang2_3tie2_2

  # 9
  Ang2_3(tie2bs!1,tie2bs!2,tie2bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang2bs!1,ang1bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang2bs!2,ang1bs) + \
  Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang2bs,ang1bs) <-> \
  Ang2_3(tie2bs!1,tie2bs!2,tie2bs!3).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang2bs!1,ang1bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang2bs!2,ang1bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang2bs!3,ang1bs) konang2_3tie2_3,koffang2_3tie2_3

  # tetramer
  # 10
  Ang2_4(tie2bs,tie2bs,tie2bs,tie2bs) + \
  Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang2bs,ang1bs) <-> \
  Ang2_4(tie2bs!1,tie2bs,tie2bs,tie2bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang2bs!1,ang1bs) konang2_4tie2_1,koffang2_4tie2_1

  # 11
  Ang2_4(tie2bs!1,tie2bs,tie2bs,tie2bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang2bs!1,ang1bs) + Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang2bs,ang1bs) <-> \
  Ang2_4(tie2bs!1,tie2bs!2,tie2bs,tie2bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang2bs!1,ang1bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang2bs!2,ang1bs) konang2_4tie2_2,koffang2_4tie2_2

  # 12
  Ang2_4(tie2bs!1,tie2bs!2,tie2bs,tie2bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang2bs!1,ang1bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang2bs!2,ang1bs) + \
  Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang2bs,ang1bs) <-> \
  Ang2_4(tie2bs!1,tie2bs!2,tie2bs!3,tie2bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang2bs!1,ang1bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang2bs!2,ang1bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang2bs!3,ang1bs) konang2_4tie2_3,koffang2_4tie2_3

  # 13
  Ang2_4(tie2bs!1,tie2bs!2,tie2bs!3,tie2bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang2bs!1,ang1bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang2bs!2,ang1bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang2bs!3,ang1bs) + \
  Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang2bs,ang1bs) <-> \
  Ang2_4(tie2bs!1,tie2bs!2,tie2bs!3,tie2bs!4).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang2bs!1,ang1bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang2bs!2,ang1bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang2bs!3,ang1bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang2bs!4,ang1bs) konang2_4tie2_4,koffang2_4tie2_4
end reaction rules

# Tie2 Activation: Rules 14-15
begin reaction rules
  # 14
  Ang1_4(tie2bs!1,tie2bs!+,tie2bs!+,tie2bs!+).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang1bs!1,ang2bs) <-> \
  Ang1_4(tie2bs!1,tie2bs!+,tie2bs!+,tie2bs!+).Tie2(tie1bs,loc~s,veptpbs,pY~p,ang1bs!1,ang2bs)  kpang1tie2,kdpang1tie2

  # 15
  Ang2_4(tie2bs!1,tie2bs!+,tie2bs!+,tie2bs!+).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang1bs,ang2bs!1) <-> \
  Ang2_4(tie2bs!1,tie2bs!+,tie2bs!+,tie2bs!+).Tie2(tie1bs,loc~s,veptpbs,pY~p,ang1bs,ang2bs!1)  kpang2tie2,kdpang2tie2
end reaction rules

# Tie1/Tie2 Junctional Localization and Interactions: Rules 16-22
begin reaction rules
  #16
  Ang1_4(tie2bs!1,tie2bs!2,tie2bs!3,tie2bs!4).Tie2(tie1bs,loc~s,veptpbs,pY~p,ang1bs!1,ang2bs).Tie2(tie1bs,loc~s,veptpbs,pY~p,ang1bs!2,ang2bs).Tie2(tie1bs,loc~s,veptpbs,pY~p,ang1bs!3,ang2bs).Tie2(tie1bs,loc~s,veptpbs,pY~p,ang1bs!4,ang2bs) <-> \
  Ang1_4(tie2bs!1,tie2bs!2,tie2bs!3,tie2bs!4).Tie2(tie1bs,loc~j,veptpbs,pY~p,ang1bs!1,ang2bs).Tie2(tie1bs,loc~j,veptpbs,pY~p,ang1bs!2,ang2bs).Tie2(tie1bs,loc~j,veptpbs,pY~p,ang1bs!3,ang2bs).Tie2(tie1bs,loc~j,veptpbs,pY~p,ang1bs!4,ang2bs)  ksjang1tie2,kjsang1tie2

  # 17
  Ang2_4(tie2bs!1,tie2bs!2,tie2bs!3,tie2bs!4).Tie2(tie1bs,loc~s,veptpbs,pY~p,ang2bs!1,ang1bs).Tie2(tie1bs,loc~s,veptpbs,pY~p,ang2bs!2,ang1bs).Tie2(tie1bs,loc~s,veptpbs,pY~p,ang2bs!3,ang1bs).Tie2(tie1bs,loc~s,veptpbs,pY~p,ang2bs!4,ang1bs) <-> \
  Ang2_4(tie2bs!1,tie2bs!2,tie2bs!3,tie2bs!4).Tie2(tie1bs,loc~j,veptpbs,pY~p,ang2bs!1,ang1bs).Tie2(tie1bs,loc~j,veptpbs,pY~p,ang2bs!2,ang1bs).Tie2(tie1bs,loc~j,veptpbs,pY~p,ang2bs!3,ang1bs).Tie2(tie1bs,loc~j,veptpbs,pY~p,ang2bs!4,ang1bs) ksjang2tie2,kjsang2tie2

  # 18
  Tie1(pY~dp,tie2bs,loc~s) <-> Tie1(pY~dp,tie2bs,loc~j) ksjtie1,kjstie1

  # Tie1 Tie2 Binding at Junction
  # 19
  Ang1_4(tie2bs!1,tie2bs!2,tie2bs!3,tie2bs!4).Tie2(tie1bs,loc~j,veptpbs,pY~p,ang1bs!1,ang2bs).Tie2(tie1bs,loc~j,veptpbs,pY~p,ang1bs!2,ang2bs).Tie2(tie1bs,loc~j,veptpbs,pY~p,ang1bs!3,ang2bs).Tie2(tie1bs,loc~j,veptpbs,pY~p,ang1bs!4,ang2bs) \
  + Tie1(pY~dp,tie2bs,loc~j) <-> \
  Ang1_4(tie2bs!1,tie2bs!2,tie2bs!3,tie2bs!4).Tie2(tie1bs!5,loc~j,veptpbs,pY~p,ang1bs!1,ang2bs).Tie2(tie1bs,loc~j,veptpbs,pY~p,ang1bs!2,ang2bs).Tie2(tie1bs,loc~j,veptpbs,pY~p,ang1bs!3,ang2bs).Tie2(tie1bs,loc~j,veptpbs,pY~p,ang1bs!4,ang2bs).Tie1(pY~dp,tie2bs!5,loc~j) konang1tie1tie2_4_j, koffang1tie1tie2_4_j

  # 20
  Ang2_4(tie2bs!1,tie2bs!2,tie2bs!3,tie2bs!4).Tie2(tie1bs,loc~j,veptpbs,pY~p,ang2bs!1,ang1bs).Tie2(tie1bs,loc~j,veptpbs,pY~p,ang2bs!2,ang1bs).Tie2(tie1bs,loc~j,veptpbs,pY~p,ang2bs!3,ang1bs).Tie2(tie1bs,loc~j,veptpbs,pY~p,ang2bs!4,ang1bs) \
  + Tie1(pY~dp,tie2bs,loc~j) <-> \
  Ang2_4(tie2bs!1,tie2bs!2,tie2bs!3,tie2bs!4).Tie2(tie1bs!5,loc~j,veptpbs,pY~p,ang2bs!1,ang1bs).Tie2(tie1bs,loc~j,veptpbs,pY~p,ang2bs!2,ang1bs).Tie2(tie1bs,loc~j,veptpbs,pY~p,ang2bs!3,ang1bs).Tie2(tie1bs,loc~j,veptpbs,pY~p,ang2bs!4,ang1bs).Tie1(pY~dp,tie2bs!5,loc~j) konang2tie1tie2_4_j, koffang2tie1tie2_4_j


  # Tie1 Tie2 Cross Phosphorylation at Junction
  # 21
  Ang1_4(tie2bs!1,tie2bs!2,tie2bs!3,tie2bs!4).Tie2(tie1bs!5,loc~j,veptpbs,pY~p,ang1bs!1,ang2bs).Tie2(tie1bs,loc~j,veptpbs,pY~p,ang1bs!2,ang2bs).Tie2(tie1bs,loc~j,veptpbs,pY~p,ang1bs!3,ang2bs).Tie2(tie1bs,loc~j,veptpbs,pY~p,ang1bs!4,ang2bs).Tie1(pY~dp,tie2bs!5,loc~j) <-> \
  Ang1_4(tie2bs!1,tie2bs!2,tie2bs!3,tie2bs!4).Tie2(tie1bs!5,loc~j,veptpbs,pY~p,ang1bs!1,ang2bs).Tie2(tie1bs,loc~j,veptpbs,pY~p,ang1bs!2,ang2bs).Tie2(tie1bs,loc~j,veptpbs,pY~p,ang1bs!3,ang2bs).Tie2(tie1bs,loc~j,veptpbs,pY~p,ang1bs!4,ang2bs).Tie1(pY~p,tie2bs!5,loc~j) kptie1ang1_j, kdpatie1ang1_j
  # 22
  Ang2_4(tie2bs!1,tie2bs!2,tie2bs!3,tie2bs!4).Tie2(tie1bs!5,loc~j,veptpbs,pY~p,ang2bs!1,ang1bs).Tie2(tie1bs,loc~j,veptpbs,pY~p,ang2bs!2,ang1bs).Tie2(tie1bs,loc~j,veptpbs,pY~p,ang2bs!3,ang1bs).Tie2(tie1bs,loc~j,veptpbs,pY~p,ang2bs!4,ang1bs).Tie1(pY~dp,tie2bs!5,loc~j) <-> \
  Ang2_4(tie2bs!1,tie2bs!2,tie2bs!3,tie2bs!4).Tie2(tie1bs!5,loc~j,veptpbs,pY~p,ang2bs!1,ang1bs).Tie2(tie1bs,loc~j,veptpbs,pY~p,ang2bs!2,ang1bs).Tie2(tie1bs,loc~j,veptpbs,pY~p,ang2bs!3,ang1bs).Tie2(tie1bs,loc~j,veptpbs,pY~p,ang2bs!4,ang1bs).Tie1(pY~p,tie2bs!5,loc~j) kptie1ang2_j, kdpatie1ang2_j
end reaction rules

# VEPTP Dephosphorylation: Rules 23-25
begin reaction rules
  # Tie2 Dephosphorylation (by VE-PTP)
  # 23
  Tie2(tie1bs,loc~j,veptpbs,pY~p) + VEPTP(tie2bs) <-> \
  Tie2(tie1bs,loc~j,veptpbs!1,pY~p).VEPTP(tie2bs!1) konveptp,koffveptp

  # 24
  Tie2(tie1bs,loc~j,veptpbs!1,ang1bs!+,ang2bs,pY~p).VEPTP(tie2bs!1) -> \
  Tie2(tie1bs,loc~j,veptpbs,ang1bs!+,ang2bs,pY~dp) + VEPTP(tie2bs) kactveptp_ang1

  # 25
  Tie2(tie1bs,loc~j,veptpbs!1,ang2bs!+,ang1bs,pY~p).VEPTP(tie2bs!1) -> \
  Tie2(tie1bs,loc~j,veptpbs,ang2bs!+,ang1bs,pY~dp) + VEPTP(tie2bs) kactveptp_ang2
end reaction rules

# Internalization, Recycling, Turnover, Synthesis: Rules 26-50
begin reaction rules
  # Ang1
  # 26
  Ang1_4(tie2bs!1,tie2bs,tie2bs,tie2bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang1bs!1,ang2bs) -> \
  Ang1_4(tie2bs,tie2bs,tie2bs,tie2bs) + Tie2(tie1bs,loc~i,veptpbs,pY~dp,ang1bs,ang2bs) kintang1tie2_1  

  # 27
  Ang1_4(tie2bs!1,tie2bs!2,tie2bs,tie2bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang1bs!1,ang2bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang1bs!2,ang2bs) -> \
  Ang1_4(tie2bs,tie2bs,tie2bs,tie2bs) + Tie2(tie1bs,loc~i,veptpbs,pY~dp,ang1bs,ang2bs) + Tie2(tie1bs,loc~i,veptpbs,pY~dp,ang1bs,ang2bs) kintang1tie2_2

  # 28
  Ang1_4(tie2bs!1,tie2bs!2,tie2bs!3,tie2bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang1bs!1,ang2bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang1bs!2,ang2bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang1bs!3,ang2bs) -> \
  Ang1_4(tie2bs,tie2bs,tie2bs,tie2bs) + Tie2(tie1bs,loc~i,veptpbs,pY~dp,ang1bs,ang2bs) + Tie2(tie1bs,loc~i,veptpbs,pY~dp,ang1bs,ang2bs) + Tie2(tie1bs,loc~i,veptpbs,pY~dp,ang1bs,ang2bs) kintang1tie2_3
  
  # 29
  Ang1_4(tie2bs!1,tie2bs!2,tie2bs!3,tie2bs!4).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang1bs!1,ang2bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang1bs!2,ang2bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang1bs!3,ang2bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang1bs!4,ang2bs) -> \
  Ang1_4(tie2bs,tie2bs,tie2bs,tie2bs) + Tie2(tie1bs,loc~i,veptpbs,pY~dp,ang1bs,ang2bs) + Tie2(tie1bs,loc~i,veptpbs,pY~dp,ang1bs,ang2bs) + Tie2(tie1bs,loc~i,veptpbs,pY~dp,ang1bs,ang2bs) + Tie2(tie1bs,loc~i,veptpbs,pY~dp,ang1bs,ang2bs) kintang1tie2_4

  # 30
  Ang1_4(tie2bs!1,tie2bs!2,tie2bs!3,tie2bs!4).Tie2(tie1bs,loc~s,veptpbs,pY~p,ang1bs!1,ang2bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang1bs!2,ang2bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang1bs!3,ang2bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang1bs!4,ang2bs) -> \
  Ang1_4(tie2bs,tie2bs,tie2bs,tie2bs) + Tie2(tie1bs,loc~i,veptpbs,pY~p,ang1bs,ang2bs) + Tie2(tie1bs,loc~i,veptpbs,pY~dp,ang1bs,ang2bs) + Tie2(tie1bs,loc~i,veptpbs,pY~dp,ang1bs,ang2bs) + Tie2(tie1bs,loc~i,veptpbs,pY~dp,ang1bs,ang2bs) kintang1p1tie2_4

  # 31
  Ang1_4(tie2bs!1,tie2bs!2,tie2bs!3,tie2bs!4).Tie2(tie1bs,loc~s,veptpbs,pY~p,ang1bs!1,ang2bs).Tie2(tie1bs,loc~s,veptpbs,pY~p,ang1bs!2,ang2bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang1bs!3,ang2bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang1bs!4,ang2bs) -> \
  Ang1_4(tie2bs,tie2bs,tie2bs,tie2bs) + Tie2(tie1bs,loc~i,veptpbs,pY~p,ang1bs,ang2bs) + Tie2(tie1bs,loc~i,veptpbs,pY~p,ang1bs,ang2bs) + Tie2(tie1bs,loc~i,veptpbs,pY~dp,ang1bs,ang2bs) + Tie2(tie1bs,loc~i,veptpbs,pY~dp,ang1bs,ang2bs) kintang1p2tie2_4

  # 32
  Ang1_4(tie2bs!1,tie2bs!2,tie2bs!3,tie2bs!4).Tie2(tie1bs,loc~s,veptpbs,pY~p,ang1bs!1,ang2bs).Tie2(tie1bs,loc~s,veptpbs,pY~p,ang1bs!2,ang2bs).Tie2(tie1bs,loc~s,veptpbs,pY~p,ang1bs!3,ang2bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang1bs!4,ang2bs) -> \
  Ang1_4(tie2bs,tie2bs,tie2bs,tie2bs) + Tie2(tie1bs,loc~i,veptpbs,pY~p,ang1bs,ang2bs) + Tie2(tie1bs,loc~i,veptpbs,pY~p,ang1bs,ang2bs) + Tie2(tie1bs,loc~i,veptpbs,pY~p,ang1bs,ang2bs) + Tie2(tie1bs,loc~i,veptpbs,pY~dp,ang1bs,ang2bs) kintang1p3tie2_4

  # 33
  Ang1_4(tie2bs!1,tie2bs!2,tie2bs!3,tie2bs!4).Tie2(tie1bs,loc~s,veptpbs,pY~p,ang1bs!1,ang2bs).Tie2(tie1bs,loc~s,veptpbs,pY~p,ang1bs!2,ang2bs).Tie2(tie1bs,loc~s,veptpbs,pY~p,ang1bs!3,ang2bs).Tie2(tie1bs,loc~s,veptpbs,pY~p,ang1bs!4,ang2bs) -> \
  Ang1_4(tie2bs,tie2bs,tie2bs,tie2bs) + Tie2(tie1bs,loc~i,veptpbs,pY~p,ang1bs,ang2bs) + Tie2(tie1bs,loc~i,veptpbs,pY~p,ang1bs,ang2bs) + Tie2(tie1bs,loc~i,veptpbs,pY~p,ang1bs,ang2bs) + Tie2(tie1bs,loc~i,veptpbs,pY~p,ang1bs,ang2bs) kintang1p4tie2_4
  
  # Ang2_2
  # 34
  Ang2_2(tie2bs!1,tie2bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang2bs!1,ang1bs) -> \
  Ang2_2(tie2bs,tie2bs) + Tie2(tie1bs,loc~i,veptpbs,pY~dp,ang2bs,ang1bs) kintang2_2tie2_1  

  # 35
  Ang2_3(tie2bs!1,tie2bs!2).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang2bs!1,ang1bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang2bs!2,ang1bs) -> \
  Ang2_2(tie2bs,tie2bs) + Tie2(tie1bs,loc~i,veptpbs,pY~dp,ang2bs,ang1bs) + Tie2(tie1bs,loc~i,veptpbs,pY~dp,ang2bs,ang1bs) kintang2_2tie2_2

  # Ang2_3
  # 36
  Ang2_3(tie2bs!1,tie2bs,tie2bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang2bs!1,ang1bs) -> \
  Ang2_3(tie2bs,tie2bs,tie2bs) + Tie2(tie1bs,loc~i,veptpbs,pY~dp,ang2bs,ang1bs) kintang2_3tie2_1  

  # 37
  Ang2_3(tie2bs!1,tie2bs!2,tie2bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang2bs!1,ang1bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang2bs!2,ang1bs) -> \
  Ang2_3(tie2bs,tie2bs,tie2bs) + Tie2(tie1bs,loc~i,veptpbs,pY~dp,ang2bs,ang1bs) + Tie2(tie1bs,loc~i,veptpbs,pY~dp,ang2bs,ang1bs) kintang2_3tie2_2

  # 38
  Ang2_3(tie2bs!1,tie2bs!2,tie2bs!3).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang2bs!1,ang1bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang2bs!2,ang1bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang2bs!3,ang1bs) -> \
  Ang2_3(tie2bs,tie2bs,tie2bs) + Tie2(tie1bs,loc~i,veptpbs,pY~dp,ang2bs,ang1bs) + Tie2(tie1bs,loc~i,veptpbs,pY~dp,ang2bs,ang1bs) + Tie2(tie1bs,loc~i,veptpbs,pY~dp,ang2bs,ang1bs) kintang2_3tie2_3  

  # Ang2_4
  # 39
  Ang2_4(tie2bs!1,tie2bs,tie2bs,tie2bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang2bs!1,ang1bs) -> \
  Ang2_4(tie2bs,tie2bs,tie2bs,tie2bs) + Tie2(tie1bs,loc~i,veptpbs,pY~dp,ang2bs,ang1bs) kintang2_4tie2_1  

  # 40
  Ang2_4(tie2bs!1,tie2bs!2,tie2bs,tie2bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang2bs!1,ang1bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang2bs!2,ang1bs) -> \
  Ang2_4(tie2bs,tie2bs,tie2bs,tie2bs) + Tie2(tie1bs,loc~i,veptpbs,pY~dp,ang2bs,ang1bs) + Tie2(tie1bs,loc~i,veptpbs,pY~dp,ang2bs,ang1bs) kintang2_4tie2_2

  # 41
  Ang2_4(tie2bs!1,tie2bs!2,tie2bs!3,tie2bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang2bs!1,ang1bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang2bs!2,ang1bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang2bs!3,ang1bs) -> \
  Ang2_4(tie2bs,tie2bs,tie2bs,tie2bs) + Tie2(tie1bs,loc~i,veptpbs,pY~dp,ang2bs,ang1bs) + Tie2(tie1bs,loc~i,veptpbs,pY~dp,ang2bs,ang1bs) + Tie2(tie1bs,loc~i,veptpbs,pY~dp,ang2bs,ang1bs) kintang2_4tie2_3

  # 42
  Ang2_4(tie2bs!1,tie2bs!2,tie2bs!3,tie2bs!4).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang2bs!1,ang1bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang2bs!2,ang1bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang2bs!3,ang1bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang2bs!4,ang1bs) -> \
  Ang2_4(tie2bs,tie2bs,tie2bs,tie2bs) + Tie2(tie1bs,loc~i,veptpbs,pY~dp,ang2bs,ang1bs) + Tie2(tie1bs,loc~i,veptpbs,pY~dp,ang2bs,ang1bs) + Tie2(tie1bs,loc~i,veptpbs,pY~dp,ang2bs,ang1bs) + Tie2(tie1bs,loc~i,veptpbs,pY~dp,ang2bs,ang1bs) kintang2_4tie2_4

  # 43
  Ang2_4(tie2bs!1,tie2bs!2,tie2bs!3,tie2bs!4).Tie2(tie1bs,loc~s,veptpbs,pY~p,ang2bs!1,ang1bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang2bs!2,ang1bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang2bs!3,ang1bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang2bs!4,ang1bs) -> \
  Ang2_4(tie2bs,tie2bs,tie2bs,tie2bs) + Tie2(tie1bs,loc~i,veptpbs,pY~p,ang2bs,ang1bs) + Tie2(tie1bs,loc~i,veptpbs,pY~dp,ang2bs,ang1bs) + Tie2(tie1bs,loc~i,veptpbs,pY~dp,ang2bs,ang1bs) + Tie2(tie1bs,loc~i,veptpbs,pY~dp,ang2bs,ang1bs) kintang2_4p1tie2_4

  # 44
  Ang2_4(tie2bs!1,tie2bs!2,tie2bs!3,tie2bs!4).Tie2(tie1bs,loc~s,veptpbs,pY~p,ang2bs!1,ang1bs).Tie2(tie1bs,loc~s,veptpbs,pY~p,ang2bs!2,ang1bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang2bs!3,ang1bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang2bs!4,ang1bs) -> \
  Ang2_4(tie2bs,tie2bs,tie2bs,tie2bs) + Tie2(tie1bs,loc~i,veptpbs,pY~p,ang2bs,ang1bs) + Tie2(tie1bs,loc~i,veptpbs,pY~p,ang2bs,ang1bs) + Tie2(tie1bs,loc~i,veptpbs,pY~dp,ang2bs,ang1bs) + Tie2(tie1bs,loc~i,veptpbs,pY~dp,ang2bs,ang1bs) kintang2_4p2tie2_4

  # 45
  Ang2_4(tie2bs!1,tie2bs!2,tie2bs!3,tie2bs!4).Tie2(tie1bs,loc~s,veptpbs,pY~p,ang2bs!1,ang1bs).Tie2(tie1bs,loc~s,veptpbs,pY~p,ang2bs!2,ang1bs).Tie2(tie1bs,loc~s,veptpbs,pY~p,ang2bs!3,ang1bs).Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang2bs!4,ang1bs) -> \
  Ang2_4(tie2bs,tie2bs,tie2bs,tie2bs) + Tie2(tie1bs,loc~i,veptpbs,pY~p,ang2bs,ang1bs) + Tie2(tie1bs,loc~i,veptpbs,pY~p,ang2bs,ang1bs) + Tie2(tie1bs,loc~i,veptpbs,pY~p,ang2bs,ang1bs) + Tie2(tie1bs,loc~i,veptpbs,pY~dp,ang2bs,ang1bs) kintang2_4p3tie2_4

  # 46
  Ang2_4(tie2bs!1,tie2bs!2,tie2bs!3,tie2bs!4).Tie2(tie1bs,loc~s,veptpbs,pY~p,ang2bs!1,ang1bs).Tie2(tie1bs,loc~s,veptpbs,pY~p,ang2bs!2,ang1bs).Tie2(tie1bs,loc~s,veptpbs,pY~p,ang2bs!3,ang1bs).Tie2(tie1bs,loc~s,veptpbs,pY~p,ang2bs!4,ang1bs) -> \
  Ang2_4(tie2bs,tie2bs,tie2bs,tie2bs) + Tie2(tie1bs,loc~i,veptpbs,pY~p,ang2bs,ang1bs) + Tie2(tie1bs,loc~i,veptpbs,pY~p,ang2bs,ang1bs) + Tie2(tie1bs,loc~i,veptpbs,pY~p,ang2bs,ang1bs) + Tie2(tie1bs,loc~i,veptpbs,pY~p,ang2bs,ang1bs) kintang2_4p4tie2_4

  # Recycling of Internalized Tie2
  # 47
  Tie2(tie1bs,loc~i,veptpbs,pY~dp,ang1bs,ang2bs) -> Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang1bs,ang2bs) krectie2

  # Degradation and Synthesis
  # 48
  Tie2(loc~i,pY~p) -> Trash() kdegptie2

  # 49
  I() -> I() + Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang1bs,ang2bs) ksyntie2
  
  # 50
  I() -> I() + Tie1(pY~dp,tie2bs,loc~s) ksyntie1
end reaction rules

# Soluble Tie2 Binding: Rules 51-63
begin reaction rules
  # Ang1 Binding
  # 51
  Ang1_4(tie2bs,tie2bs,tie2bs,tie2bs) + \
  Tie2(tie1bs,loc~sol,veptpbs,pY~dp,ang1bs,ang2bs) <-> \
  Ang1_4(tie2bs!1,tie2bs,tie2bs,tie2bs).Tie2(tie1bs,loc~sol,veptpbs,pY~dp,ang1bs!1,ang2bs) konang1tie2_1,koffang1tie2_1

  # 52
  Ang1_4(tie2bs!1,tie2bs,tie2bs,tie2bs).Tie2(tie1bs,loc~sol,veptpbs,pY~dp,ang1bs!1,ang2bs) + Tie2(tie1bs,loc~sol,veptpbs,pY~dp,ang1bs,ang2bs) <-> \
  Ang1_4(tie2bs!1,tie2bs!2,tie2bs,tie2bs).Tie2(tie1bs,loc~sol,veptpbs,pY~dp,ang1bs!1,ang2bs).Tie2(tie1bs,loc~sol,veptpbs,pY~dp,ang1bs!2,ang2bs) konang1tie2_2,koffang1tie2_2

  # 53
  Ang1_4(tie2bs!1,tie2bs!2,tie2bs,tie2bs).Tie2(tie1bs,loc~sol,veptpbs,pY~dp,ang1bs!1,ang2bs).Tie2(tie1bs,loc~sol,veptpbs,pY~dp,ang1bs!2,ang2bs) + \
  Tie2(tie1bs,loc~sol,veptpbs,pY~dp,ang1bs,ang2bs) <-> \
  Ang1_4(tie2bs!1,tie2bs!2,tie2bs!3,tie2bs).Tie2(tie1bs,loc~sol,veptpbs,pY~dp,ang1bs!1,ang2bs).Tie2(tie1bs,loc~sol,veptpbs,pY~dp,ang1bs!2,ang2bs).Tie2(tie1bs,loc~sol,veptpbs,pY~dp,ang1bs!3,ang2bs) konang1tie2_3,koffang1tie2_3

  # 54
  Ang1_4(tie2bs!1,tie2bs!2,tie2bs!3,tie2bs).Tie2(tie1bs,loc~sol,veptpbs,pY~dp,ang1bs!1,ang2bs).Tie2(tie1bs,loc~sol,veptpbs,pY~dp,ang1bs!2,ang2bs).Tie2(tie1bs,loc~sol,veptpbs,pY~dp,ang1bs!3,ang2bs) + \
  Tie2(tie1bs,loc~sol,veptpbs,pY~dp,ang1bs,ang2bs) <-> \
  Ang1_4(tie2bs!1,tie2bs!2,tie2bs!3,tie2bs!4).Tie2(tie1bs,loc~sol,veptpbs,pY~dp,ang1bs!1,ang2bs).Tie2(tie1bs,loc~sol,veptpbs,pY~dp,ang1bs!2,ang2bs).Tie2(tie1bs,loc~sol,veptpbs,pY~dp,ang1bs!3,ang2bs).Tie2(tie1bs,loc~sol,veptpbs,pY~dp,ang1bs!4,ang2bs) konang1tie2_4,koffang1tie2_4

  # Ang2 Binding
  # dimer
  # 55
  Ang2_2(tie2bs,tie2bs) + \
  Tie2(tie1bs,loc~sol,veptpbs,pY~dp,ang2bs,ang1bs) <-> \
  Ang2_2(tie2bs!1,tie2bs).Tie2(tie1bs,loc~sol,veptpbs,pY~dp,ang2bs!1,ang1bs) konang2_2tie2_1,koffang2_2tie2_1

  # 56
  Ang2_2(tie2bs!1,tie2bs).Tie2(tie1bs,loc~sol,veptpbs,pY~dp,ang2bs!1,ang1bs) + \
  Tie2(tie1bs,loc~sol,veptpbs,pY~dp,ang2bs,ang1bs) <-> \
  Ang2_2(tie2bs!1,tie2bs!2).Tie2(tie1bs,loc~sol,veptpbs,pY~dp,ang2bs!1,ang1bs).Tie2(tie1bs,loc~sol,veptpbs,pY~dp,ang2bs!2,ang1bs) konang2_2tie2_2,koffang2_2tie2_2

  # trimer
  # 57
  Ang2_3(tie2bs,tie2bs,tie2bs) + \
  Tie2(tie1bs,loc~sol,veptpbs,pY~dp,ang2bs,ang1bs) <-> \
  Ang2_3(tie2bs!1,tie2bs,tie2bs).Tie2(tie1bs,loc~sol,veptpbs,pY~dp,ang2bs!1,ang1bs) konang2_3tie2_1,koffang2_3tie2_1

  # 58
  Ang2_3(tie2bs!1,tie2bs,tie2bs).Tie2(tie1bs,loc~sol,veptpbs,pY~dp,ang2bs!1,ang1bs) + \
  Tie2(tie1bs,loc~sol,veptpbs,pY~dp,ang2bs,ang1bs) <-> \
  Ang2_3(tie2bs!1,tie2bs!2,tie2bs).Tie2(tie1bs,loc~sol,veptpbs,pY~dp,ang2bs!1,ang1bs).Tie2(tie1bs,loc~sol,veptpbs,pY~dp,ang2bs!2,ang1bs) konang2_3tie2_2,koffang2_3tie2_2

  # 59
  Ang2_3(tie2bs!1,tie2bs!2,tie2bs).Tie2(tie1bs,loc~sol,veptpbs,pY~dp,ang2bs!1,ang1bs).Tie2(tie1bs,loc~sol,veptpbs,pY~dp,ang2bs!2,ang1bs) + \
  Tie2(tie1bs,loc~sol,veptpbs,pY~dp,ang2bs,ang1bs) <-> \
  Ang2_3(tie2bs!1,tie2bs!2,tie2bs!3).Tie2(tie1bs,loc~sol,veptpbs,pY~dp,ang2bs!1,ang1bs).Tie2(tie1bs,loc~sol,veptpbs,pY~dp,ang2bs!2,ang1bs).Tie2(tie1bs,loc~sol,veptpbs,pY~dp,ang2bs!3,ang1bs) konang2_3tie2_3,koffang2_3tie2_3

  # tetramer
  # 60
  Ang2_4(tie2bs,tie2bs,tie2bs,tie2bs) + \
  Tie2(tie1bs,loc~sol,veptpbs,pY~dp,ang2bs,ang1bs) <-> \
  Ang2_4(tie2bs!1,tie2bs,tie2bs,tie2bs).Tie2(tie1bs,loc~sol,veptpbs,pY~dp,ang2bs!1,ang1bs) konang2_4tie2_1,koffang2_4tie2_1

  # 61
  Ang2_4(tie2bs!1,tie2bs,tie2bs,tie2bs).Tie2(tie1bs,loc~sol,veptpbs,pY~dp,ang2bs!1,ang1bs) + Tie2(tie1bs,loc~sol,veptpbs,pY~dp,ang2bs,ang1bs) <-> \
  Ang2_4(tie2bs!1,tie2bs!2,tie2bs,tie2bs).Tie2(tie1bs,loc~sol,veptpbs,pY~dp,ang2bs!1,ang1bs).Tie2(tie1bs,loc~sol,veptpbs,pY~dp,ang2bs!2,ang1bs) konang2_4tie2_2,koffang2_4tie2_2

  #62
  Ang2_4(tie2bs!1,tie2bs!2,tie2bs,tie2bs).Tie2(tie1bs,loc~sol,veptpbs,pY~dp,ang2bs!1,ang1bs).Tie2(tie1bs,loc~sol,veptpbs,pY~dp,ang2bs!2,ang1bs) + \
  Tie2(tie1bs,loc~sol,veptpbs,pY~dp,ang2bs,ang1bs) <-> \
  Ang2_4(tie2bs!1,tie2bs!2,tie2bs!3,tie2bs).Tie2(tie1bs,loc~sol,veptpbs,pY~dp,ang2bs!1,ang1bs).Tie2(tie1bs,loc~sol,veptpbs,pY~dp,ang2bs!2,ang1bs).Tie2(tie1bs,loc~sol,veptpbs,pY~dp,ang2bs!3,ang1bs) konang2_4tie2_3,koffang2_4tie2_3

  # 63
  Ang2_4(tie2bs!1,tie2bs!2,tie2bs!3,tie2bs).Tie2(tie1bs,loc~sol,veptpbs,pY~dp,ang2bs!1,ang1bs).Tie2(tie1bs,loc~sol,veptpbs,pY~dp,ang2bs!2,ang1bs).Tie2(tie1bs,loc~sol,veptpbs,pY~dp,ang2bs!3,ang1bs) + \
  Tie2(tie1bs,loc~sol,veptpbs,pY~dp,ang2bs,ang1bs) <-> \
  Ang2_4(tie2bs!1,tie2bs!2,tie2bs!3,tie2bs!4).Tie2(tie1bs,loc~sol,veptpbs,pY~dp,ang2bs!1,ang1bs).Tie2(tie1bs,loc~sol,veptpbs,pY~dp,ang2bs!2,ang1bs).Tie2(tie1bs,loc~sol,veptpbs,pY~dp,ang2bs!3,ang1bs).Tie2(tie1bs,loc~sol,veptpbs,pY~dp,ang2bs!4,ang1bs) konang2_4tie2_4,koffang2_4tie2_4
end reaction rules

# Tie1:Tie2 Heterodimers: Rules 64-69
begin reaction rules 
  # Heterodimerization
  # 64
  Tie1(pY~dp,loc~s,tie2bs) + Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang1bs,ang2bs) <-> Tie1(pY~dp,loc~s,tie2bs!1).Tie2(tie1bs!1,loc~s,veptpbs,pY~dp,ang1bs,ang2bs) kontie1tie2, kofftie1tie2

  # Ang1 binding to Tie1:Tie2
  # 65
  Tie1(pY~dp,loc~s,tie2bs!1).Tie2(tie1bs!1,loc~s,veptpbs,pY~dp,ang1bs,ang2bs) + \
  Ang1_4(tie2bs,tie2bs,tie2bs,tie2bs) <-> \
  Tie1(pY~dp,loc~s,tie2bs!1).Tie2(tie1bs!1,loc~s,veptpbs,pY~dp,ang1bs!2,ang2bs).Ang1_4(tie2bs!2,tie2bs,tie2bs,tie2bs) konang1_4tie1tie2, koffang1_4tie1tie2

  # 66
  Tie1(pY~dp,loc~s,tie2bs!1).Tie2(tie1bs!1,loc~s,veptpbs,pY~dp,ang1bs!2,ang2bs).Ang1_4(tie2bs!2,tie2bs,tie2bs,tie2bs) -> \
  Tie1(pY~dp,loc~s,tie2bs) + Tie2(tie1bs,loc~s,veptpbs,pY~dp,ang1bs!2,ang2bs).Ang1_4(tie2bs!2,tie2bs,tie2bs,tie2bs) kdissang1tie1tie2

  # Ang2 binding to Tie1:Tie2
  # 67
  Tie1(pY~dp,loc~s,tie2bs!1).Tie2(tie1bs!1,loc~s,veptpbs,pY~dp,ang1bs,ang2bs) + \
  Ang2_2(tie2bs,tie2bs) <-> \
  Tie1(pY~dp,loc~s,tie2bs!1).Tie2(tie1bs!1,loc~s,veptpbs,pY~dp,ang1bs,ang2bs!2).Ang2_2(tie2bs!2,tie2bs) konang2_2tie1tie2, koffang2_2tie1tie2

  # 68
  Tie1(pY~dp,loc~s,tie2bs!1).Tie2(tie1bs!1,loc~s,veptpbs,pY~dp,ang1bs,ang2bs) + \
  Ang2_3(tie2bs,tie2bs,tie2bs) <-> \
  Tie1(pY~dp,loc~s,tie2bs!1).Tie2(tie1bs!1,loc~s,veptpbs,pY~dp,ang1bs,ang2bs!2).Ang2_3(tie2bs!2,tie2bs,tie2bs) konang2_3tie1tie2, koffang2_3tie1tie2

  # 69
  Tie1(pY~dp,loc~s,tie2bs!1).Tie2(tie1bs!1,loc~s,veptpbs,pY~dp,ang1bs,ang2bs) + \
  Ang2_4(tie2bs,tie2bs,tie2bs,tie2bs) <-> \
  Tie1(pY~dp,loc~s,tie2bs!1).Tie2(tie1bs!1,loc~s,veptpbs,pY~dp,ang1bs,ang2bs!2).Ang2_4(tie2bs!2,tie2bs,tie2bs,tie2bs) konang2_4tie1tie2, koffang2_4tie1tie2
end reaction rules

# Receptor Cleavage and Clearance: Rules 70-73
begin reaction rules 
  # Tie1 and Tie2 Cleavage and Degradation
  # 70
  Tie2(tie1bs,loc~s,veptpbs,ang1bs,ang2bs) -> Tie2(tie1bs,loc~sol,veptpbs,ang1bs,ang2bs) kcleavetie2

  # 71
  Tie1(pY~dp,tie2bs,loc~s) -> Tie1(pY~dp,tie2bs,loc~sol) kcleavetie1

  # 72
  Tie2(tie1bs,loc~sol,veptpbs,ang1bs,ang2bs) -> Trash() kdegsTie2

  # 73
  Tie1(pY~dp,tie2bs,loc~sol) -> Trash() kdegstie1
end reaction rules

# Downstream Signaling - Akt: Rules 74-84
begin reaction rules  
  # PI3K, Akt
  # 74, 75
  PI3K(state~inactive) + Tie2(loc~j,pY~p) -> PI3K(state~active) + Tie2(loc~j,pY~p) kactPI3KTie2
  PI3K(state~active) -> PI3K(state~inactive)   kinactPI3KTie2

  # 76
  PI(PIsite~3P) -> Trash() kPIP2gen

  # 77
  PI3K(state~active) + PI(PIsite~3P)  -> PI3K(state~active) + PI(PIsite~4P)  kcatPI3KPIP2/(kmPIP2PI3K+freepip2)

  # 78
  PTEN(PIP3docking) + PI(PIsite~4P) -> PTEN(PIP3docking) + PI(PIsite~3P)  kcatPTENPIP3/(kmPIP3PTEN+freepip3)

  # 79
  PDK1(PHpdk1) + PI(PIsite~4P) <-> PDK1(PHpdk1!1).PI(PIsite~4P!1) konPDK1PIP3,koffPDK1PIP3
  
  # 80
  Akt(PHakt) + PI(PIsite~4P) <-> Akt(PHakt!1).PI(PIsite~4P!1) konAKTPIP3,koffAKTPIP3

  # 81
  Akt(PHakt!+,S473~S) -> Akt(PHakt!+,S473~pS)  kpmTORAKT

  # 82
  Akt(PHakt!+,S473~pS,T308~S) + PDK1(PHpdk1!+) -> \
  PDK1(PHpdk1!+) + Akt(PHakt!+,S473~pS,T308~pS) kpAKTPDK1

  # 83, 84
  Akt(S473~pS) ->   Akt(S473~S)   kdp473AKTPPase
  Akt(T308~pS) ->   Akt(T308~S)   kdp308AKTPPase
end reaction rules

# Downstream Signaling - RhoA, mDia: Rules 85-94
begin reaction rules
  # 85,86
  RhoA(G~GDP,mDiabs) + Tie2(loc~j,pY~p) ->  RhoA(G~GTP,mDiabs) + Tie2(loc~j,pY~p)  kprhoa
  RhoA(G~GTP,mDiabs) -> RhoA(G~GDP,mDiabs)  kdprhoa

  # 87,88
  RhoA(G~GTP,mDiabs)  + mDia(RhoAbs,srcbs) <-> RhoA(G~GTP,mDiabs!1).mDia(RhoAbs!1,srcbs) konrhoamdia,koffrhoamdia
  Src(mDiabs,Y1~Y) + RhoA(G~GTP,mDiabs!1).mDia(RhoAbs!1,srcbs) <-> Src(mDiabs!2,Y1~Y).RhoA(G~GTP,mDiabs!1).mDia(RhoAbs!1,srcbs!2) konmdiasrc,koffmdiasrc

  # 89
  Src(mDiabs,Y1~Y) <-> Src(mDiabs,Y1~pY) kpsrc, kdpsrc  
  
  # 90,91,92
  VECadherin(S665~S,c~j) + Src(mDiabs,Y1~pY) <-> VECadherin(S665~pS,c~j) + Src(mDiabs,Y1~pY) kpvecad, kdpvecad
  VECadherin(S665~pS,c~j) <-> VECadherin(S665~pS,c~i) kintvecad,krecvecad
  VECadherin(S665~pS,c~i) -> Trash() kdegvecad

  # 93,94
  ABIN2(state~inactive) + Tie2(loc~j,pY~p) -> ABIN2(state~active) + Tie2(loc~j,pY~p) kactabin2
  ABIN2(state~active) -> ABIN2(state~inactive)  kinactabin2
end reaction rules

end model

## actions ##
generate_network({overwrite=>1})
writeSBML({})