Explaining Response to Drugs Using Pathway Logic 259
Eif4ebp1-phos!S65,Eif4ebp1-phos!T37,Gsk3b-phos!S9,Gsk3s-phos!SFAE,
Rps6-phos!S235,Rps6-phos!S240,S6k1-phos!T412,andTsc2-phos!T1462in
response to AktI12 is explained by the unreachability of the corresponding occur-
rences. The increase in Irs1 protein expression is explained by the inhibition of
the degradation of Irs1 by ubiquitination and degradation in the proteasome.
The remaining changes are increases in protein expression of Cav1, Fn1, Pai1,
and Tp53 and a decrease in Cox2 and CyclinB1, which are not represented in
our model.
5.2 Effects of Temsirolimus
Temsirolimus (PubChemCID 23724530) inhibits Mtorc1 activity (a complex of
Mtor, Mlst8, and Raptor) but enhances Mtorc2 activity (a complex of Mtor,
Mlst8, Sin1, and Rictor) [ 5 ]. Figure 5 shows the annotated model of Temsirolimus
response.
The model explains measured decrease in events downstream ofMtorc1:
Eif4ebp1-phos!T37,Rps6-phos!S235,Rps6-phos!S240,S6k1-phos!T412,and
Irs1-degradation. It also explains measured increase in events that are down-
stream ofMtorc2:Akts-phos!FSY,Akts-phos!KTF.
The model also predicts increases inEif4ebp1-phos!S65@CLc(the data
shows a decrease) andGsk3s-phos!SFAE@CLc(the data shows no change). What
might cause this discrepancy? A common cause of such discrepancy is a miss-
ing control on the phosphorylation rule, either because there are no published
Mek1-act-phos!SMANS@CLc
014c
431c
Ybx1@CLc
3826c
Ybx1-phos!S102@CLc
Axin1@CLc
1340c
Ctnnb1-phos!S33-phos!S37-phos!S45-phos!T41@CLc
Raptor@CLc
916c
Raptor@CLcMlst8@CLc
Mtor@CLc
535c
Ctnnb1@CLc
1357c
Pld1@CLi
498c
Ctnnb1-phos!S45@CLc
Csnk1a1-act@CLc
Raptor@CLcMlst8@CLc
Mtor-act@CLc
Rps6-phos!S235-phos!S236@CLc
3815c
TRANSLATION-ON@Sig
Rps6-phos!S235-phos!S236-phos!S240-phos!S244@CLc
3815c-1
Akts-phos!FSY-phos!KTF@CLc
619c
Erks@CLc
Akts-act-phos!FSY-phos!KTF@CLc
1350c
1350c-1
819c 122c 3824c
3784c
Bim-phos!S69@CLc
3832c
Bim-phos!S69-ubiq@CLc
3833c
Rsk1-phos!S363-phos!S380-phos!T359@CLc
1001c
Rsk1-act-phos!S363-phos!S380-phos!T359@CLc
1648c
S6k1-phos!T252-phos!T412@CLc
885c
Rictor@CLc
BrafV600E@CLc
3808c
Sin1@CLc
Braf-act@CLc
Mlst8@CLcSin1@CLc
Mtor-act@CLcRictor@CLc
Irs1-phos!S1101-phos!S270-phos!S307-phos!S636-ubiq@CLc
3823c
Tsc2-phos!S540-phos!S664@CVcTsc1@CVc
1618c
Cul7@CLc
3822c
Tsc1@CVc
Fbxw8@CLc
Tsc2-phos!S540-phos!S664@CLc
Rbx1@CLcSkp1@CLc
Tsc2-phos!S540-phos!S664-phos!T1462@CVcTsc1@CVc
1618c-1
Tsc2-phos!S540-phos!S664-phos!T1462@CLc
3816c
Irs1-degraded@Sig
S6k1-act-phos!T252-phos!T412@CLc
3813c 1650c
3838c
Ctnnb1-phos!S33-phos!S37-phos!S45-phos!T41-ubiq@CLc
3830c
Btrc@CLc
Tp53-gene-on@NUc
3825c
Tp53-gene-off@NUc
Maz@NUc
Mlst8@CLc
472c
Mtor@CLc
Mlst8@CLcMtor@CLc
PIP2@CLm
3820c
PIP3@CLm
3818c
Pi3k@CLi
Pdpk1@CLc
Pdpk1-act@CLc
109c
109c-1
Bim-degraded@Sig
Proteasome@CLc
Ywhas@CLc Ctnnb1-degraded@Sig
Tsc2-phos!S540-phos!S664-phos!T1462@CLcYwhas@CLc
Rheb-GTP@CVc
1126c
Rheb-GDP@CVc
Tsc1@CVcTsc2@CVc
1617c Tsc1@CVc
1617c-1Tsc2-phos!T1462@CVc
Erks-act-phos!TEY@CLc
1647c
3831c
Eif4ebp1@CLc
911c
Eif4ebp1-phos!S65-phos!T37-phos!T46-phos!T70@CLc
654c
S6k1@CLc
S6k1-phos!T412@CLc
553c
Akts@CLc
632c 060c
Akts-phos!FSY@CLc
060c-1
Akts-phos!KTF@CLc
632c-1
Ilk-act@CLc
Eif4ebp1-phos!S65@CLc
Gsk3s-act@CLc
Rsk1@CLc
Irs1@CLc
Irs1-phos!S1101-phos!S270-phos!S307-phos!S636@CLc
Gsk3s-phos!SFAE@CLc
Rps6@CLc
Maz-phos!T385@NUc
Bim@CLc
Mek1@CLc
Occurrences in initial state
1126c Rules
Occurrence is changed
Occurrence is required
but unchanged
Cells treated with Temsirolimus
Occurrences decreased
in data
Occurrences increased
in data
Unreachable occurrences
Mtorc1 complex
formation and
activity is inhibited
Mtorc2 activity is
increased
Decrease in
phosphorylation of
Eif4ebp1-phos(S65)
Eif4ebp1-phos(T37/T46)
Rps6-phos(S235)
Rps6-phos(S240)
S6k1-phos(T412)
Decrease in Irs1
protein degradation
Increase in
phosphorylation of
Akts-phos(FSY)
Akts-phos(KTF)
Tsc2-phos(T1462)
Decrease in
phosphorylation of
Eif4ebp1-phos(S65)
GSKs-phos(SFAE)
not explained by the
model
Fig. 5.The SKMEL133 model treated with Temsirolimus.