Computational Methods in Systems Biology

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.