Computational Methods in Systems Biology

258 C. Talcott and M. Knapp

and Temsirolimus in some detail, and briefly summarize the results for the other
three drugs. Recall that the SKMEL133 model and a guided tour allowing the user
to reproduce these results and carry out other gedanken experiments are available
for download or in the Online collection at [ 13 ].

5.1 Effects of AktI12

AktI12 (PubChemCID 10196499) is a reversible allosteric inhibitor of Akt1 and
Akt2 which prevents the conformational change that permits phosphorylation
and activation [ 11 ]. To model the effect of AktI12 we use PLA to block (avoid)
the occurrenceAkts-act-phos!FSY-phos!KTF@CLcin the SKMEL133 dishnet.
Recall, this occurrence can be interpreted as Akt1 phosphorylated at S473/T308
and/or Akt2 phosphorylated at S474/T309 in the cytoplasm. Now we compute
the resulting reachable network, and compare it to the untreated model to deter-
mine what has become unreachable.
Figure 4 shows the explanation as an annotated version of network pro-
duced by PLA in the context of the unperturbed model. It shows how drug
perturbations interrupt the path between the initial state and the measured
goals. The key in the figure describes the color coding in detail. Yellow col-
oring highlights the unreachable part of the SKMEL133 dishnet. Occurrences
outlined in red are directly inhibited by the drug. Occurrences outlined in
green decrease in response to the drug. In particular the measured decrease in

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

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

Rictor@CLcMtor-act@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@CLc Skp1@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

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

Tsc2-phos!T1462@CVcTsc1@CVc

1617c-1

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

Rps6@CLc

Gsk3s-phos!SFAE@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 AktI12

Occurrences decreased

in data

Occurrences directly

inhibited by drugs

Unreachable occurrences phosphorylation are Akt activity and

inhibited by AktI12

Decrease in

phosphorylation of

Eif4ebp1-phos(S65)

Gsk3s-phos(SFAE)

Tsc2-phos(T1462)

Proteasome@CLc

Bim-degraded@Sig

Bim-phos!S69-ubiq@CLc

Decrease in

phosphorylation of

Eif4ebp1-phos(S65)

Rps6-phos(S235)

Rps6-phos(S240)

S6k1-phos(T412)

Decrease in Irs1

protein degradation

Fig. 4.The SKMEL133 model treated with AktI12.