Supplementary Information
Table S1: Description of key nodes of the model.
Node / Equation / Mechanism and Assumption / References /Hsp90-CDC37 binding / CDC37 + Hsp90 = Hsp90_CDC37 / This is modeled as reversible mass action kinetics
The Kd for the interaction of CDC37 and Hsp90 has been taken as 2.5uM / (Siligardi et al. 2004; Zhang et al. 2004; Roe et al. 2004)
Hsp90-CDC37 complex binding to AKT1 / Hsp90_CDC37 + AKT1_Par_Act = Hsp90_CDC37_AKT1_Par_Act / This is modeled as reversible mass action kinetics
The kinetics has been optimized. It has been assumed that Hsp90 binds to all the protein kinases with the same affinity. / (Lawlor and Alessi, 2004; Schulte et al. 1995)
Hsp90-ATP-AKT1 hydrolysis / Hsp90_ATP_AKT1_Par_Act = AKT1_Act + Pi + Hsp90_ADP / This is modeled as reversible mass action kinetics
The value for kf has been optimized to 0.15 sec-1 as against 1.5E-3 sec-1 as mentioned in the literature and the value of Kr has also been optimized / (Kamal et al. 2004)
Hsp90-CDC37-RAF1 binding / Hsp90_CDC37 + RAF1 = Hsp90_CDC37_RAF1 / This is modeled as reversible mass action kinetics
The binding affinity for all the protein kinase to the Hsp90_CDC37 complex has been assumed to be same. / (Kamal et al. 2003; Roe et al. 2004)
ATP binding to the Hsp90-CDC37-RAF1 complex / Hsp90_CDC37_RAF1 + ATP = Hsp90_ATP_RAF1 + CDC37 / This is modeled as reversible mass action kinetics
This is the reaction node where the generic inhibitor would act / (Sato et al. 2000; Roe et al. 2004)
HRAS-GTP mediated activation of RAF1 / Hsp90_ATP_RAF1 = Hsp90_ATP_RAF1p / This is modeled as a modified Michaelis Menten reaction. / (Kholodenko, 2000)
Hsp90 deacetylation by HDAC6 / Hsp90 = Hsp90_Da / This is modeled as a simple Michealis Menton equation
The Km and Kcat values have been assumed. / (Yang et al. 2006)
Deacetylated Hsp90 binding to EGFR / Hsp90_Da + EGFR = Hsp90_Da_EGFR / This is modeled as reversible mass action kinetics
The Kinetic parameters have been optimized. It has been assumed that all the growth factors bind to Hsp90 with the same binding affinities with a Kd of 0.02 uM. The value of Kd has been optimized / (Yang et al. 2006)
EGFR-EGFL6 binding / EGFL6 + EGFR = EGFL6_EGFR / This is modeled as reversible mass action kinetics / (Kholodenko, 2000)
Hsp90 binding to IGF-1R / Hsp90 + IGF1R = IGF1R_Hsp90 / This is modeled as reversible mass action kinetics
It has been assumed that all the growth factors bind to Hsp90 with the same binding affinities with a Kd of 0.02 uM. The value of Kd has been optimized. / (Di Paola et al. 2006)
IGF-1R binding to its ligand IGF1 / IGF1R + IGF1 = IGF1_IGF1R / This is modeled as reversible mass action kinetics
here the data are taken as same as that of EGF binding to its receptor. / (Kholodenko, 2000)
IGF1-IGF-1R mediated activation and phosphorylation of IRS / IRS = IRSp / This is modeled as modified Michaelis Menten reaction
The kinetics have been assumed / (Rui et al. 2001)
IRSp binding to PI3k and activation / PIK3R1_InAct + IRSp = PI3KR1_InAct_IRSp / This is modeled as reversible mass action kinetics / (Kim et al. 1999)
Hsp90 binding to HER2/ERBB2 / Hsp90 + ERBB2_Inact = Hsp90_ERBB2_Inact / This is modeled as reversible mass action kinetics / (Hellyer et al. 2001)
Hsp90-ATP binding / Hsp90 + ATP = Hsp90_ATP / Bi-substrate Michaelis Menten reaction / (McLaughlin et al. 2002; Siligardi et al. 2002; Banerji et al. 2005)
Hsp90-ATP complex binding to p23 and immunophilin / IP + p23 + Hsp90_ATP = Hsp90_ATP_p23_IP / This is modeled as reversible mass action kinetics
The kinetics has been assumed / (Pratt and Toft, 2003)
Hsp70 binding to ATP / ATP + Hsp70 = Hsp70_ATP / This is modeled as reversible mass action kinetics
The kinetics has been assumed / (Pratt and Toft, 2003)
Hsp40 binding to HIP / Hsp40 +HIP= HSp40_HIP / This is modeled as reversible mass action kinetics
The kinetics has been assumed / (Pratt and Toft, 2003)
Hsp40-Hip complex binding to Hsp70-ATP complex / Hsp40_HIP + Hsp70_ATP = Hsp40_HIP_Hsp70_ADP / This is modeled as reversible mass action kinetics
This binding activates the ATPase activity for Hsp70 / (Pratt and Toft, 2003)
Hsp70-Hip-Hsp40 complex binding to Hsp90 bound to HOP / Hsp90_HOP + Hsp40_Hip_Hsp70_ADP = Hsp90_HOP_Hsp70_Hsp40_Hip / This is modeled as reversible mass action kinetics
This binding activates the ATPase activity for Hsp70 / (Pratt and Toft, 2003)
Hsp90-Hsp70 complex binding to mutant TP53 / Hsp90_ATP_Hsp70_Hsp40 + mTP53c = Hsp90_ATP_Hsp70_Hsp40_mTP53c / This is modeled as reversible mass action kinetics
It has been assumed that p53 also binds to Hsp90 with the same affinity as AKT or RAF1 / (Pratt and Toft, 2003)
P23 and IP binding to the Hsp90-hsp70-mTP53 complex / Hsp90_ATP_Hsp70_Hsp40_TP53c + p23 + Cyp40 = Hsp40 + Hsp70 + Hsp90_ATP_TP53c_p23_Cyp40 / This is modeled as reversible mass action kinetics
The Kd for the interaction of p23 with Hsp90 is 1.5 uM.
This interaction results in the formation of the mature complex / (Siligardi et al. 2004)
Hsp90 binding to CDK4 / Hsp90_CDC37 + CDK4 = Hsp90_CDC37_CDK4 / This is modeled as reversible mass action kinetics
It has been assumed that CDK4 also binds to Hsp90 with the same affinity as AKT or RAF1 / (Siligardi et al. 2002; Banerji et al. 2005; Stepanova et al. 1996)
List of Abbreviations:
ATP – Adenosine tri phosphate
ADP – Adenosine di phosphate
Pi – Inorganic phosphate
Hsp90 - Heat shock protein 90
Hsp70 - Heat shock protein 70
Hsp40 - Heat shock protein 40
HIP- Hsp70 interacting protein
HOP: Hop factor
IP – immunophilins
CDC37 - cell division cycle 37 homolog
CCND1 – CyclinD1
TP53 – p53 Tumor suppressor protein
mTP53 – mutant TP53
EGFR – Epidermal growth factor receptor
IGF-1R – Insulin growth factor receptor-1
HER2/ ERBB2 - Human Epidermal growth factor Receptor 2
CDK4 - Cyclin dependent kinase 4
IRS – Insulin receptor substrate
RAF1 - v-raf-1 murine leukemia viral oncogene homolog 1