A Process Model of Rho GTP-binding Proteins

Luca Cardelli 1, 4 Emmanuelle Caron 2, 4

Philippa Gardner 3, 4 Ozan Kahramanoğulları 3, 4 Andrew Phillips 1

1. Microsoft Research Cambridge2. Centre for Molecular Biology and Infection, Imperial College

3. Department of Computing, Imperial College4. CISBIC, Imperial College

20.11.2007 – CISB’07, Newcastle

Overview

• Why Rho GTP-binding proteins?

• Why ‘a process model’?

• What are we doing?

• How are we doing?

• Outlook

Modelling FcR-mediated phagocytosis…

Opsinized particle binds Fc Receptor.

Src is activated.

Src phosphorylates two tyrosine residues on ITAM, which then recruits Syk-kinase.

Active Syk recruits Vav and activates it.

Vav activates Rac.

Cdc42 gets activated (somehow).

Cdc42 and Rac are Rho GTP-binding proteins

Rho GTP-binding proteins serve as switches that interact with their environment.

GEF and GAP are their regulators.

Etienne-Manneville & Hall. Nature 2002

Overview

• Why Rho GTP-binding proteins?

• Why ‘a process model’?

• What are we doing?

• How are we doing?

• Outlook

Why ‘a process model’?• Process algebra: used to study complex reactive systems

• Rich arsenal of mathematical techniques and tools available

• Biological systems process information: concurrent, reactive

• Complexation can be easily modeled, e.g., actin polymerization.

• Process algebra allow modular building of mechanistic models.

Compositionality:

Overview

• Why Rho GTP-binding proteins?

• Why ‘a process model’?

• What are we doing?

• How are we doing?

• Outlook

An ODE model of Rho GTP-binding Proteins

Overview

• Why Rho GTP-binding proteins?

• Why ‘a process model’?

• What are we doing?

• How are we doing?

• Outlook

Biological Processes as Computations

Rho GTP-binding Proteins with GEF and without GAP

Rho GTP-binding Proteins with GEF and without GAP

Rho GTP-Binding Proteins with GEF and GAP

Extending the Model with GDIs

Parameter analysis for the extended model

We vary the parameters of the processes for 4 GDI reactions between 10-4,…,104.

r1 =1, r2 =1 r1 =104, r2 =104 r1 =104, r2 =1 r1 =104, r2 =10-4 r1=1, r2 =10-4

and with varying r3 and r4, there is no effect on the inhibitory behavior of the GDIs.

r1=1, r2=104

r1=10-4, r2=104 r1=10-4, r2=10-4

Outlook

• A process model of Rho GTP-binding proteins.• Our model successfully mimics the ODE model.• We compositionally extend the model with GDIs. • Parameter estimation by hand (and automated?).• Rho GTP-binding proteins: experimental validation

of GDI and active Rho binding.• By composing this model with other components of

FcR-mediated phagocytosis, e.g., actin polymerisation, obtain a systems understanding.

• Reuse the Rho-GTP model as a template for Ras super-family proteins.

Acknowledgements

• Jaroslav Stark

• George Tzircotis

• Jeroen van Zon

• Simon Moon