Computational modelling of ErbB family phosphorylation dynamics in response to transforming growth factor alpha and heregulin indicates spatial compartmentation of phosphatase activity.
Members of the ErbB receptor family are associated with several cancers and appear to be providing useful targets for pharmacological therapeutics for tumours of the lung and breast. Further improvements of these therapies may be guided by a quantitative, dynamic integrative systems understanding of the complexities of ErbB dimerisation, trafficking and activation, for it is these complexities that render difficult intuiting how perturbations such as drug intervention will affect ErbB signalling activities. Towards this goal, we have developed a computational model implementing commonly accepted principles governing ErbB receptor interaction, trafficking, phosphorylation and dephosphorylation. Using this model, we are able to investigate several hypotheses regarding the compartmental localisation of dephosphorylation. Model results applied to experimental data on ErbB 1, ErbB2 and ErbB3 phosphorylation in H292 human lung carcinoma cells support a hypothesis that key dephosphorylation activity for these receptors occurs largely in an intracellular, endosomal compartment rather than at the cell surface plasma membrane. Thus, the endocytic trafficking-related compartmentalisation of dephosphorylation may define a critical aspect of the ErbB signalling response to ligand.
Hendriks
B S
BS
Pathways Capability, AstraZenica R&D Boston, Waltham, MA 02451, USA.
Cook
J
J
Burke
J M
JM
Beusmans
J M
JM
Lauffenburger
D A
DA
de Graaf
D
D
D002460:Cell Line; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism*; D008657:Metabolic Clearance Rate / Q000187:drug effects; D008954:Models, Biological; D020890:Neuregulin-1 / Q000008:administration & dosage*; D018739:Oncogene Proteins v-erbB / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D010766:Phosphorylation / Q000528:radiation effects; D015398:Signal Transduction / Q000187:drug effects*; D016211:Transforming Growth Factor alpha / Q000008:administration & dosage*
D004338:Drug Combinations; D020890:Neuregulin-1; D018739:Oncogene Proteins v-erbB; D016211:Transforming Growth Factor alpha; D010744:Phosphoric Monoester Hydrolases