Bistable switching and excitable behaviour in the activation of Src at mitosis.
BACKGROUND
The protein tyrosine kinase Src is involved in a multitude of biochemical pathways and cellular functions. A complex network of interactions with other kinases and phosphatases obscures its precise mode of operation.


RESULTS
We have constructed a semi-quantitative computational dynamic systems model of the activation of Src at mitosis based on protein interactions described in the literature. Through numerical simulation and bifurcation analysis we show that Src regulation involves a bistable switch, a pattern increasingly recognised as essential to biochemical signalling. The switch is operated by the tyrosine kinase CSK, which itself is involved in a negative feedback loop with Src. Negative feedback generates an excitable system, which produces transient activation of Src. One of the system parameters, which is linked to the cyclin dependent kinase cdc2, controls excitability via a second bistable switch. This topology allows for differentiated responses to a multitude of signals. The model offers explanations for the existence of the positive and negative feedback loops involving protein tyrosine phosphatase alpha (PTPalpha) and translocation of CSK and predicts a specific relationship between Src phosphorylation and activity.
Fuss
Hendrik
H
University of Ulster, School of Biomedical Sciences, Cromore Road, Coleraine, BT52 1SA, Northern Ireland. fuss-h@ulster.ac.uk
Dubitzky
Werner
W
Downes
Stephen
S
Kurth
Mary Jo
MJ
D018797:Cell Cycle Proteins / Q000378:metabolism; D003198:Computer Simulation; D004789:Enzyme Activation; D020869:Gene Expression Profiling / Q000379:methods*; D008938:Mitosis / Q000502:physiology*; D008954:Models, Biological; D009097:Multienzyme Complexes / Q000378:metabolism*; D025941:Protein Interaction Mapping / Q000379:methods*; D015398:Signal Transduction / Q000502:physiology*; D019061:src-Family Kinases / Q000378:metabolism*
D018797:Cell Cycle Proteins; D009097:Multienzyme Complexes; D019061:src-Family Kinases