Systems biology of JAK/STAT signalling.

Signalling in multicellular organisms is mediated by complex networks that integrate extracellular and intracellular signals to generate appropriate responses regulating cell proliferation, differentiation and survival. Downstream of many cytokine and growth hormone receptors, receptor-associated JAKs (Janus kinases) activate transcription factors of the STAT (signal transducer and activator of transcription) protein family and thereby mediate signal transduction from the plasma membrane to the nucleus. The JAK/STAT pathway has been shown to be constitutively activated in a wide array of human malignancies. To elucidate mechanisms contributing to tumour formation and identify system properties of the JAK/STAT signalling pathway, a systems biology approach can be employed. So far the majority of studies available have focused on down-regulation of the signalling pathway based on simulations. However, a data-based model of the core module of the JAK2/STAT5 signalling pathway showed that rapid nucleocytoplasmic cycling of STAT5 is an essential pathway property. In the future, combining assays for quantitative analysis at different levels will be important to gain deeper insight into molecular mechanisms regulating intracellular communication mediated by such complex dynamic systems as signalling pathways and their targets.