3 February 2011 00:00 hrs.
From Molecules to Patients - Information Processing through the Erthyropoietin Receptor as Paradigm.

Ursula Klingmüller, PhD, Division Systems Biology of Signal Transduction German Cancer Research Center (DKFZ), Heidelberg, Germany


Prof. Roland Brock

03-02-2011 00:00:00Europe/AmsterdamFrom Molecules to Patients - Information Processing through the Erthyropoietin Receptor as Paradigm.

Remarks / more information:

Ursula KingmullerProliferation and differentiation of mammalian cells are tightly regulated by the coordinated activation of multiple signaling pathways. Loss of control promotes tumor progression. The components of many signaling cascades have been identified, yet mechanisms that facilitate information processing and coordinate cellular decisions are unresolved. To elucidate general design principles regulating cell fate decisions and to link them to effects at the tissue level, it is essential to integrate the dynamic behavior of signaling pathways, gene regulatory networks and physiological responses. The hormone erythropoietin (Epo), in conjunction with its cognate receptor the EpoR, is a key regulator in the hematopoietic system facilitating proliferation, survival and differentiation of erythroid progenitor cells. However in addition the EpoR is expressed on cancer cell lines and the treatment with Epo has been linked with an adverse outcome for certain tumors such as lung cancer.

By data-based mathematical modeling we showed that key dynamic properties of the Epo/EpoR system are rapid ligand depletion and recovery of the receptor on the cell surface. The model indicated that rapid receptor turnover facilitates linear signal integration for a broad range of ligand concentrations that are characteristic for the Epo/EpoR system. This notion was experimentally validated assigning an essential role to the large intracellular receptor pools. Furthermore, we identified a panel of lung cancer cell lines that express a signaling competent EpoR and showed that ligand depletion is retained but at a different time scale.

The goal is to link our mechanistic insights into EpoR signaling to physiological responses and, through integration in multi-scale models, gain access to predicting the behavior at the organ level.

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