Global analysis of the biophysical properties of ErbB4

The cell membrane contains receptors whose activation by growth factors induces cells to undergo differentiation or cell proliferation. Understanding of these processes is of utmost importance since both normal ontogeny and organogenesis as well as cancer development are determined by the balance or lack of balance of these signals. The epidermal growth factor (EGF) receptor, also known as ErbB1, has been well characterized at the molecular level in terms of the activation mechanism. It has been established that EGF-induced dimerization of ErbB1 functions as an activation switch, and the same principle has been identified to function for another member of the receptor family, ErbB4. Since detailed molecular characterization of ErbB4 has not been carried out, we propose to investigate the formation of dimers and higher-order clusters in resting and growth factor stimulated cells and to link these events to transmembrane signaling. We plan to join the competences of the Hungarian and Austrian collaboration partners to build upon recent advances in microscopic approaches, which permit the interrogation of single molecules allowing unprecedented insight into these kinds of molecular events. Such a combination of approaches can provide a detailed quantitative model for the activation of the ErbB4 receptor. The receptor planned to be studied in our project, ErbB4, has been shown to play an important role in the development of one of the most malignant tumors, melanoma. Given the importance of receptor interactions in the activation of cells our results can pinpoint diagnostic and therapeutical targets against this devastating disease.