Die Rolle des hnRNPK-Signalkomplexes in Erk1/2-aktivierten Melanomzellen

• Applicant: Professor Dr. Andreas Baur
• Subject Area: Dermatology
• Term: from 2009 to 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 159234558

The long-term goal of our research is the analysis of molecular mechanisms in melanoma cells in order to discover new means of therapeutic intervention. In our first grant application we suggested to determine the role of the adapter protein hnRNPK in melanoma cells. We hypothesized that hnRNPK is involved in the activation of ADAM proteases, an important subclass of the matrixmetalloproteases. As demonstrated in our recent publication, we could confirm this assumption. We show that hnRNPK and the integrin-associated Paxillin protein serve as a signaling platform for the activation of two ADAM proteases, namely TNFalpha converting enzyme (TACE or ADAM17) and ADAM10. Almost all of 31 analyzed melanoma cell lines revealed activated ADAM10 and also activated (phosphorylated) Paxillin. Thus the activation of both markers seemed to be a common denominator of melanoma cells. Surprisingly also the polycomb protein Eed was identified as beeing directly involved in the activation of the ADAM proteases. Notably, all of these factors are activated through - or recruited by integrin receptors. These findings led to the conclusion that activated integrins recruit and form an ADAM-activating signaling complex. Based on own as well as published data we hypothesize that activation and increased expression of integrins in tumor cells leads to the recruitment of signaling proteins like hnRNPK and Paxillin, which then form the ADAM-activating signaling complex. In this grant proposal we intend to test this hypothesis. Furthermore we will investigate a possible link to a recently described signaling mechanism involving the interaction of Eed with nSMase2.

• DFG Programme: Research Grants