Tyrosine Kinase Signaling by LTK at the Endoplasmic Reticulum: Relevance for Proteostasis, Secretion and Malignant Cell Growth

Our cells usually use 70% of their entire energy to make new proteins. Therefore, it is important to regulate the production and secretion of proteins because it is linked to several human diseases. Better understanding of how secretion is regulated can provide new insights into mechanisms that lead to human pathologies or may lead to new therapeutic strategies. This project investigates a protein called LTK and characterizes its role as a regulator of secretion. Furthermore, we will investigate the involvement of LTK in cancer and autoimmune conditions. Because LTK has an enzymatic activity, our research will set the basis for future development of drugs that modulate secretion to treat human pathologies. We found the LTK regulates protein secretion and that it can be inhibited using drugs that are currently approved in cancer therapy. Inhibition of LTK in myeloma cells results in cell death. Thus, we propose that LTK represents a useful terget in cancer therapy, which should be investigated in further detail in the future.

- Publications: The main highlights were the paper in Science and in the Journal of Cell Biology. In addition, further publications are under way based on this project. - Patent: as a consequence of our discoveries, we are now in the position to propose LTK as a therapeutic target in cancer. A patent has been filed on this subject. - Scientific impact: through the discoveries that were made in the course of this project we are proposing that LTK is the founding component of a totally new biologic process, which we will call the "Folded Protein Response". This has never been proposed before and only through our work on LTK and secretion did we appreciate this new role, which is currently being investigated in a new NFR-project.

Secretion is key component of cellular proteostasis, which is deregulated in a plethora of diseases such as cancer, neurodegeneration and many genetic disorders. The regulation of secretion by cellular signaling is an emerging, but incompletely understood research area. In particular, we know little about signaling circuits that originate from the secretory pathway to regulate protein trafficking. In this project, we will dissect how the receptor tyrosine kinase LTK regulates export from the endoplasmic reticulum (ER). Notably, LTK localizes to the ER and is activated by challenges to the proteostatic balance of the ER. Studying the role of LTK and its downstream signaling pathways will contribute to a better understanding of the regulation of the secretory pathway and thereby link signaling to proteostasis. Building on the relevance of secretion for cell growth survival, we will study the role of LTK and its downstream signaling pathways in the differentiation of B-lymphocytes towards plasma cells and the role of LTK in B-cell malignancies as well as in immunoglobulin secretion. Our work will be of high relevance for basic research, as it will establish LTK as a signaling first receptor tyrosine kinase that autochthonously signals at the ER. In addition, our work on B-lymphocytes will be of relevance for future efforts to establish LTK as a therapeutic target for B-cell malignancies and autoimmunity.