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

Vår celler bruker vanligvis 70% av hele energien sin for å lager nye proteiner. Derfor er det viktig å regulerer produksjon og sekresjon av proteiner fordi det er knyttet til flere sykdommer. Bedre forståelse hvordan sekresjon reguleres kan gi nye innsikter i mekanismer som fører til sykdommer eller kan fører til nye terapeutiske strategier. Dette prosjektet undersøker et protein (LTK) og karakteriserer sin rolle som regulator av sekresjon. I tillegg skal vi undersøke involvering av LTK i kreft og autoimmune tilstander. Fordi LTK har enzymatisk aktivitet, vil vår forskning satt grunnlaget for fremtidig utvikling av legemidler som modulerer sekresjon å behandle menneskelige sykdommer. Vi fant ut at LTK regulerer sekresjon av proteiner og at LTK kan hemmes av medikamenter som brukes i kreftterapi. Hemming av LTK i myelomatose celler fører til celledød. Derfor foreslår vi at LTK kan betraktes som en mulig målprotein i kreftterapi som må undersøkes i fremtiden.

- 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.