Our research
The insulin-like growth factor 1 receptor (IGF-1R) is an evolutionarily very ancient receptor tyrosine kinase (RTK). IGF-1R is a heterotetramer consisting of two ligand-binding extracellular alpha-subunits and two beta-subunits composing of a transmembrane domain, an intracellular tyrosine kinase domain, and a C-terminal tail. Ligand (IGF-1 or IGF-2) binding induces tyrosines within the TK domain to be trans-phosphorylated by the dimeric subunit partner.
During the last 15 years it has becoming increasingly evident that the IGF-1R is crucial for tumor transformation, cancer cell growth, tumor progression, and therapy resistance. IGF-1R is expressed in almost all types of malignancies and generally the receptor levels are substantially higher in cancer compared to normal tissues. Accordingly, IGF-1R is currently being one of the most promising targets for modern cancer treatment.
The mechanisms underlying the fundamental roles of IGF-1R in cancer biology are still not well understood. Actually, IGF-1R shares the major signaling pathways with many RTKs, like the insulin receptor isoform B (IR-B) which is not important for tumor growth. Probably, IGF-1R promotes alternative IGF-1R signaling and actions in cancer cells. Since several years ago we have sought to disclose novel and alternative IGF-1R mechanisms with relevance to cancer cell growth. We have e.g. demonstrated ubiquitination of the receptor and that this modification promotes MAPK/ERK signaling and cell cycle progression, and we have identified two involved E3-ligases (enzymes catalysing ubiquitination) with distinct mode of actions.
Our recent finding that IGF-1R undergoes SUMOylation, leading to its nuclear accumulation and gene activation by binding to enhancer regions, constitutes a novel and alternative regulatory mechanism for the receptor. The SUMOylation sites of IGF-1R were identified as three evolutionarily conserved lysine residuesLys1025, Lys1100, and Lys1120in the b-subunit of the receptor. If these SUMO sites were mutated the IGF-1R could not accumulate in the cell nucleus and enhance transcription. The whole receptor, the heterotetramer, was shown to undergo SUMO-dependent translocation to the cell nucleus. Our findings represent a breakthrough in IGF-1R research and have potentially wide implications for cell signaling.
Our current research focuses on role of nuclear IGF-1R in the cancer cell. The long-term aims are to develop improved diagnostic and therapeutic tools using IGF-1R as a target.