Olle Larsson's Group
Studies on insulin-like growth factor 1 receptor (IGF-1R) and its role in malignant cell growth. IGF-1R is critical for malignant cell growth but is not an absolute requirement for normal cells. Our research attempts to identify mechanisms responsible for the critical roles of IGF-1R in cancer as well as to develop selective anti-IGF-1R agents for tumor treatment.
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.
IGF-1R : Studies on the expression and role in transformation
29 maj 2009
The many faces of IGF-1R from cell surface to the nucleus
22 maj 2009
Targeting the GH/IGF-1 axis with novel, small molecule inhibitors.
26 oktober 2007
SUMO and ubiquitin : The Yin and Yang of IGF-1R function
25 oktober 2007
Mario A Economou
Uveal melanoma and macular degeneration : Molecular biology and potential therapeutic applications
September 7, 2007
Regulation of insulin-like growth factor-1 receptor expression and signaling.
June 15, 2007
IGF-1R inhibition : A tool for functional studies of insulin-like growth factor family in malignant cells.
February 3, 2006
Targeting insulin-like growth factor-1 receptor in cancer
October 15, 2004
Synovial sarcoma : molecular, biological and clinical implications
September 3, 2004
Growth factor pathways in human cancer : Functional and therapeutic implications.
October 25, 2002
Uveal melanoma : Cytogenetics, molecular biology and tumor immunology.
October 4, 2002
The biological role and clinical impact of SYT-SSX fusion gene and IGF-1R in synovial sarcoma
June 12, 2002
Picropodophyllin causes mitotic arrest and catastrophe by depolymerizing microtubules via insulin-like growth factor-1 receptor-independent mechanism.
Waraky A, Akopyan K, Parrow V, Strömberg T, Axelson M, Abrahmsén L, et al
Oncotarget 2014 Sep;5(18):8379-92
Nuclear translocation of IGF-1R via p150(Glued) and an importin-β/RanBP2-dependent pathway in cancer cells.
Packham S, Warsito D, Lin Y, Sadi S, Karlsson R, Sehat B, et al
Oncogene 2015 Apr;34(17):2227-38
Nuclear IGF1R is a transcriptional co-activator of LEF1/TCF.
Warsito D, Sjöström S, Andersson S, Larsson O, Sehat B
EMBO Rep. 2012 Mar;13(3):244-50
Local control of nuclear calcium signaling in cardiac myocytes by perinuclear microdomains of sarcolemmal insulin-like growth factor 1 receptors.
Ibarra C, Vicencio JM, Estrada M, Lin Y, Rocco P, Rebellato P, et al
Circ. Res. 2013 Jan;112(2):236-45
SUMOylation mediates the nuclear translocation and signaling of the IGF-1 receptor.
Sehat B, Tofigh A, Lin Y, Trocmé E, Liljedahl U, Lagergren J, et al
Sci Signal 2010 Feb;3(108):ra10