Olle Larsson's Group

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.

Dissertations

Natalia Natalishvili
IGF-1R : Studies on the expression and role in transformation
29 maj 2009
Abstract

Sandra Andersson
The many faces of IGF-1R from cell surface to the nucleus
22 maj 2009
Abstract

Linda Rosengren
Targeting the GH/IGF-1 axis with novel, small molecule inhibitors.
26 oktober 2007
Abstract

Bita Sehat
SUMO and ubiquitin : The Yin and Yang of IGF-1R function
25 oktober 2007
Abstract

Mario A Economou
Uveal melanoma and macular degeneration : Molecular biology and potential therapeutic applications
September 7, 2007
Abstract

Radu Vasilcanu
Regulation of insulin-like growth factor-1 receptor expression and signaling.
June 15, 2007
Abstract

Daiana Vasilcanu
IGF-1R inhibition : A tool for functional studies of insulin-like growth factor family in malignant cells.
February 3, 2006
Abstract

Ada Girnita
Targeting insulin-like growth factor-1 receptor in cancer
October 15, 2004
Abstract

Maria Törnkvist
Synovial sarcoma : molecular, biological and clinical implications
September 3, 2004
Abstract

Leonard Girnita
Growth factor pathways in human cancer : Functional and therapeutic implications.
October 25, 2002
Abstract

Charlotta All-Ericsson
Uveal melanoma : Cytogenetics, molecular biology and tumor immunology.
October 4, 2002
Abstract

Yuntao Xie
The biological role and clinical impact of SYT-SSX fusion gene and IGF-1R in synovial sarcoma
June 12, 2002
Abstract

Group members

Olle Larsson, MD, Professor, Group leader
Thomas Strömberg, MD, PhD, Researcher
Yingbo Lin, PhD
Dudi Warsito, Postdoc
Sylvia Packham, Postdoc
Ahmed Waraky, PhD student
Maria Fili, PhD student

Selected publications

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