SUMOylation mediates the nuclear translocation and signaling of the IGF-1 receptor.
The insulin-like growth factor 1 receptor (IGF-1R) plays crucial roles in developmental and cancer biology. Most of its biological effects have been ascribed to its tyrosine kinase activity, which propagates signaling through the phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways. Here, we report that IGF-1 promotes the modification of IGF-1R by small ubiquitin-like modifier protein-1 (SUMO-1) and its translocation to the nucleus. Nuclear IGF-1R associated with enhancer-like elements and increased transcription in reporter assays. The SUMOylation sites of IGF-1R were identified as three evolutionarily conserved lysine residues-Lys(1025), Lys(1100), and Lys(1120)-in the beta subunit of the receptor. Mutation of these SUMO-1 sites abolished the ability of IGF-1R to translocate to the nucleus and activate transcription but did not alter its kinase-dependent signaling. Thus, we demonstrate a SUMOylation-mediated mechanism of IGF-1R signaling that has potential implications for gene regulation.
1Department of Oncology and Pathology, Karolinska Institutet, Cancer Center Karolinska, R8:04, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
Bita
B
Sehat
Ali
A
Tofigh
Yingbo
Y
Lin
Eric
E
Trocmé
Ulrika
U
Liljedahl
Jens
J
Lagergren
Olle
O
Larsson
D021581:Active Transport, Cell Nucleus; D002467:Cell Nucleus / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008239:Lysine / Q000737:chemistry; D020935:MAP Kinase Signaling System; D008545:Melanoma / Q000378:metabolism; D008954:Models, Biological; D009154:Mutation; D011487:Protein Conformation; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000378:metabolism
D017526:Receptor, IGF Type 1; D008239:Lysine