Project within the RTG
The role of the intrinsically disordered regions of the RNA-binding protein IGF2BP2 in metabolic-associated liver cancer
Insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs) are a family of RNA-binding proteins mainly involved in RNA stabilization and localization. IGF2BPs have two RNA-recognition motifs (RRMs) and four K-homology (KH) domains. In addition, an approximately 50 amino acids-long IDR links RRM2 and KH1 and contains two serine residues that have been described to be phosphorylated by mTOR, thereby promoting translation of IGF2 mRNA isoforms with extended 5’UTRs (Dai et al., 2011). Another, shorter IDR links KH2 and KH3. However, little is known about the functional significance of the IDRs, the mTOR-dependent phosphorylation of IGF2BP2, and the target mRNA spectrum modulated by this regulation. Moreover, knowledge about the role of the IDRs in the phosphorylation-dependent functions of IGF2BP2 is completely lacking.
Literature references
Dahlem, C., Abuhaliema, A., Kessler, S. M., Kröhler, T., Zoller, B. G., Chanda, S., … & Kiemer, A. K. (2022). First Small-Molecule Inhibitors Targeting the RNA-Binding Protein IGF2BP2/IMP2 for Cancer Therapy. ACS Chemical Biology, 17(2), 361-375.
Dai, N., Rapley, J., Angel, M., Yanik, M. F., Blower, M. D., & Avruch, J. (2011). mTOR phosphorylates IMP2 to promote IGF2 mRNA translation by internal ribosomal entry. Genes & Development, 25(11), 1159-1172.
Huang, S., Wu, Z., Cheng, Y., Wei, W., & Hao, L. (2019). Insulin-like growth factor 2 mRNA binding protein 2 promotes aerobic glycolysis and cell proliferation in pancreatic ductal adenocarcinoma via stabilizing GLUT1 mRNA. Acta Biochimica et Biophysica Sinica, 51(7), 743-752.
Kessler, S. M., Laggai, S., Barghash, A., Schultheiss, C. S., Lederer, E., Artl, M., … & Kiemer, A. K. (2015). IMP2/p62 induces genomic instability and an aggressive hepatocellular carcinoma phenotype. Cell Death & Disease, 6(10), e1894-e1894.
Kessler, S. M., Laggai, S., Van Wonterghem, E., Gemperlein, K., Müller, R., Haybaeck, J., … & Kiemer, A. K. (2016). Transient hepatic overexpression of insulin-like growth factor 2 induces free cholesterol and lipid droplet formation. Frontiers in Physiology, 7, 147.
Laggai, S., Kessler, S. M., Boettcher, S., Lebrun, V., Gemperlein, K., Lederer, E., … & Kiemer, A. K. (2014). The IGF2 mRNA binding protein p62/IGF2BP2-2 induces fatty acid elongation as a critical feature of steatosis[S]. Journal of Lipid Research, 55(6), 1087-1097.
Simon, Y., Kessler, S. M., Bohle, R. M., Haybaeck, J., & Kiemer, A. K. (2014). The insulin-like growth factor 2 (IGF2) mRNA-binding protein p62/IGF2BP2-2 as a promoter of NAFLD and HCC?. Gut, 63(5), 861-863.
Simon, Y., Kessler, S. M., Gemperlein, K., Bohle, R. M., Müller, R., Haybaeck, J., & Kiemer, A. K. (2014). Elevated free cholesterol as a hallmark of non-alcoholic steatohepatitis in p62/insulin-like growth factor 2 mRNA binding protein 2-2 transgenic animals. World Journal of Gastroenterology, 20, 17839-17850.
Tybl, E., Shi, F. D., Kessler, S. M., Tierling, S., Walter, J., Bohle, R. M., … & Kiemer, A. K. (2011). Overexpression of the IGF2-mRNA binding protein p62 in transgenic mice induces a steatotic phenotype. Journal of Hepatology, 54(5), 994-1001.
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