International Clinical and Medical Case Reports Journal (ISSN: 2832-5788) | Volume 2, Issue 2 | Research Article | Open Access
Alex Sobko*
8762728, Ofakim, Israel. Previously at The Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, 76100, Israel.
*Correspondence to: Alex Sobko
Fulltext PDFWe characterized dynamic localization, PTMs and activities of MAP2K1/2 homologue in social slime mould Dictyostelium (DdMEK1), in which MAP kinase pathways play central role in directional cell migration (chemotaxis) and development. DdMEK1 is subject to SUMOylation and Ubiquitination in response to chemoattractant stimulation. We also identified SUMO-directed RING finger Ubiquitin ligase, which forms a complex with SUMOylated DdMEK1 and ubiquitinates this protein kinase. Specific lysine residue in DdMEK1, modified by SUMO, was mapped, and SUMOylation-deficient mutant was characterized and shown to affect DdMEK1 subcellular localization, cell motility and multicellular development. More recently, MAP2K1 SUMOylation was demonstrated in mammalian cells and the mutation eliminating MAP2K1 SUMOylation was shown to be associated with cancer phenotype. These mutations can be associated with de novo and inherited neurodevelopmental syndromes called Rasopathies, that exhibit the defects in cell proliferation, growth, and invasiveness. We applied machine learning Artificial Intelligence (AI) modeling approach developed by the laboratory of Dr. Jüri Reimand PhD, OICR Informatics and Biocomputing, to characterize and validate disease-associated mutations that affect MAP2K1/2 PTMs (https://activedriverdb.org). Certain sequence variants in MAP2K1/2 genes identified in the patient’s biobank samples world-wide were predicted to affect MAP2K1/2 SUMOylation and/or Ubiquitination. In our ongoing and future work, we set to study patient-derived IPSP-based, and non-transformed cells engineered to possess particular mutations in order to examine how individual mutations in MAP2K1/2 genes affect kinase localization, activity and PTMs (SUMOylation, Ubiquitination). We plan to apply base/prime CRISPR gene editing strategies (“PTM modifiers”) in order to eliminate those sequence variants that affect MAP2K1/2 SUMOylation and/or Ubiquitination and characterize cellular phenotypes.
RASopathies; Ras-MAP kinase pathway; mutations; Single Nucleotide Polymorphisms (SNPs); sequence variants; SUMOylation; Ubiquitination; Post-translational protein modifications (PTMs)
Alex Sobko. Artificial Intelligence-Predicted Impact of Sequence Variants on Post-Translational Protein Modifications in MAP Kinase Kinases MAP2K1/2 in Rasopathies. Int Clinc Med Case Rep Jour. 2023;2(2):1-10.