dictyNews
Electronic Edition
Volume 49, number 2
January 20, 2023
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Abstracts
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Artificial Intelligence-Predicted Impact of Sequence Variants on
Post-Translational Protein Modifications in MAP Kinase Kinases
MAP2K1/2 in Rasopathies
Alex Sobko
Corresponding author: Alex Sobko, 8762728, Ofakim, Israel.
Previously at The Department of Molecular Cell Biology, Weizmann
Institute of Science, Rehovot, 76100, Israel.
Int Clin Med Case Rep Jour. 2023;2(2):1-10.
https://tinyurl.com/4zm8estt
We 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 IPSC-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 toapply
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.
Submitted by Alex Sobko[[log in to unmask]]
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Expanding ring-shaped cleavage furrows in multi-nucleate cells
Mary Ecke1, Jana Prassler2, Günther Gerisch3*
1, 2, 3 Max Planck Institute of Biochemistry, Am Klopferspitz 18,
D-82152 Martinsried, Germany
*Corresponding author: [log in to unmask]
Molecular Biology of the Cell, in press
https://www.molbiolcell.org/doi/10.1091/mbc.E22-10-0487
Multi-nucleate cells of Dictyostelium discoideum divide usually
by unilateral cleavage furrows that ingress from the cell border.
Along their path into the cell, they follow regions that are rich
in myosin II and cortexillin and spare out the areas around the
spindle poles that are populated with microtubule asters. In cells
of a D. discoideum mutant that remain spread during mitosis we
observed, as a rare event, cleavage by the expansion of a hole
that is initiated in the middle of the cell area and has no connection
with the cell’s periphery. Here we show that these ring-shaped
furrows develop in two phases, the first being reversible. During
the first phase, the dorsal and ventral cell cortices come in close
apposition and the cell membrane detaches locally from the substrate
surface. The second phase comprises formation of the hole by
membrane fusion and expansion of the opening toward the border
of the cell, eventually cutting the multi-nucleate cell into pieces. We
address the 3-dimensional organization of ring-shaped furrows, their
interaction with lateral furrows, and their association with filamentous
myosin II and cortexillin. Thus, despite their geometrical divergence,
similar molecular mechanisms might link the expanding hole to the
standard contractile ring.
Submitted by Mary Ecke [[log in to unmask]]
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[End dictyNews, volume 49, number 2]
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