Figure 9 (IMAGE)
Caption
Proposed model for the ibuprofen-inhibited expression of alternative spliced RAC1B. HT29 cells represent a subgroup of colorectal cancer cells, in which alternative splicing of the RAC1 pre-mRNA yields a second transcript that becomes translated into the tumor-promoting RAC1B protein variant. In these cells, a cytoplasmic protein complex composed of WNK1, GSK3β and SRPK1 assures that GSK3β can phosphorylate SRPK1, allowing its translocation into the nucleus. SRPK1 phosphorylates the splicing factor SRSF1, first in the cytoplasm to promote its nuclear translocation, and then inside the nucleus to retain SRSF1 so that it can bind to its specific recognition motif in exon 3b of the RAC1 pre-mRNA. This promotes exon 3b inclusion and subsequent expression of alternative spliced RAC1B. In the presence of ibuprofen or after experimental depletion of endogenous WNK1, the interaction between WNK1 and GSK3β is disrupted, leading to exposure of the N-terminal serine 9 of GSK3β, which is then phosphorylated by AKT1. This phosphorylation is inhibitory and prevents GSK3β from phosphorylating SRPK1. As a result, SRPK1 remains cytosolic, nuclear phosphorylation of SRSF1 is no longer sustained, and SRSF1 leaves the nucleus so that exon 3b is no longer recognized by the spliceosome.
Credit
Correspondence to - Peter Jordan - peter.jordan@insa.min-saude.pt
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Copyright: © 2020 Gonçalves et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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