Biology subjects

El Sayed, A. R.

Publications and source records attributed to El Sayed, A. R..

2 recordsLinked to original sources

bioRxiv2026

SHIP2-SRC-β-catenin signaling axis sustains thymidylate synthase expression and promotes fluoropyrimidine resistance.

Fluoropyrimidine-based chemotherapies, including 5-fluorouracil (5-FU) and floxuridine (FuDR), are widely used in cancer treatment, but their efficacy is limited by adaptive resistance driven by TYMS upregulation. The upstream mechanisms controlling TYMS expression remain poorly defined. Here, we identify INPPL1 (SHIP2) as a critical regulator of TYMS expression and fluoropyrimidine response in breast cancer cells. We show that SHIP2 enhances basal and drug-induced TYMS expression at the transcriptional level independently of its phosphatase activity. Mechanistically, SHIP2 increases SRC levels and nuclear accumulation of {beta}-catenin, driving TYMS expression. Inhibition of SRC or {beta}-catenin suppresses TYMS induction and restores sensitivity to FuDR. Importantly, SHIP2 rewires TYMS regulation from a P53-dependent program to a {beta}-catenin-driven pathway, enabling sustained TYMS expression under chemotherapeutic stress. Consistent with this model, differential sensitivity to SHIP2 depletion correlates with baseline TYMS levels across cell lines. Analysis of patient cancer datasets reveals that high INPPL1 expression correlates with increased TYMS levels and poor clinical outcomes. These findings identify SHIP2 as a non-canonical regulator of TYMS and a potential therapeutic target to overcome fluoropyrimidine resistance.

cancer biology↗

bioRxiv2026

SHIP2 oligomeric states and activity regulate cellular responses to sodium arsenate-induced stress granule dynamics.

Protein dimerization plays a central role in regulating enzymatic activity, signal transduction, and transcription factor function. Within the PI3K family, different modes of oligomerization have been reported. However, the oligomerization of lipid 5-phosphatases and its functional consequences have not been described. Here, we show for the first time that the lipid 5-phosphatase SHIP2 exists as a homodimer in cells, with its N-terminal region serving as the primary dimerization domain. We further demonstrate that SHIP2 dimerization has no major impact on its catalytic activity but instead profoundly affects its interactome. Interestingly, we identify the stress granule marker G3BP1 as one of the SHIP2 interactors whose association is moderately influenced by SHIP2 oligomerization states. Furthermore, we show that changes in SHIP2 protein levels, enzymatic activity, and oligomeric state alter the cellular response to sodium arsenate-induced stress. In addition, variation in SHIP2 levels and activity affects stress granule size and dynamics. Together, these findings identify SHIP2 oligomerization as a previously unrecognized regulatory mechanism linking phosphoinositide signaling to stress granule biology.

biochemistry↗