Biology subjects

Abdelnaby, A. E.

Publications and source records attributed to Abdelnaby, A. E..

4 recordsLinked to original sources

bioRxiv2026

A Quartet of Native Orai Channel Isoforms Orchestrates Graded NFAT Activation and Transcription

The Ca{superscript 2} release-activated Ca{superscript 2} (CRAC) channel mediates store-operated calcium entry (SOCE), a ubiquitous pathway essential for many cell types, including immune cells. Three Orai (Orai1/2/3) proteins constitute the plasma membrane pore-forming units of CRAC channels that are activated by the endoplasmic reticulum (ER) Ca2+-sensing STIM1/2 proteins when ER Ca2+ stores are depleted. Orai1/2/3 are differentially expressed across primary cells with discernible differences in their structures and biophysical properties. Further, Orai1 has two alternatively translated isoforms: long mammalian-specific Orai1 and the 63-residue shorter Orai1{beta}, which is evolutionarily older and conserved across vertebrates. Whether Orai1/1{beta}/2/3 produce unique cytosolic Ca{superscript 2} signatures that bias transcriptional responses through effectors like NFAT is unclear. Here, we used HEK293 cells engineered to express one native Orai isoform and show that all Orai isoforms couple to NFAT1/4 induction. The magnitude of NFAT1/4 induction for each Orai isoform matches that of SOCE, with the following profile: Orai1{beta}>Orai1>>Orai2>Orai3. Near-native re-expression of either Orai1 or Orai1{beta} in primary murine Orai1-/- CD4 T cells restored SOCE, NFAT activation, cytokine production and promoted near identical transcriptional responses enriched for immune activation pathways. An analysis of genetic and clinical data of human individuals showed that homozygous null mutations selectively abolishing Orai1 are not associated with disease resembling CRAC channelopathy. Primary T cells from individuals homozygous or heterozygous for an Orai1 null mutation showed enhanced, rather than impaired, SOCE and NFAT induction. Our data indicate that NFAT activation and transcriptional outputs are primarily driven by the graded strength of SOCE mediated by each isoform of the Orai quartet.

cell biology↗

bioRxiv2025

RHOV is a Detachment-Responsive Rho GTPase Necessary for Ovarian Cancer Peritoneal Metastasis

All ovarian cancer subtypes spread via transcoelomic metastasis, where cells disseminate into the peritoneal fluid, resist anoikis, and form multicellular aggregates that invade the peritoneum. This represents the main driver of morbidity and mortality for peritoneal cancer patients. Mechanisms necessary for cancer cells to survive matrix detachment and initiate transcoelomic metastasis remain poorly defined. To address this, we identified a conserved detachment-sensitive gene signature activated shortly after matrix-detachment across multiple ascites-derived cancer cell lines. RHOV, an atypical, constitutively active and understudied member of the Rho GTPase family, emerged as a top upregulated transcript, which was confirmed in patient ascites-derived tumor cells. Functionally, loss of RHOV impairs anoikis resistance, multicellular aggregate integrity, migration and invasion, and completely abolishes transcoelomic tumor progression in vivo. RHOV enhances c-Jun signaling and cytoskeletal remodeling, which is dependent on both RHOV GTP-binding and membrane localization. These findings define RHOV as a novel detachment-sensitive Rho GTPase and establish RHOV as a critical regulator of peritoneal metastasis for the first time.

cancer biology↗

bioRxiv2023

Loss of STIM2 in colorectal cancer drives growth and metastasis through metabolic reprogramming and PERK-ATF4 endoplasmic reticulum stress pathway

The endoplasmic reticulum (ER) stores large amounts of calcium (Ca2+), and the controlled release of ER Ca2+ regulates a myriad of cellular functions. Although altered ER Ca2+ homeostasis is known to induce ER stress, the mechanisms by which ER Ca2+ imbalance activate ER stress pathways are poorly understood. Stromal-interacting molecules STIM1 and STIM2 are two structurally homologous ER-resident Ca2+ sensors that synergistically regulate Ca2+ influx into the cytosol through Orai Ca2+ channels for subsequent signaling to transcription and ER Ca2+ refilling. Here, we demonstrate that reduced STIM2, but not STIM1, in colorectal cancer (CRC) is associated with poor patient prognosis. Loss of STIM2 causes SERCA2-dependent increase in ER Ca2+, increased protein translation and transcriptional and metabolic rewiring supporting increased tumor size, invasion, and metastasis. Mechanistically, STIM2 loss activates cMyc and the PERK/ATF4 branch of ER stress in an Orai-independent manner. Therefore, STIM2 and PERK/ATF4 could be exploited for prognosis or in targeted therapies to inhibit CRC tumor growth and metastasis. HighlightsO_LISTIM2 regulates ER Ca2+ homeostasis independently of Orai and SOCE. C_LIO_LISTIM2 downregulation in colorectal cancer cells causes enhanced ER Ca2+ and is associated with poor patient prognosis. C_LIO_LISTIM2 downregulation induces PERK/ATF4 dependent ER stress in colorectal cancer. C_LIO_LIIncreased ER stress drives colorectal cancer metabolic reprogramming, growth, and metastasis. C_LI

cancer biology↗

bioRxiv2023

Alternate splice variants of the mitochondrial fission protein DNM1L/Drp1 regulate mitochondrial dynamics and cell fate in ovarian cancer.

Aberrant mitochondrial fission/fusion dynamics have been reported in cancer cells. While post translational modifications are known regulators of the mitochondrial fission/fusion machinery, we show that alternative splice variants of the fission protein Drp1 (DNM1L) have specific and unique roles in cancer, adding to the complexity of mitochondrial fission/fusion regulation in tumor cells. Ovarian cancer specimens express an alternative splice transcript variant of Drp1 lacking exon 16 of the variable domain, and high expression of this splice variant relative to other transcripts is associated with poor patient outcome. Unlike the full-length variant, expression of Drp1 lacking exon 16 leads to decreased association of Drp1 to mitochondrial fission sites, more fused mitochondrial networks, enhanced respiration, and TCA cycle metabolites, and is associated with a more metastatic phenotype in vitro and in vivo. These pro-tumorigenic effects can also be inhibited by specific siRNA-mediated inhibition of the endogenously expressed transcript lacking exon 16. Moreover, lack of exon 16 abrogates mitochondrial fission in response to pro-apoptotic stimuli and leads to decreased sensitivity to chemotherapeutics. These data emphasize the significance of the pathophysiological consequences of Drp1 alternative splicing and divergent functions of Drp1 splice variants, and strongly warrant consideration of Drp1 splicing in future studies.

cancer biology↗