Biology subjects

Soroko, K.

Publications and source records attributed to Soroko, K..

3 recordsLinked to original sources

bioRxiv2026

A PI3K-RAC1 signaling axis downstream of mutant TIE2 promotes endothelial dysfunction in venous malformation

Background: Activating mutations in the endothelial receptor tyrosine kinase TIE2 are a cause of venous malformations (VMs), primarily through dysregulated PI3K/AKT signaling. However, the downstream mechanisms linking constitutively active mutant TIE2 to enlarged vascular lumens, endothelial dysfunction and VM remain incompletely understood. Here, we investigated the role of RAC1 signaling in mutant TIE2 p.L914F driven VM. Methods: Human umbilical vein endothelial cells (HUVECs) expressing wild-type TIE2 or constitutively active mutant TIE2-L914F were analyzed using RAC1 GTP pull-down assays, immunoblotting, and endothelial cell (EC) 2D and 3D functional assays. The role of RAC1 was evaluated using the RAC1 inhibitor NSC23766 in vitro and in vivo xenograft model of VM. Results & Conclusions: ECs expressing mutant TIE2-L914F showed increased active GTP-bound RAC1. TIE2-L914F ECs exhibited cytoskeletal changes with enhanced lamellipodia formation and maturation, accompanied by increased migration. Pharmacological inhibition of RAC1 significantly attenuated the aberrant vascular lumen area and migration in the mutant TIE2 ECs. Mechanistically, we showed that RAC1 hyperactivation is PI3K-dependent but not MEK/ERK-dependent. Consistent with these findings, RAC1 inhibition significantly reduced vascular lesion formation in a xenograft model of VM with TIE2-L914F ECs. Our study identifies RAC1 as a downstream mediator of TIE2-L914F driven endothelial dysfunction. These results establish a previously unrecognized PI3K-RAC1 signaling axis in the pathogenesis of TIE2-mutated VMs.

cell biology↗

bioRxiv2026

An endothelial-specific TIE2-L914F mouse model reveals cellular mechanisms of venous malformation progression and recapitulates the patient's response to targeted therapy

TIE2 p.L914F is the most common driver mutation of sporadic venous malformation (VM), a disease characterized by massively enlarged veins. The study of the molecular and cellular mechanisms contributing to TIE2-driven VM has been hindered by the lack of a genetic in vivo model. We generated a mouse system in which TIE2L914F is expressed postnatally in endothelial cells (EC). Mutant mice develop visible lesions with dilated veins with irregular smooth muscle cell coverage, histologically mimicking patients VM. With the use of an mCherry reporter we demonstrate that lesions form within the venous vasculature, and mutant ECs undergo clonal expansion fueled by a biphasic mechanism consisting of an early burst of proliferation followed by cell size increase. Targeted treatment with rapamycin partially reduces lesion growth by targeting increased proliferation and prolongs mouse survival, demonstrating this genetic murine model recapitulates the patients therapeutic response. Together, these findings provide new cellular and mechanistic insights into TIE2 p.L914F-driven venous malformation and establish a genetic platform for preclinical therapeutic studies.

cell biology↗

bioRxiv2025

Expression of mutant TIE2 p.L914F during mouse development causes embryonic lethality and defects in vascular remodeling

BackgroundSporadic venous malformation (VM) is associated with the hyperactivating p.L914F mutation in TIE2, a receptor tyrosine kinase essential for vascular development. This mutation is not found in hereditary VM, suggesting incompatibility with life when expressed during early vascular development. Therefore, we utilized a novel genetic mouse model that expresses TIE2 p.L914F to determine the phenotypical effects of this mutation during development. ResultsB6-Tg(Rosa26-TIE2L914F)EBos (TIE2L914F) mice were generated and then validated for the presence of the transgene. The constitutive endothelial-specific Tie2-Cre line was used to activate expression of the mutant gene during early embryonic development. Tie2-Cre;TIE2L914Fembryos experienced lethality at approximately embryonic day (E)9.5. 3-dimensional imaging of embryos and yolk sacs revealed impaired vascular remodeling in mutant animals, resulting in malformed vasculature with disorganized, dilated, and non-functional blood vessels. The abnormal vascular phenotype was not associated with total loss of erythroid cells or increased cell proliferation. ConclusionsThe TIE2L914F mice used in this study represent a novel genetic model of TIE2 p.L914F-driven vascular disease. This study provides the first experimental evidence that this mutation is incompatible with early prenatal development due to its deleterious effects on the vasculature, illustrating the vital role of TIE2 signaling during vessel development and remodeling.

developmental biology↗