Abstract LB451: Leukemia associated RhoGEF (LARG/ARHGEF12) phosphorylation at S1288 induces LARG plasma membrane localization and its ability to bind RhoA

Abstract Leukemia-associated RhoGEF (LARG) is a guanine nucleotide exchange factor (GEF) known for its specificity towards RhoA. LARG plays a crucial regulatory role in various cellular processes such as migration, proliferation, invasion, and metastasis by facilitating the exchange of GDP to GTP on RhoA. Activation of LARG at S1288 through phosphorylation by active RSK2 is key to triggering RhoA activation. However, the precise mechanism through which this phosphorylation event influences LARG and enhances the activation of the LARG-RhoA complex at S1288 remains unclear. Herein, we present findings demonstrating the essential role of S1288 phosphorylation in facilitating LARG-mediated invasiveness in response to Epidermal Growth Factor (EGF). Upon EGF stimulation, phosphorylation of LARG at S1288 is triggered by the activation of RSK2, thereby promoting the membrane translocation of LARG. Furthermore, phosphorylation of LARG at S1288 markedly enhances the assembly of the LARG-RhoA complex and RhoA activity. Analysis of patient-derived Glioblastoma Multiforme (GBM) cell lines and GBM tissue samples revealed a significant correlation between RSK activity, LARG S1288 phosphorylation and RhoA-GTPase activity. Elucidating the regulatory mechanisms governing this process is crucial for the development of targeted therapeutic interventions. Citation Format: Steven D. Scahill, Won Seok Yang, Joe Ramos. Leukemia associated RhoGEF (LARG/ARHGEF12) phosphorylation at S1288 induces LARG plasma membrane localization and its ability to bind RhoA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB451.