Stabilization of IQGAP1 by the mTORC2 component PRR5 mediates mitogenic LINC01133-to-ERK signaling in triple-negative breast cancer
Menée à l'aide de lignée cellulaires, de sphéroïdes, de données de séquençage d'ARN et d'échantillons tumoraux de patientes atteintes d'un cancer du sein triple négatif, cette étude met en évidence un mécanisme par lequel la stabilisation, par le long ARN non codant LINC01133, de la sous unité PRR5 du complexe protéique mTORC2 favorise la croissance tumorale en activant la signalisation de la kinase AKT et en protégeant de la dégradation la protéine d'échafaudage IQGAP1, elle-même impliquée dans l'augmentation de la signalisation de la kinase ERK
Triple-negative breast cancers (TNBCs) lack targeted therapeutics that can inhibit their growth and progression. The long intergenic noncoding RNA LINC01133 promotes TNBC pathogenesis by increasing the abundance of proline-rich protein 5 (PRR5), an mTORC2 component that activates the kinase AKT in a PI3K-independent, mTORC2-dependent manner. Here, however, we found that TNBC cell proliferation was incompletely sensitive to AKT inhibitors alone because PRR5 also stimulated the mitogen-activated protein kinase (MAPK) cascade in an mTORC2-dependent manner. PRR5 associated with and prevented the ubiquitin-dependent proteasomal degradation of IQGAP1, an adaptor protein that promotes activation of the MAP kinase ERK. ERK signaling was essential for LINC01133-mediated TNBC proliferation in two- and three-dimensional cultures, and ERK inhibitors synergized with AKT blockade to suppress LINC01133-induced TNBC cell growth. Furthermore, PRR5 abundance was particularly enriched and correlated with that of phosphorylated ERK in samples from patients with TNBC. Our results highlight cross-talk between mTORC2 and ERK signaling downstream of LINC01133 and PRR5 that may be therapeutically targeted to treat TNBC. A lincRNA promotes TNBC growth by activating the kinases AKT and ERK through an mTORC2 component. High abundance of the long intergenic noncoding RNA LINC01133 promotes the growth of triple-negative breast cancer (TNBC) and activates AKT signaling through the mTORC2 component PRR5. However, Tu et al. found that AKT inhibitors alone were ineffective at suppressing TNBC cell proliferation. In addition to activating AKT, PRR5 stabilized by LINC01133 shielded the scaffold protein IQGAP1 from proteasomal degradation, leading to enhanced ERK signaling. Combining AKT and ERK inhibitors effectively suppressed clonogenic and three-dimensional spheroid growth in multiple TNBC cell lines, suggesting that this combination of drugs or the development of PRR5-targeted therapeutics might be effective in patients. —Leslie K. Ferrarelli
Science Signaling , résumé, 2026