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Signal."],"published-print":{"date-parts":[[2026,2,10]]},"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.1126\/scisignal.adr4063","type":"journal-article","created":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T18:58:21Z","timestamp":1770749901000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":1,"title":["Stabilization of IQGAP1 by the mTORC2 component PRR5 mediates mitogenic LINC01133-to-ERK signaling in triple-negative breast cancer"],"prefix":"10.1126","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3720-7844","authenticated-orcid":true,"given":"Zhenbo","family":"Tu","sequence":"first","affiliation":[{"name":"Department of Pathology and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leah","family":"Moses","sequence":"additional","affiliation":[{"name":"Department of Pathology and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8724-2763","authenticated-orcid":true,"given":"Yi","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Pathology and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-4944-5814","authenticated-orcid":true,"given":"Sworaj","family":"Sapkota","sequence":"additional","affiliation":[{"name":"Department of Pathology and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liza M.","family":"Quintana","sequence":"additional","affiliation":[{"name":"Department of Pathology and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leismi","family":"Guerrero","sequence":"additional","affiliation":[{"name":"Department of Pathology and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6826-2507","authenticated-orcid":true,"given":"George W.","family":"Bell","sequence":"additional","affiliation":[{"name":"Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0634-7510","authenticated-orcid":true,"given":"Antoine E.","family":"Karnoub","sequence":"additional","affiliation":[{"name":"Department of Pathology and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA."},{"name":"Harvard Stem Cell Institute, Cambridge, MA 02138, USA."},{"name":"Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA."},{"name":"Boston Veterans Affairs Healthcare System, Boston, MA 02132, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21763"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/dju055"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2018.19323"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2203180119"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2019.11.014"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1002\/stem.3055"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20070540"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.227694"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.444182"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41418-020-00708-5"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2017.00132"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2022.05.027"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdz133"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13058-020-01354-y"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aao3810"},{"key":"e_1_3_2_17_2","first-page":"3065","article-title":"Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer","volume":"118","author":"Carracedo A.","year":"2008","unstructured":"A. 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