A1 Vertaisarvioitu alkuperäisartikkeli tieteellisessä lehdessä
SHANK3 depletion leads to ERK signalling overdose and cell death in KRAS-mutant cancers
Tekijät: Lilja, Johanna; Kaivola, Jasmin; Conway, James R. W.; Vuorio, Joni; Parkkola, Hanna; Roivas, Pekka; Dibus, Michal; Chastney, Megan R.; Varila, Taru; Jacquemet, Guillaume; Peuhu, Emilia; Wang, Emily; Pentikäinen, Ulla; Posada, Itziar Martinez D.; Hamidi, Hellyeh; Najumudeen, Arafath K.; Sansom, Owen J.; Barsukov, Igor L.; Abankwa, Daniel; Vattulainen, Ilpo; Salmi, Marko; Ivaska, Johanna
Kustantaja: Springer Science and Business Media LLC
Kustannuspaikka: BERLIN
Julkaisuvuosi: 2024
Journal: Nature Communications
Tietokannassa oleva lehden nimi: Nature Communications
Lehden akronyymi: NAT COMMUN
Artikkelin numero: 8002
Vuosikerta: 15
Numero: 1
Sivujen määrä: 20
eISSN: 2041-1723
DOI: https://doi.org/10.1038/s41467-024-52326-1
Verkko-osoite: https://doi.org/10.1038/s41467-024-52326-1
Rinnakkaistallenteen osoite: https://research.utu.fi/converis/portal/detail/Publication/458413344
The KRAS oncogene drives many common and highly fatal malignancies. These include pancreatic, lung, and colorectal cancer, where various activating KRAS mutations have made the development of KRAS inhibitors difficult. Here we identify the scaffold protein SH3 and multiple ankyrin repeat domain 3 (SHANK3) as a RAS interactor that binds active KRAS, including mutant forms, competes with RAF and limits oncogenic KRAS downstream signalling, maintaining mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) activity at an optimal level. SHANK3 depletion breaches this threshold, triggering MAPK/ERK signalling hyperactivation and MAPK/ERK-dependent cell death in KRAS-mutant cancers. Targeting this vulnerability through RNA interference or nanobody-mediated disruption of the SHANK3-KRAS interaction constrains tumour growth in vivo in female mice. Thus, inhibition of SHANK3-KRAS interaction represents an alternative strategy for selective killing of KRAS-mutant cancer cells through excessive signalling.The multidomain scaffold protein SH3 and multiple ankyrin repeat domain 3 (SHANK3) can bind GTP-bound Ras and Rap small GTPases. Here the authors show that, by binding active KRAS, SHANK3 maintains oncogenic KRAS/MAPK/ERK signaling at an optimal level while its depletion in KRAS-mutant cancer cell lines results in ERK signalling overdose and impaired cell proliferation.
Ladattava julkaisu This is an electronic reprint of the original article. |  |
Julkaisussa olevat rahoitustiedot:
The Cell Imaging and Cytometry Core (Turku Bioscience Centre, University of Turku) and Turku Centre for Disease Modelling (TCDM), both supported by Biocenter Finland, the Euro-BioImaging Finnish Node (Turku Finland), the University of Turku Histocore and Genome Editing core are acknowledged for services, instrumentation, and expertise. We also gratefully acknowledge CSC – IT Center for Science (Espoo, Finland) for providing ample computing resources. This work was supported by the Research Council of Finland through the following programs: an InFLAMES Flagship Programme (337530, UTU and 337531, Åbo Akademi), Research project grants (325464, J.I., and 331349, I.V.), Research Fellowships (338537 G.J. and 323096 E.P.), the CoE for Biological Barrier Mechanics and Disease (346131 & 364182, J.I., and 346135 & 364185, I.V.,). Additional funding was provided by an ERC consolidator (615258, J.I.) and a proof of concept grant (899155, J.I.), the Sigrid Juselius Foundation (J.I., G.J., E.P., and I.V.), the Finnish Cultural Foundation (J.L. and E.P), the Cancer Foundation Finland (J.I., M.S., G.J., and I.V.), the Frontier Science Program (RGP0059/2019, I.V.), the Helsinki Institute of Life Science (HiLIFE) Fellow program (I.V.), the Lundbeck Foundation (I.V.) and a Novo Nordisk pre-seed grant (J.I.). J.L., and J.K., were supported by the Turku Doctoral Programme of Molecular Medicine (TuDMM), J.L by the Instrumentarium Foundation, the Orion Research Foundation Sr and the K. Albin Johansson Foundation, and P.R. by the Drug Research Doctoral Programme at the University of Turku. J.R.W.C. was supported by the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement [841973] and a Research Council of Finland postdoctoral research grant (338585), M.D. by the European Union’s Horizon Europe research and innovation programme under Marie Sklodowska-Curie grant [101108089], M.C. by a Research Council of Finland postdoctoral research grant (343239) and AKN by CRUK Scotland Institute core funding (A17196, and A31287 - awarded to O.J.S.,). O.J.S., was supported by CRUK grants (A21139, A12481, A17196 and A31287) and an ERC Starting grant (311301).
