[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-333769-105":59,"doc-detail-333769-en":130},{"code":4,"msg":5,"data":6},0,"success",[7,13,18,23,28,33,38,43,48,51,55],{"id":8,"doc_module":4,"doc_module_name":9,"category_name":10,"show_sort_weight":11,"slug":12},1,"Document","Story & Novel",90,"story-novel",{"id":14,"doc_module":4,"doc_module_name":9,"category_name":15,"show_sort_weight":16,"slug":17},2,"Literature",80,"literature",{"id":19,"doc_module":4,"doc_module_name":9,"category_name":20,"show_sort_weight":21,"slug":22},4,"Exam",70,"exam",{"id":24,"doc_module":4,"doc_module_name":9,"category_name":25,"show_sort_weight":26,"slug":27},5,"Comic",60,"comic",{"id":29,"doc_module":4,"doc_module_name":9,"category_name":30,"show_sort_weight":31,"slug":32},6,"Technology",50,"technology",{"id":34,"doc_module":4,"doc_module_name":9,"category_name":35,"show_sort_weight":36,"slug":37},7,"Healthcare",40,"healthcare",{"id":39,"doc_module":4,"doc_module_name":9,"category_name":40,"show_sort_weight":41,"slug":42},8,"Research & Report",30,"research-report",{"id":44,"doc_module":4,"doc_module_name":9,"category_name":45,"show_sort_weight":46,"slug":47},9,"Religion & Spirituality",20,"religion-spirituality",{"id":46,"doc_module":4,"doc_module_name":9,"category_name":49,"show_sort_weight":46,"slug":50},"World Cup","world-cup",{"id":52,"doc_module":4,"doc_module_name":9,"category_name":53,"show_sort_weight":52,"slug":54},10,"Lifestyle","lifestyle",{"id":56,"doc_module":4,"doc_module_name":9,"category_name":57,"show_sort_weight":24,"slug":58},19,"General","general",{"code":4,"msg":60,"data":61},"ok",{"site_id":62,"language":63,"slug":64,"title":65,"keywords":66,"description":67,"schema_data":68,"social_meta":123,"head_meta":125,"extra_data":127,"updated_unix":129},105,"en","shank3-depletion-leads-to-erk-signalling-overdose-and-cell-death-in-kras-mutant-cancers","SHANK3 depletion leads to ERK signalling overdose and cell death in KRAS-mutant cancers","","SHANK3 is identified as a scaffold protein and RAS interactor that binds active KRAS, including oncogenic mutant forms. SHANK3 competes with RAF and restrains downstream KRAS signalling, keeping MAPK/ERK activity at an optimal level. When SHANK3 is depleted, MAPK/ERK signalling becomes hyperactivated, triggering MAPK/ERK-dependent cell death specifically in KRAS-mutant cancers. Disrupting the SHANK3–KRAS interaction via RNA interference or nanobody strategies limits tumour growth in vivo.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/shank3-depletion-leads-to-erk-signalling-overdose-and-cell-death-in-kras-mutant-cancers/333769/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/shank3-depletion-leads-to-erk-signalling-overdose-and-cell-death-in-kras-mutant-cancers/333769.png","ImageObject",300,407,{"name":92,"@type":93},"Theodore","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-13","2026-09-21",true,{"@type":102,"interactionType":103,"userInteractionCount":52},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What role does SHANK3 play in KRAS signalling?","Question",{"text":112,"@type":113},"SHANK3 binds active KRAS, including mutant KRAS forms, competes with RAF, and limits oncogenic KRAS downstream signalling by maintaining MAPK/ERK activity at an optimal level.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"What happens to cells when SHANK3 is depleted in KRAS-mutant cancers?",{"text":117,"@type":113},"SHANK3 depletion breaches the signalling threshold, causing MAPK/ERK hyperactivation and MAPK/ERK-dependent cell death in KRAS-mutant cancers.",{"name":119,"@type":110,"acceptedAnswer":120},"How can the SHANK3–KRAS vulnerability be targeted for therapy?",{"text":121,"@type":113},"The document describes targeting the SHANK3–KRAS interaction using RNA interference or nanobody-mediated disruption, which constrains tumour growth in vivo.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},333769,1790127547,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":52,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":46,"language":139,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":140,"faqs":141,"seo_title":142,"seo_description":67,"update_tm":143,"read_time":31,"preview_page_count":4},7971461740886,"https://ap-avatar.wpscdn.com/davatar_3d24733baf745e90a7e4bdd5f77d97b2","Article [https://doi.org/10.1038/s41467-024-52326-1](https://doi.org/10.1038/s41467-024-52326-1)  \n\n| SHANK3 depletion leads to ERK signalling overdose and cell death in KRAS-mutant cancers |  |  |\n| --- | --- | --- |\n| Received: 9 December 2022\u003Cbr>Accepted: 3 September 2024 Check for updates | Johanna Lilja1,18, Jasmin Kaivola 1,18, James R. W. Conway 1, Joni Vuorio 2, Hanna Parkkola 1, Pekka Roivas1,3, Michal Dibus 1, Megan R. Chastney 1, Taru Varila1, Guillaume Jacquemet 1,4,5,6, Emilia Peuhu 1,7, Emily Wang8, Ulla Pentikäinen1,3, Itziar Martinez D. Posada1, Hellyeh Hamidi 1,\u003Cbr>Arafath K. Najumudeen 9,10, Owen J. Sansom 10,11, Igor L. Barsukov 8, Daniel Abankwa 1,12, Ilpo Vattulainen 2, Marko Salmi3,13,14 &\u003Cbr>Johanna Ivaska 1,14,15,16,17 \u003Cbr>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/ERKdependent 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 ofSHANK3–KRAS interaction represents an alternative strategy for selective killing ofKRAS-mutant cancer cells through excessive signalling. |  |\n| Aberrant KRAS activity has been identified in >20% of human cancers1 with a substantially higher incidence in some of the most inherently therapy-resistant cancer types, including non-small cell lung cancers (NSCLC; 30% incidence), colorectal cancer (CRC; 50% |  | incidence), and pancreatic ductal adenocarcinoma (PDAC; 95% incidence)1,2. Oncogenic mutations in KRAS induce the constitutive activation of proliferative signalling cascades, promoting cancer progression and conferring resistance to standard-of-care |\n\n1Turku Bioscience Centre, University of Turku, FI-20520 Turku, Finland. 2Department of Physics, University of Helsinki, Helsinki, Finland. 3Institute of Biomedicine, University of Turku, FI-20520 Turku, Finland. 4Faculty of Science and Engineering, Cell Biology, Åbo Akademi University, FI-20520 Turku, Finland. 5Turku Bioimaging, University of Turku and Åbo Akademi University, FI-20520 Turku, Finland. 6InFLAMES Research Flagship Center, Åbo Akademi University, FI-20520 Turku, Finland. 7Institute of Biomedicine, Cancer Research Laboratory FICAN West, University of Turku, FI-20520 Turku, Finland. 8Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK. 9Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland. 10CRUK Scotland Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK. 11Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1QH, UK. 12Department of Life Sciences and Medicine, University of Luxembourg, 4365 Esch-sur-Alzette, Luxembourg. 13MediCity Research Laboratory, University of Turku, FI-20520 Turku, Finland. 14InFLAMES Research Flagship Center, University of Turku, FI-20520 Turku, Finland. 15Department of Life Technologies, University of Turku, Turku, Finland. 16Foundation for the Finnish Cancer Institute, Tukholmankatu 8, FI- 00014 Helsinki, Finland. 17Western Finnish Cancer Center, University of Turku, Turku FI-20520, Finland. 18These authors contributed equally: Johanna Lilja, Jasmin Kaivola. e-mail: Johanna. ivaska@utu.fi  \ntreatments3–5. Unfortunately, the survival of patients with KRASmutated NSCLC or PDAC has barely improv","cbCaiaY5rGWFWlFr","https://ap.wps.com/l/cbCaiaY5rGWFWlFr","pdf",4317997,"English","# Received and accepted details\n# Central findings: SHANK3–KRAS interaction and MAPK/ERK regulation\n## Mechanism: SHANK3 binds KRAS and limits RAF signalling\n## Consequence of SHANK3 depletion: ERK hyperactivation and cell death\n# Therapeutic approach: targeting SHANK3–KRAS in vivo\n## RNA interference and nanobody disruption","[{\"question\":\"What role does SHANK3 play in KRAS signalling?\",\"answer\":\"SHANK3 binds active KRAS, including mutant KRAS forms, competes with RAF, and limits oncogenic KRAS downstream signalling by maintaining MAPK/ERK activity at an optimal level.\"},{\"question\":\"What happens to cells when SHANK3 is depleted in KRAS-mutant cancers?\",\"answer\":\"SHANK3 depletion breaches the signalling threshold, causing MAPK/ERK hyperactivation and MAPK/ERK-dependent cell death in KRAS-mutant cancers.\"},{\"question\":\"How can the SHANK3–KRAS vulnerability be targeted for therapy?\",\"answer\":\"The document describes targeting the SHANK3–KRAS interaction using RNA interference or nanobody-mediated disruption, which constrains tumour growth in vivo.\"}]","SHANK3 depletion leads to ERK signalling overdose and cell death in KRAS-mutant cancers | PDF",1790003977]