Home Newsletters Pancreatic Cell News Oncogenic KRAS Engages an RSK1/NF1 Pathway to Inhibit Wild-Type RAS Signaling in...

Oncogenic KRAS Engages an RSK1/NF1 Pathway to Inhibit Wild-Type RAS Signaling in Pancreatic Cancer

0
Investigators used proximity labeling to identify protein interactors of active KRAS in pancreatic ductal adenocarcinoma (PDAC) cells. We expressed fusions of wild-type (WT) (BirA-KRAS4B), mutant (BirA-KRAS4BG12D), and nontransforming cytosolic double mutant (BirA-KRAS4BG12D/C185S) KRAS with the BirA biotin ligase in murine PDAC cells.
[Proceedings of the National Academy of Sciences of the United States of America]
7753456 {7753456:TQHXVBP4} apa 50 1 162575 https://www.stemcellsciencenews.com/wp-content/plugins/zotpress/
%7B%22status%22%3A%22success%22%2C%22updateneeded%22%3Afalse%2C%22instance%22%3A%22zotpress-57cdbf2f8bd414954567020e650bf568%22%2C%22meta%22%3A%7B%22request_last%22%3A0%2C%22request_next%22%3A0%2C%22used_cache%22%3Atrue%7D%2C%22data%22%3A%5B%7B%22key%22%3A%22TQHXVBP4%22%2C%22library%22%3A%7B%22id%22%3A7753456%7D%2C%22meta%22%3A%7B%22creatorSummary%22%3A%22Cheng%20et%20al.%22%2C%22parsedDate%22%3A%222021-05-25%22%2C%22numChildren%22%3A0%7D%2C%22bib%22%3A%22%3Cdiv%20class%3D%5C%22csl-bib-body%5C%22%20style%3D%5C%22line-height%3A%202%3B%20padding-left%3A%201em%3B%20text-indent%3A-1em%3B%5C%22%3E%5Cn%20%20%3Cdiv%20class%3D%5C%22csl-entry%5C%22%3ECheng%2C%20D.%20K.%2C%20Oni%2C%20T.%20E.%2C%20Thalappillil%2C%20J.%20S.%2C%20Park%2C%20Y.%2C%20Ting%2C%20H.-C.%2C%20Alagesan%2C%20B.%2C%20Prasad%2C%20N.%20V.%2C%20Addison%2C%20K.%2C%20Rivera%2C%20K.%20D.%2C%20Pappin%2C%20D.%20J.%2C%20Aelst%2C%20L.%20V.%2C%20%26amp%3B%20Tuveson%2C%20D.%20A.%20%282021%29.%20Oncogenic%20KRAS%20engages%20an%20RSK1%5C%2FNF1%20pathway%20to%20inhibit%20wild-type%20RAS%20signaling%20in%20pancreatic%20cancer.%20%3Ci%3EProceedings%20of%20the%20National%20Academy%20of%20Sciences%3C%5C%2Fi%3E%2C%20%3Ci%3E118%3C%5C%2Fi%3E%2821%29.%20%3Ca%20href%3D%27https%3A%5C%2F%5C%2Fdoi.org%5C%2F10.1073%5C%2Fpnas.2016904118%27%3Ehttps%3A%5C%2F%5C%2Fdoi.org%5C%2F10.1073%5C%2Fpnas.2016904118%3C%5C%2Fa%3E%20%3Ca%20title%3D%27Cite%20in%20RIS%20Format%27%20class%3D%27zp-CiteRIS%27%20href%3D%27https%3A%5C%2F%5C%2Fwww.stemcellsciencenews.com%5C%2Fwp-content%5C%2Fplugins%5C%2Fzotpress%5C%2Flib%5C%2Frequest%5C%2Frequest.cite.php%3Fapi_user_id%3D7753456%26amp%3Bitem_key%3DTQHXVBP4%27%3ECite%3C%5C%2Fa%3E%20%3C%5C%2Fdiv%3E%5Cn%3C%5C%2Fdiv%3E%22%2C%22data%22%3A%7B%22itemType%22%3A%22journalArticle%22%2C%22title%22%3A%22Oncogenic%20KRAS%20engages%20an%20RSK1%5C%2FNF1%20pathway%20to%20inhibit%20wild-type%20RAS%20signaling%20in%20pancreatic%20cancer%22%2C%22creators%22%3A%5B%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Derek%20K.%22%2C%22lastName%22%3A%22Cheng%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Tobiloba%20E.%22%2C%22lastName%22%3A%22Oni%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Jennifer%20S.%22%2C%22lastName%22%3A%22Thalappillil%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Youngkyu%22%2C%22lastName%22%3A%22Park%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Hsiu-Chi%22%2C%22lastName%22%3A%22Ting%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Brinda%22%2C%22lastName%22%3A%22Alagesan%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Nadia%20V.%22%2C%22lastName%22%3A%22Prasad%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Kenneth%22%2C%22lastName%22%3A%22Addison%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Keith%20D.%22%2C%22lastName%22%3A%22Rivera%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Darryl%20J.%22%2C%22lastName%22%3A%22Pappin%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Linda%20Van%22%2C%22lastName%22%3A%22Aelst%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22David%20A.%22%2C%22lastName%22%3A%22Tuveson%22%7D%5D%2C%22abstractNote%22%3A%22Pancreatic%20ductal%20adenocarcinoma%20%28PDAC%29%20is%20a%20lethal%20malignancy%20with%20limited%20treatment%20options.%20Although%20activating%20mutations%20of%20the%20KRAS%20GTPase%20are%20the%20predominant%20dependency%20present%20in%20%3E90%25%20of%20PDAC%20patients%2C%20targeting%20KRAS%20mutants%20directly%20has%20been%20challenging%20in%20PDAC.%20Similarly%2C%20strategies%20targeting%20known%20KRAS%20downstream%20effectors%20have%20had%20limited%20clinical%20success%20due%20to%20feedback%20mechanisms%2C%20alternate%20pathways%2C%20and%20dose-limiting%20toxicities%20in%20normal%20tissues.%20Therefore%2C%20identifying%20additional%20functionally%20relevant%20KRAS%20interactions%20in%20PDAC%20may%20allow%20for%20a%20better%20understanding%20of%20feedback%20mechanisms%20and%20unveil%20potential%20therapeutic%20targets.%20Here%2C%20we%20used%20proximity%20labeling%20to%20identify%20protein%20interactors%20of%20active%20KRAS%20in%20PDAC%20cells.%20We%20expressed%20fusions%20of%20wild-type%20%28WT%29%20%28BirA-KRAS4B%29%2C%20mutant%20%28BirA-KRAS4BG12D%29%2C%20and%20nontransforming%20cytosolic%20double%20mutant%20%28BirA-KRAS4BG12D%5C%2FC185S%29%20KRAS%20with%20the%20BirA%20biotin%20ligase%20in%20murine%20PDAC%20cells.%20Mass%20spectrometry%20analysis%20revealed%20that%20RSK1%20selectively%20interacts%20with%20membrane-bound%20KRASG12D%2C%20and%20we%20demonstrate%20that%20this%20interaction%20requires%20NF1%20and%20SPRED2.%20We%20find%20that%20membrane%20RSK1%20mediates%20negative%20feedback%20on%20WT%20RAS%20signaling%20and%20impedes%20the%20proliferation%20of%20pancreatic%20cancer%20cells%20upon%20the%20ablation%20of%20mutant%20KRAS.%20Our%20findings%20link%20NF1%20to%20the%20membrane-localized%20functions%20of%20RSK1%20and%20highlight%20a%20role%20for%20WT%20RAS%20signaling%20in%20promoting%20adaptive%20resistance%20to%20mutant%20KRAS-specific%20inhibitors%20in%20PDAC.%22%2C%22date%22%3A%222021%5C%2F05%5C%2F25%22%2C%22language%22%3A%22en%22%2C%22DOI%22%3A%2210.1073%5C%2Fpnas.2016904118%22%2C%22ISSN%22%3A%220027-8424%2C%201091-6490%22%2C%22url%22%3A%22https%3A%5C%2F%5C%2Fwww.pnas.org%5C%2Fcontent%5C%2F118%5C%2F21%5C%2Fe2016904118%22%2C%22deleted%22%3A1%2C%22collections%22%3A%5B%223XSKJF5U%22%5D%2C%22dateModified%22%3A%222021-05-25T17%3A15%3A07Z%22%7D%7D%5D%7D
Cheng, D. K., Oni, T. E., Thalappillil, J. S., Park, Y., Ting, H.-C., Alagesan, B., Prasad, N. V., Addison, K., Rivera, K. D., Pappin, D. J., Aelst, L. V., & Tuveson, D. A. (2021). Oncogenic KRAS engages an RSK1/NF1 pathway to inhibit wild-type RAS signaling in pancreatic cancer. Proceedings of the National Academy of Sciences, 118(21). https://doi.org/10.1073/pnas.2016904118 Cite
Full Article
Exit mobile version