Determining the ERK-regulated phosphoproteome driving KRAS-mutant cancer.

Autor: Klomp JE; Lineberger Comprehensive Cancer Center; University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., Diehl JN; Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., Klomp JA; Lineberger Comprehensive Cancer Center; University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., Edwards AC; Cell Biology and Physiology Curriculum, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., Yang R; Lineberger Comprehensive Cancer Center; University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., Morales AJ; Lineberger Comprehensive Cancer Center; University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., Taylor KE; Lineberger Comprehensive Cancer Center; University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., Drizyte-Miller K; Lineberger Comprehensive Cancer Center; University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., Bryant KL; Lineberger Comprehensive Cancer Center; University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., Schaefer A; Lineberger Comprehensive Cancer Center; University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., Johnson JL; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.; Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.; Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA., Huntsman EM; Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA.; Englander Institute for Precision Medicine, Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY 10021, USA., Yaron TM; Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA.; Englander Institute for Precision Medicine, Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY 10021, USA.; Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA., Pierobon M; School of Systems Biology, George Mason University, Fairfax, VA 22030, USA., Baldelli E; School of Systems Biology, George Mason University, Fairfax, VA 22030, USA., Prevatte AW; UNC Michael Hooker Proteomics Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., Barker NK; UNC Michael Hooker Proteomics Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., Herring LE; UNC Michael Hooker Proteomics Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., Petricoin EF 3rd; School of Systems Biology, George Mason University, Fairfax, VA 22030, USA., Graves LM; Lineberger Comprehensive Cancer Center; University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.; UNC Michael Hooker Proteomics Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., Cantley LC; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.; Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.; Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA., Cox AD; Lineberger Comprehensive Cancer Center; University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.; Cell Biology and Physiology Curriculum, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.; Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., Der CJ; Lineberger Comprehensive Cancer Center; University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.; Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.; Cell Biology and Physiology Curriculum, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., Stalnecker CA; Lineberger Comprehensive Cancer Center; University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Jazyk: angličtina
Zdroj: Science (New York, N.Y.) [Science] 2024 Jun 07; Vol. 384 (6700), pp. eadk0850. Date of Electronic Publication: 2024 Jun 07.
DOI: 10.1126/science.adk0850
Abstrakt: To delineate the mechanisms by which the ERK1 and ERK2 mitogen-activated protein kinases support mutant KRAS-driven cancer growth, we determined the ERK-dependent phosphoproteome in KRAS-mutant pancreatic cancer. We determined that ERK1 and ERK2 share near-identical signaling and transforming outputs and that the KRAS-regulated phosphoproteome is driven nearly completely by ERK. We identified 4666 ERK-dependent phosphosites on 2123 proteins, of which 79 and 66%, respectively, were not previously associated with ERK, substantially expanding the depth and breadth of ERK-dependent phosphorylation events and revealing a considerably more complex function for ERK in cancer. We established that ERK controls a highly dynamic and complex phosphoproteome that converges on cyclin-dependent kinase regulation and RAS homolog guanosine triphosphatase function (RHO GTPase). Our findings establish the most comprehensive molecular portrait and mechanisms by which ERK drives KRAS-dependent pancreatic cancer growth.
Databáze: MEDLINE
Nepřihlášeným uživatelům se plný text nezobrazuje