Determining the ERK-regulated phosphoproteome driving KRAS-mutant cancer

Jennifer E. Klomp(University of North Carolina at Chapel Hill), J. Nathaniel Diehl(University of North Carolina at Chapel Hill), Jeffrey A. Klomp(University of North Carolina at Chapel Hill), A. Cole Edwards(University of North Carolina at Chapel Hill), Runying Yang(University of North Carolina at Chapel Hill), Alexis Jean Morales(University of North Carolina at Chapel Hill), Khalilah E. Taylor(University of North Carolina at Chapel Hill), Kristina Drizyte‐Miller(University of North Carolina at Chapel Hill), Kirsten L. Bryant(University of North Carolina at Chapel Hill), Antje Schaefer(University of North Carolina at Chapel Hill), Jared L. Johnson(Harvard University), Emily M. Huntsman(Cornell University), Tomer M. Yaron(Cornell University), Mariaelena Pierobon(George Mason University), Elisa Baldelli(George Mason University), Alex W. Prevatte(University of North Carolina at Chapel Hill), Natalie K. Barker(University of North Carolina at Chapel Hill), Laura E. Herring(University of North Carolina at Chapel Hill), Emanuel F. Petricoin(George Mason University), Lee M. Graves(University of North Carolina at Chapel Hill), Lewis C. Cantley(Harvard University), Adrienne D. Cox(University of North Carolina at Chapel Hill), Channing J. Der(University of North Carolina at Chapel Hill), Clint A. Stalnecker(University of North Carolina at Chapel Hill)
Science
June 6, 2024
10.1126/science.adk0850
Cited by 79Open Access
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Abstract

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.

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