Researchers have conducted a comprehensive study to define the ways in which the ERK1 and ERK2 mitogen-activated protein kinases support mutant KRAS-driven cancer growth in pancreatic ductal adenocarcinoma (PDAC). Through quantitative phosphoproteomics, they identified 4,666 ERK-dependent phosphosites on 2,123 proteins. Respectively, 79% and 66% of those were not previously associated with ERK, significantly expanding the known ERK-dependent phosphorylation events.

The study revealed that ERK controls a complex, dynamic phosphoproteome that converges on cyclin-dependent kinase regulation and RAS homolog guanosine triphosphatase function (RHO GTPase). The researchers established that ERK1 and ERK2 share near-identical transforming and signaling outputs, and that the KRAS-regulated phosphoproteome is driven nearly completely by ERK.

This study provides the most extensive molecular picture to date of how ERK drives KRAS-dependent pancreatic cancer growth, highlighting the dominant role of the RAF-MEK-ERK signaling network in driving KRAS-mediated oncogenesis.

The IonOpticks Aurora Elite XT 15×75 C18 UHPLC column was used in this study, enabling improved phosphosite coverage and depth of analysis.

Publication
Science

Authors

Jennifer E. Klomp, J. Nathaniel Diehl, Jeffrey A. Klomp, A. Cole Edwards, Runying Yang, Alexis J. Morales, Khalilah E. Taylor, Kristina Drizyte-Miller, Kirsten L. Bryant , Antje Schaefer , Jared L. Johnson , Emily M. Huntsman, Tomer M. Yaron, Mariaelena Pierobon, Elisa Baldelli, Alex W. Prevatte, Natalie K. Barker, Laura E. Herring, Emanuel F. Petricoin Iii, Lee M. Graves, Lewis C. Cantley, Adrienne D. Cox, Channing J. Der, Clint A. Stalnecker

Title

Determining the ERK-regulated phosphoproteome driving KRAS-mutant cancer