| Title | Determining the ERK-regulated phosphoproteome driving KRAS-mutant cancer. |
| Publication Type | Journal Article |
| Year of Publication | 2024 |
| Authors | Klomp JE, J Diehl N, Klomp JA, A Edwards C, Yang R, Morales AJ, Taylor KE, Drizyte-Miller K, Bryant KL, Schaefer A, Johnson JL, Huntsman EM, Yaron TM, Pierobon M, Baldelli E, Prevatte AW, Barker NK, Herring LE, Petricoin EF, Graves LM, Cantley LC, Cox AD, Der CJ, Stalnecker CA |
| Journal | Science |
| Volume | 384 |
| Issue | 6700 |
| Pagination | eadk0850 |
| Date Published | 2024 Jun 07 |
| ISSN | 1095-9203 |
| Keywords | Animals, Cell Line, Tumor, Cyclin-Dependent Kinases, HEK293 Cells, Humans, MAP Kinase Signaling System, Mice, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Mutation, Pancreatic Neoplasms, Phosphoproteins, Phosphorylation, Proteome, Proto-Oncogene Proteins p21(ras) |
| 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. |
| DOI | 10.1126/science.adk0850 |
| Alternate Journal | Science |
| PubMed ID | 38843329 |