%0 Journal Article
%T Determining the ERK-regulated phosphoproteome driving KRAS-mutant cancer.
%A Klomp JE
%A Diehl JN
%A Klomp JA
%A Edwards AC
%A Yang R
%A Morales AJ
%A Taylor KE
%A Drizyte-Miller K
%A Bryant KL
%A Schaefer A
%A Johnson JL
%A Huntsman EM
%A Yaron TM
%A Pierobon M
%A Baldelli E
%A Prevatte AW
%A Barker NK
%A Herring LE
%A Petricoin EF
%A Graves LM
%A Cantley LC
%A Cox AD
%A Der CJ
%A Stalnecker CA
%J Science
%V 384
%N 6700
%D 2024 Jun 7
%M 38843329
%F 63.714
%R 10.1126/science.adk0850
%X 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.