{Reference Type}: Journal Article
{Title}: Determining the ERK-regulated phosphoproteome driving KRAS-mutant cancer.
{Author}: Klomp JE;Diehl JN;Klomp JA;Edwards AC;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
{Year}: 2024 Jun 7
{Factor}: 63.714
{DOI}: 10.1126/science.adk0850
{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.