Determining the ERK-regulated phosphoproteome driving KRAS-mutant cancer
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.
Authors
- Jennifer E. Klomp (ORCID: https://orcid.org/0000-0003-1781-648X)
- A. Cole Edwards (ORCID: https://orcid.org/0000-0001-9220-9642)
- Clint A. Stalnecker (ORCID: https://orcid.org/0000-0002-0570-4416)
- Adrienne D. Cox (ORCID: https://orcid.org/0000-0002-4901-2454)
- Emily M. Huntsman (ORCID: https://orcid.org/0000-0002-8541-4944)
- Kristina Drizyte‐Miller (ORCID: https://orcid.org/0000-0001-7049-2934)
- Emanuel F. Petricoin (ORCID: https://orcid.org/0000-0001-9146-5572)
- Elisa Baldelli (ORCID: https://orcid.org/0000-0002-6288-4599)
- Natalie K. Barker (ORCID: https://orcid.org/0000-0001-9248-2710)
- Antje Schaefer (ORCID: https://orcid.org/0000-0002-2716-9899)
- Laura E. Herring (ORCID: https://orcid.org/0000-0003-4496-7312)
- Jared L. Johnson (ORCID: https://orcid.org/0000-0003-1802-6527)
- Lewis C. Cantley (ORCID: https://orcid.org/0000-0002-1298-7653)
- Alex W. Prevatte
- Tomer M. Yaron (ORCID: https://orcid.org/0000-0001-6574-7314)
- Jeffrey A. Klomp (ORCID: https://orcid.org/0000-0002-5243-6987)
- Channing J. Der (ORCID: https://orcid.org/0000-0002-7751-2747)
- Mariaelena Pierobon (ORCID: https://orcid.org/0000-0003-2084-1029)
- Khalilah E. Taylor (ORCID: https://orcid.org/0009-0003-2136-2713)
- Kirsten L. Bryant (ORCID: https://orcid.org/0000-0003-4026-0942)
- Alexis Jean Morales (ORCID: https://orcid.org/0009-0002-3711-934X)
- J. Nathaniel Diehl (ORCID: https://orcid.org/0000-0002-7309-0903)
- Lee M. Graves (ORCID: https://orcid.org/0000-0002-4736-9855)
- Runying Yang (ORCID: https://orcid.org/0000-0002-5983-9439)
Institutions
- University of North Carolina at Chapel Hill (US)
Publication Details
- Journal
- UNC Libraries
- Published
- 2024-09-04
- DOI
- https://doi.org/10.17615/9151-b253
- Primary Topic
- Protein Kinase Regulation and GTPase Signaling
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- U.S. Department of Defense
- Pancreatic Cancer Action Network
- Revolution Medicines
- University of Texas MD Anderson Cancer Center
- University of California, San Diego
- National Cancer Institute
- National Institute of General Medical Sciences
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill