Determining the ERK-regulated phosphoproteome driving KRAS-mutant cancer-Reference-Cited by-同舟云学术

Determining the ERK-regulated phosphoproteome driving KRAS-mutant cancer

Published:2024-06-07 Issue:6700 Volume:384 Page:
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

Klomp Jennifer E.¹^ORCID,Diehl J. Nathaniel²^ORCID,Klomp Jeffrey A.¹³^ORCID,Edwards A. Cole⁴,Yang Runying¹^ORCID,Morales Alexis J.¹^ORCID,Taylor Khalilah E.¹^ORCID,Drizyte-Miller Kristina¹^ORCID,Bryant Kirsten L.¹³^ORCID,Schaefer Antje¹³^ORCID,Johnson Jared L.⁵⁶⁷^ORCID,Huntsman Emily M.⁷⁸,Yaron Tomer M.⁷⁸⁹^ORCID,Pierobon Mariaelena¹⁰,Baldelli Elisa¹⁰^ORCID,Prevatte Alex W.¹¹,Barker Natalie K.¹¹^ORCID,Herring Laura E.¹¹^ORCID,Petricoin Emanuel F.¹⁰,Graves Lee M.¹³¹¹^ORCID,Cantley Lewis C.⁵⁶⁷^ORCID,Cox Adrienne D.¹³⁴¹²^ORCID,Der Channing J.¹²³⁴^ORCID,Stalnecker Clint A.¹³^ORCID

Affiliation:

1. Lineberger Comprehensive Cancer Center; University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

2. Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

3. Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

4. Cell Biology and Physiology Curriculum, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

5. Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.

6. Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.

7. Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA.

8. Englander Institute for Precision Medicine, Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY 10021, USA.

9. Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA.

10. School of Systems Biology, George Mason University, Fairfax, VA 22030, USA.

11. UNC Michael Hooker Proteomics Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

12. Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

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.

Publisher

American Association for the Advancement of Science (AAAS)

Link

https://www.science.org/doi/pdf/10.1126/science.adk0850

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