Determining the ERK-regulated phosphoproteome driving KRAS-mutant cancer

Jennifer E. Klomp; J. Nathaniel Diehl; Jeffrey A. Klomp; A. Cole Edwards; Runying Yang; Alexis J. Morales; Khalilah E. Taylor; Kristina Drizyte-Miller; Kirsten L. Bryant; Antje Schaefer; Jared L. Johnson; Emily M. Huntsman; Tomer M. Yaron; Mariaelena Pierobon; Elisa Baldelli; Alex W. Prevatte; Natalie K. Barker; Laura E. Herring; Emanuel F. Petricoin; Lee M. Graves; Lewis C. Cantley; Adrienne D. Cox; Channing J. Der; Clint A. Stalnecker

doi:10.1126/science.adk0850

Determining the ERK-regulated phosphoproteome driving KRAS-mutant cancer

Jennifer E. Klomp, J. Nathaniel Diehl, Jeffrey A. Klomp, A. Cole Edwards, Runying Yang, Alexis J. Morales, Khalilah E. Taylor, Kristina Drizyte-Miller, Kirsten L. Bryant, Antje Schaefer, Jared L. Johnson, Emily M. Huntsman, Tomer M. Yaron, Mariaelena Pierobon, Elisa Baldelli, Alex W. Prevatte, Natalie K. Barker, Laura E. Herring, Emanuel F. Petricoin, Lee M. GravesLewis C. Cantley, Adrienne D. Cox, Channing J. Der, Clint A. Stalnecker

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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.

Original language	English
Pages (from-to)	eadk0850
Journal	Science
Volume	384
Issue number	6700
DOIs	https://doi.org/10.1126/science.adk0850
State	Published - 7 Jun 2024
Externally published	Yes

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Klomp, J. E., Diehl, J. N., Klomp, J. A., Edwards, A. C., Yang, R., Morales, A. J., Taylor, K. E., Drizyte-Miller, K., Bryant, K. L., Schaefer, A., Johnson, J. L., Huntsman, E. M., Yaron, T. M., Pierobon, M., Baldelli, E., Prevatte, A. W., Barker, N. K., Herring, L. E., Petricoin, E. F., ... Stalnecker, C. A. (2024). Determining the ERK-regulated phosphoproteome driving KRAS-mutant cancer. Science, 384(6700), eadk0850. https://doi.org/10.1126/science.adk0850

@article{7b1a3fc749034320a056540d63a04c2d,

title = "Determining the ERK-regulated phosphoproteome driving KRAS-mutant cancer",

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.",

author = "Klomp, {Jennifer E.} and Diehl, {J. Nathaniel} and Klomp, {Jeffrey A.} and Edwards, {A. Cole} and Runying Yang and Morales, {Alexis J.} and Taylor, {Khalilah E.} and Kristina Drizyte-Miller and Bryant, {Kirsten L.} and Antje Schaefer and Johnson, {Jared L.} and Huntsman, {Emily M.} and Yaron, {Tomer M.} and Mariaelena Pierobon and Elisa Baldelli and Prevatte, {Alex W.} and Barker, {Natalie K.} and Herring, {Laura E.} and Petricoin, {Emanuel F.} and Graves, {Lee M.} and Cantley, {Lewis C.} and Cox, {Adrienne D.} and Der, {Channing J.} and Stalnecker, {Clint A.}",

year = "2024",

month = jun,

day = "7",

doi = "10.1126/science.adk0850",

language = "English",

volume = "384",

pages = "eadk0850",

journal = "Science",

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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 2024, 'Determining the ERK-regulated phosphoproteome driving KRAS-mutant cancer', Science, vol. 384, no. 6700, pp. eadk0850. https://doi.org/10.1126/science.adk0850

TY - JOUR

T1 - Determining the ERK-regulated phosphoproteome driving KRAS-mutant cancer

AU - Klomp, Jennifer E.

AU - Diehl, J. Nathaniel

AU - Klomp, Jeffrey A.

AU - Edwards, A. Cole

AU - Yang, Runying

AU - Morales, Alexis J.

AU - Taylor, Khalilah E.

AU - Drizyte-Miller, Kristina

AU - Bryant, Kirsten L.

AU - Schaefer, Antje

AU - Johnson, Jared L.

AU - Huntsman, Emily M.

AU - Yaron, Tomer M.

AU - Pierobon, Mariaelena

AU - Baldelli, Elisa

AU - Prevatte, Alex W.

AU - Barker, Natalie K.

AU - Herring, Laura E.

AU - Petricoin, Emanuel F.

AU - Graves, Lee M.

AU - Cantley, Lewis C.

AU - Cox, Adrienne D.

AU - Der, Channing J.

AU - Stalnecker, Clint A.

PY - 2024/6/7

Y1 - 2024/6/7

N2 - 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.

AB - 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.

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U2 - 10.1126/science.adk0850

DO - 10.1126/science.adk0850

M3 - Article

C2 - 38843329

AN - SCOPUS:85195439364

SN - 0036-8075

VL - 384

SP - eadk0850

JO - Science

JF - Science

IS - 6700

ER -

Determining the ERK-regulated phosphoproteome driving KRAS-mutant cancer

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