Phosphorylation Protects Oncogenic RAS from LZTR1-Mediated Degradation
9 affiliations
- 1Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
- 2Protein Mass Spectrometry Group, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland.
- 3Department of Medicine, Hematology and Oncology, University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt am Main, Germany.
- 4Frankfurt Cancer Institute (FCI), Frankfurt am Main, Germany.
- 5German Cancer Consortium (DKTK), partner site Frankfurt/Mainz, a partnership between DKFZ and UCT Frankfurt-Marburg, Frankfurt am Main, Germany.
- 6German Cancer Research Center (DKFZ), Heidelberg, Germany.
- 7University Cancer Center (UCT), Frankfurt am Main, Germany.
- 8University of Maryland Greenbaum Comprehensive Cancer Center, Baltimore, Maryland.
- 9Laboratory of Cell and Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.
Abstract
Oncogenic KRAS and NRAS mutations are common in hematologic malignancies, but their signaling in this context remains less well characterized than in carcinomas. Using multiomics screens in multiple myeloma, we sought to identify regulators of RAS activity. We found that the phosphatase PP1C dephosphorylated conserved RAS residue T148, permitting LZTR1-dependent proteasomal degradation. LZTR1 was ineffective against KRAS A146 gain-of-function mutations, which lie adjacent to T148 and are enriched in hematologic cancers, such as diffuse large B-cell lymphoma (DLBCL) and acute myeloid leukemia (AML). Remarkably, KRAS protein stability was 4-fold lower in hematologic versus carcinoma cells, revealing a unique therapeutic opportunity targeting RAS protein stability. PAK1 and PAK2 shielded RAS from LZTR1-dependent degradation by phosphorylating T148, and inhibiting PAK1/2 activity improved RAS-directed therapy. Collectively, these findings reveal a regulatory circuit governing RAS stability that is preferentially active in blood cancers and potentially druggable.
Significance:: We found that PP1C and PAK1/2 regulate RAS T148 phosphorylation, controlling LZTR1-mediated RAS degradation in multiple myeloma, DLBCL, and AML. PAK1/2 inhibition reduces RAS expression, enhancing the efficacy of RAS-directed therapies in multiple myeloma. Notably, KRAS A146 mutations, prevalent in blood cancers, can shield RAS from this degradation.
See related commentary by Boise, p. 860
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BibTeX
@article{zhang2026phosphorylation,
title = {{Phosphorylation Protects Oncogenic RAS from LZTR1-Mediated Degradation}},
author = {Lin Zhang and Arnold Bolomsky and Omar S. Al-Odat and Callie K. VanWinkle and Aaliyah Battle and Papiya Chakraborty and Ronald J. Holewinski and Thorkell Andresson and Björn Häupl and Thomas Oellerich and Elizabeth Hill and Mehmet Kocoglu and Qingcai Meng and James D. Phelan and Jagan Muppidi and Ryan M. Young},
journal = {Blood Cancer Discovery},
year = {2026},
month = aug,
doi = {10.1158/2643-3230.bcd-26-0028},
url = {https://doi.org/10.1158/2643-3230.bcd-26-0028},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Phosphorylation Protects Oncogenic RAS from LZTR1-Mediated Degradation
AU - Lin Zhang
AU - Arnold Bolomsky
AU - Omar S. Al-Odat
AU - Callie K. VanWinkle
AU - Aaliyah Battle
AU - Papiya Chakraborty
AU - Ronald J. Holewinski
AU - Thorkell Andresson
AU - Björn Häupl
AU - Thomas Oellerich
AU - Elizabeth Hill
AU - Mehmet Kocoglu
AU - Qingcai Meng
AU - James D. Phelan
AU - Jagan Muppidi
AU - Ryan M. Young
PY - 2026
DA - 2026/08/31
JO - Blood Cancer Discovery
DO - 10.1158/2643-3230.bcd-26-0028
UR - https://doi.org/10.1158/2643-3230.bcd-26-0028
AB - Oncogenic KRAS and NRAS mutations are common in hematologic malignancies, but their signaling in this context remains less well characterized than in carcinomas. Using multiomics screens in multiple myeloma, we sought to identify regulators of RAS activity. We found that the phosphatase PP1C dephosphorylated conserved RAS residue T148, permitting LZTR1-dependent proteasomal degradation. LZTR1 was ineffective against KRAS A146 gain-of-function mutations, which lie adjacent to T148 and are enriched in hematologic cancers, such as diffuse large B-cell lymphoma (DLBCL) and acute myeloid leukemia (AML). Remarkably, KRAS protein stability was 4-fold lower in hematologic versus carcinoma cells, revealing a unique therapeutic opportunity targeting RAS protein stability. PAK1 and PAK2 shielded RAS from LZTR1-dependent degradation by phosphorylating T148, and inhibiting PAK1/2 activity improved RAS-directed therapy. Collectively, these findings reveal a regulatory circuit governing RAS stability that is preferentially active in blood cancers and potentially druggable. Significance:: We found that PP1C and PAK1/2 regulate RAS T148 phosphorylation, controlling LZTR1-mediated RAS degradation in multiple myeloma, DLBCL, and AML. PAK1/2 inhibition reduces RAS expression, enhancing the efficacy of RAS-directed therapies in multiple myeloma. Notably, KRAS A146 mutations, prevalent in blood cancers, can shield RAS from this degradation. See related commentary by Boise, p. 860
SN - 2643-3230
SN - 2643-3249
ER -