Vollständiger Abstract
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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 multi-omics 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 and acute myeloid leukemia. Remarkably, KRAS protein stability was four-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.
Bibliografischer Nachweis
Publikationsdaten
- Autor:innen
- Lin Zhang, Arnold Bolomsky, Omar S. Al-Odat, Callie K. VanWinkle, Aaliyah Battle, Papiya Chakraborty, Ronald J. Holewinski, Thorkell Andresson, Bjorn Haupl, Thomas Oellerich, Elizabeth Hill, Mehmet Kocoglu, Qingcai Meng, James D. Phelan, Jagan Muppidi, Ryan M. Young
- Quelle
- Blood Cancer Discovery
- Publikation
- 2026-01-01
- Band / Ausgabe
- Nicht angegeben
- Seiten
- Nicht angegeben
- ISSN / ISBN
- 2643-3230, 2643-3249
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Zitierfähiger Nachweis
Lin Zhang, Arnold Bolomsky, Omar S. Al-Odat, Callie K. VanWinkle, Aaliyah Battle, Papiya Chakraborty, Ronald J. Holewinski, Thorkell Andresson, Bjorn Haupl, Thomas Oellerich, Elizabeth Hill, Mehmet Kocoglu, Qingcai Meng, James D. Phelan, Jagan Muppidi, Ryan M. Young (2026). Phosphorylation Protects Oncogenic RAS from LZTR1-Mediated Degradation. Blood Cancer Discovery. https://doi.org/10.1158/2643-3230.bcd-26-0028
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