Related Experiment Video
Updated: Jan 18, 2026
Rab10 Phosphorylation Detection by LRRK2 Activity Using SDS-PAGE with a Phosphate-binding Tag
Published on: December 14, 2017
Phosphorylation Protects Oncogenic RAS from LZTR1-Mediated Degradation
Lin Zhang1, Arnold Bolomsky1, Omar S Al-Odat1
1Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Abstract:
Oncogenic KRAS and NRAS mutations are common in hematologic malignancies, but how they signal is less well characterized than in carcinomas. To uncover novel RAS biology and potential therapeutic vulnerabilities, we employed a multi-omics screening approach in multiple myeloma to identify regulators of RAS activity. We report that the phosphatase PP1C dephosphorylates the conserved T148 residue on RAS, which in turn permits LZTR1-dependent proteasomal degradation. Notably, LZTR1 is ineffective against KRAS A146 gain-of-function mutations, which are adjacent to T148 and prevalent in hematologic cancers. Remarkably, we find that KRAS protein is four-fold less stable in hematologic versus carcinoma cells, offering a unique therapeutic opportunity targeting RAS protein stability mechanisms. The kinases PAK1 and PAK2 shield RAS from LZTR1-dependent degradation by phosphorylating T148, and targeting PAK1/2 activity improves RAS-directed therapy. Collectively, our findings reveal a novel regulatory circuit governing RAS stability that is preferentially active in blood cancers and potentially druggable.
Insights
Researchers discovered a new way cancer cells control RAS protein stability, finding that blood cancers are particularly vulnerable to targeting this mechanism for therapy.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Oncogenic KRAS and NRAS mutations are prevalent in hematologic malignancies, yet their signaling pathways remain less understood compared to carcinomas.
- Identifying regulators of RAS activity is crucial for uncovering novel biology and therapeutic vulnerabilities in these cancers.
Purpose of the Study:
- To identify novel regulators of RAS activity in multiple myeloma using a multi-omics screening approach.
- To investigate the mechanisms governing RAS protein stability and explore potential therapeutic strategies targeting these pathways in hematologic cancers.
Main Methods:
- Multi-omics screening in multiple myeloma models.
- Analysis of RAS protein dephosphorylation and degradation pathways.
- Investigation of the role of PP1C, LZTR1, PAK1, and PAK2 in RAS regulation.
- Comparison of RAS protein stability in hematologic versus carcinoma cells.
Main Results:
- PP1C dephosphorylates RAS at T148, enabling LZTR1-mediated proteasomal degradation.
- LZTR1 is ineffective against KRAS A146 gain-of-function mutations common in hematologic cancers.
- KRAS protein exhibits four-fold lower stability in hematologic cells compared to carcinoma cells.
- PAK1 and PAK2 phosphorylate T148, shielding RAS from LZTR1 degradation; targeting PAK1/2 enhances RAS-directed therapy.
Conclusions:
- A novel regulatory circuit controlling RAS stability, preferentially active in blood cancers, has been identified.
- This circuit involves PP1C, LZTR1, PAK1, and PAK2, offering potential therapeutic vulnerabilities.
- Targeting RAS protein stability mechanisms presents a unique therapeutic opportunity for hematologic malignancies.
Related Concept Videos
02:38The Ras Gene
Ras is a...
01:22PI3K/mTOR/AKT Signaling Pathway
02:54Protein Kinases and Phosphatases
Protein kinases
Many proteins in the cell are regulated by phosphorylation, the addition of a phosphate group. A family of enzymes called kinases...
02:54Protein Kinases and Phosphatases
01:02Phosphorylation
During phosphorylation, protein kinases transfer the terminal phosphate group of ATP to specific amino acid side chains of substrate proteins. Serine, threonine, and tyrosine are the most commonly...
01:07MAPK Signaling Cascades